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Mental Health
4 Min Read
Last Updated: 20.06.23

Understanding & Conquering Depression

In this episode, Huberman provides an in-​​depth exploration of major depression, covering its biological and psychological aspects, various treatments, chemical systems, genetic predispositions, stress, inflammation, and more. Huberman discusses science-​​supported protocols, ongoing clinical trials, and the potential benefits of ketogenic diets. A comprehensive guide by Huberman for understanding and addressing depression.

Key Takeaways

High level takeaways from the episode.

Pleasure-​​Pain Balance is crucial for understanding mood disorders and motivation

  • Pursuit of pleasure releases dopamine, increasing motivation and drive
  • Constant pursuit of pleasure leads to addiction and depression
  • Resetting the balance requires entering states of boredom or non-pleasure-seeking

Bipolar depression: characterized by manic highs and lows

  • Manic episodes: lack of sleep, fast talking, impulsive behavior
  • Depressive episodes: feeling low, lethargic

Major depression (unipolar depression): characterized by lows

  • Affects 5% of the population
  • Number four cause of disability

Criteria for major depression:

  • Presence of grief and sadness
  • Lower threshold to cry
  • Anhedonia: lack of ability to enjoy things previously enjoyed

Criteria for major depression:

  • Guilt: feeling guilty about past actions or general self-worth
  • Delusional thinking and anti-​​self confabulation: creating negative stories about oneself that don’t match reality
  • Vegetative symptoms: exhaustion, disrupted sleep patterns (early waking)

Accurate diagnosis should be done by a qualified healthcare professional

  • Do not self-​​diagnose based on symptoms mentioned in this discussion

Disruptions in sleep patterns and brain activity during sleep in depression

  • Waking up early and not being able to fall back asleep is a common symptom

Exhaustion and lethargy do not necessarily mean an absence of anxiety

  • Anxiety about future, goals, and escaping depressive state can be present

SSRIs (selective serotonin reuptake inhibitors) discovered in the 1980s

  • Prevent serotonin from being cleared from the synapse, increasing its efficacy
  • Side effects vary among individuals and over time
  • About a third of people don’t derive benefit from SSRIs, but they have saved and improved many lives

Relief from depression symptoms usually occurs two weeks after starting SSRIs.

SSRIs may improve depression symptoms through neuroplasticity

  • Norepinephrine: related to psychomotor defects of depression (lethargy, exhaustion)
  • Dopamine: related to anhedonia aspects of depression (lack of ability to experience pleasure)
  • Serotonin: related to grief, guilt, and emotional aspects of depression

Pain is also involved in depression

  • Substance P: manufactured by neurons, underlies sensation of pain

20% of people with major depression have low thyroid hormone

  • Low thyroid hormone leads to low energy and low metabolism

Conditions that can impact thyroid hormone system and depression:

  • Childbirth (postpartum depression)
  • Menstrual cycle
  • Menopause and postmenopausal women

Cortisol hormone also plays a role in depression

  • More stress is correlated with more bouts of major depression
  • Controlling stress system can help avoid depression

Genetic predisposition to depression

  • 5‑HTTLPR gene: serotonin transporter
  • Polymorphism increases susceptibility to depression under stress
  • Mitigating stress is crucial for those with a genetic predisposition to depression

Behavioral tools can adjust levels of chemicals related to depression

  • Cold showers: release norepinephrine and epinephrine
  • Exercise: increases norepinephrine, dopamine, and serotonin

Prescription drugs and supplementation may be necessary for those who cannot access behavioral tools due to the severity of their depression.

Inflammation can lead to or exacerbate depression

  • Chronic stress can cause inflammation in the brain and body
  • Inflammatory cytokines (e.g., IL‑6, TNF alpha, C‑reactive protein) are major players in creating chronic inflammation

Increasing intake of essential fatty acids (EPA) can help relieve depressive symptoms

  • Studies show relief from depressive symptoms matches SSRIs
  • 1000 mg of EPA seems to be the critical threshold for benefiting from its effects

Inflammation can cause tryptophan to be diverted into a neurotoxic pathway, leading to depression

  • Tryptophan is an amino acid found in food and is a precursor to serotonin

Ingesting EPA limits inflammation, promoting the conversion of tryptophan into serotonin

  • Exercise sequesters the neurotoxin that would lead to depression, promoting the conversion of tryptophan into serotonin

Phosphocreatine system in the brain involved in mood regulation and depression

  • Creatine supplementation (3–5 grams per day) shown to improve mood and treat depression

Creatine may increase mania in people already experiencing mania.

Creatine supplementation may affect NMDA receptor function, leading to changes in neural circuits and mood improvement.

Ketamine trials show promising results for depression treatment

  • Ketamine: dissociating from experience during the session with the psychiatrist
  • Relief from symptoms without many treatments
  • Works on NMDA receptor related to neuroplasticity

Study published in JAMA Psychiatry (May 2021): Effects of Psilocybin Assisted Therapy on Major Depressive Disorder

  • Administered one or two rounds of psilocybin (dosages based on body weight) for patients with major depressive disorder
  • Significant improvement in mood and relief from depressive symptoms in 50–70% of subjects

Psilocybin rewires associations between emotional events, past events, current events, and future events

  • Allows people to gain relief or distance from depressive narratives and see new opportunities for optimism
  • Immersing oneself in the experience and being fully present

Ketogenic diet: can help maintain euthymia (balance between manic and depressive episodes)

  • Can help reduce depressive symptoms in people who don’t respond to classical antidepressants


Science-​​based tools and supplements that push the needle.

EPA Fish Oil for Depression


Cold Exposure for Depression


Exercise for Depression


Controlling Stress to Prevent Depression


Creatine for Depression


Ketamine Therapy for Depression


Psilocybin for Depression


Pharmaceutical Treatments for Depression



We recommend using this distillation as a supplemental resource to the source material.

  • Understanding & Conquering Depression

    Huberman Lab Podcast #34

    In this episode, Huberman explores major depression, including its biological and psychological aspects, as well as available treatments and interventions.

Full Notes

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