Published August 2021 on YouTube

Understanding & Conquering Depression | Huberman Lab Podcast #34

1. Mood & Pleasure

Mood Disorders & Pleasure System:Andrew discusses the biological and psychological underpinnings of mood disorders and how they are related to the pleasure system in our brains. He explains how pursuing pleasure releases dopamine and how this is linked to mental anguish and pain. By understanding the biology of one mood disorder, we can gain insight into other mood disorders as well.+
Dopamine and Addiction:Andrew explains how dopamine is associated with motivation and drive, but constant pursuit of pleasure can lead to addiction and depression. He shares a real-life example of a young man struggling with a disruption in his pleasure-pain balance and how rebalancing the pathway can help counter depression.+

2. Sponsors

Andrew discusses the importance of regular blood work and how InsideTracker can help interpret the data. He also talks about the benefits of Athletic Greens and Belcampo for maintaining a healthy lifestyle.+

3. Major Depression

Understanding Major Depression:Andrew discusses the differences between major depression and bipolar depression, emphasizing the importance of accurate diagnosis by a qualified healthcare professional. He also talks about various treatments for depression, including behavioral, drug, supplementation, diet, and exercise, and highlights the need for more understanding of the mechanisms behind promising treatments.+
Understanding Depression:Andrew Huberman discusses the mechanisms behind depression and the challenges in diagnosing it. He explains the specific criteria for clinical depression and the common symptoms associated with it, such as anhedonia and guilt. This episode provides valuable insights into the complexities of depression and the importance of taking it seriously.+

4. “Anti-Self” Confabulation

Andrew explains how confabulation is a normal aspect of our mind and nervous system, but in major depression, it can lead to delusional anti-self confabulation. This type of confabulation is not linked to reality and can make the person seem sick or not well. Andrew gives an example of an athlete with a physical injury who is also depressed and how they may confabulate their progress as being worse than it actually is.+

5. Depression and Sleep

Depression and Sleep:Andrew discusses the relationship between depression and the autonomic nervous system, specifically how disrupted sleep patterns and decreased appetite are common symptoms of major depression. He emphasizes that these are real physiological signs that something is off in the autonomic or vegetative nervous system.+
Understanding Depression:Andrew Huberman discusses the underlying biology of depression and how it impacts various aspects of our lives such as appetite, sleep, and emotions. He explains the disruptions in the autonomic nervous system and hormone levels associated with depression, shedding light on the complexity of the condition.+

6. Biology of Depression

Andrew explains the biology of depression, discussing the discovery of tricyclic antidepressants and MAO inhibitors, which increase norepinephrine levels in the brain, and the pleasure pathways involving dopamine-rich areas of the brain. He also mentions the side effects of these drugs and how they impact systems in the brain and body.+

7. Understanding SSRIs

How SSRIs Work:Andrew explains how SSRIs work by preventing serotonin from being wiped up from the synapse, increasing the efficacy of serotonin already in the brain, and changing the activity of neurons.+
SSRIs and Neuroplasticity:Andrew discusses the mysteries surrounding SSRIs and their varying effects on individuals. He explores the potential role of neuroplasticity in the relief of depression symptoms through the use of SSRIs, including the production of new neurons and the reopening of critical periods of plasticity.+

8. Chemical Systems of Depression

Andrew explains the three major chemical systems in the brain that relate to and can adjust the symptoms of depression: norepinephrine, dopamine, and serotonin. He also discusses how these systems can be divided into separate categories and how they impact depression symptoms such as lethargy, anhedonia, and grief. However, finding the right combination of drugs for each individual can be complicated and requires a good psychologist or psychiatrist.+

9. Pain and Depression

Andrew discusses the link between physical and emotional pain, and how pain relievers can sometimes help with emotional pain. He also talks about substance P and its role in pain and depression, and how understanding the chemistry behind depression can help us know more about it than most people.+

10. Hormones and Depression

Hormones and Depression:Andrew discusses the impact of low thyroid hormone on depression and how it can lead to low energy and metabolism in the brain and body. He also mentions how certain conditions like childbirth can make people more susceptible to depression.+
Hormones and Depression:Andrew discusses how hormones like cortisol and thyroid hormone can impact depression in women during different stages of their life, and how controlling stress is key to avoiding depression.+

11. Genetic Predisposition

Andrew explains how certain genes, such as the 5HTTLPR gene, can increase one's susceptibility to depression under conditions of stress. He also discusses the strong genetic component to depression and the importance of learning how to mitigate stress to prevent depressive episodes.+

12. Tools for Positive Mood

Andrew explains specific tools to maintain a positive mood and adjust serotonin and dopamine levels. Understanding the mechanism behind these tools is key to working with your system for a healthy mind and body.+

13. Relieving Depression

Andrew Huberman discusses the potential of behavioral tools and exercise in relieving symptoms of depression, such as increasing levels of norepinephrine and dopamine. However, for those suffering from major depression, accessing these circuits can be difficult and may require additional support.+

14. Inflammation and Depression

Andrew discusses the relationship between inflammation and depression, explaining how chronic inflammation can lead to or exacerbate depression. He identifies the major players in creating chronic inflammation in the brain and body, and emphasizes the importance of reducing inflammation to control depression.+

15. EPA and Depression

Andrew discusses the positive effects of increasing intake of EPA omega-3 fatty acids in reducing inflammation and relieving symptoms of major depression. Studies have shown that a certain level of EPA can match the relief from SSRIs and can lower the effective dose of prescription antidepressants. The threshold level seems to be about one gram of EPA, but people who took two grams seem to do better.+

16. Inflammation and Mood

Andrew explains how inflammation impacts the circuits of the brain that relate to mood and how EPAs and exercise can positively impact this process. He also discusses the importance of tryptophan in maintaining healthy mood and how excessive inflammation can divert tryptophan into a neurotoxic pathway, leading to depression.+

17. Exercise and EPA

Exercise and EPA:Andrew explains how exercise and EPA can increase serotonin levels in the body by limiting the inflammation pathway that diverts tryptophan into a neurotoxic pathway, which can lead to depression. By hitting a certain threshold level of EPA intake and exercising regularly, tryptophan is converted into serotonin, leading to a positive effect on the tryptophan to serotonin conversion pathway.+
Omega-3 and Exercise:Andrew explains the benefits of EPA, a type of omega-3, and exercise on mood regulation. He emphasizes the importance of hitting a certain threshold level of EPA to relieve depression and elevate mood.+

18. Creatine for Mood

Creatine for Mood:Andrew discusses the surprising benefits of creatine for mood disorders and depression. Studies have shown that low dose creatine supplementation can increase the activity of the phosphocreatine system in the forebrain, resulting in improvements in mood. This episode explores the potential of creatine as a treatment for depression.+
Creatine and Depression:Andrew discusses the potential benefits of creatine supplementation for treating depression, including its ability to enhance the response to SSRIs and increase activity in the forebrain phosphocreatine system, which may lead to changes in neural circuits and a shift from negative to positive mood.+
Creatine and Mood:Andrew discusses the positive effects of creatine on mood and how it can potentially help with major depression. He explains the logical biochemical pathway that supports this finding and suggests talking to a healthcare provider before supplementing with creatine.+

19. Dissociative States

Dissociative States:Andrew explains how dissociative states are created and how they are being leveraged for the treatment of depression using drugs like ketamine and PCP, which are known drugs of abuse. He also discusses the common mechanism behind these states and how they relate to the NMDA receptor.+
Ketamine Therapy:Andrew discusses the use of ketamine therapy for depression and how it induces a dissociative state that separates individuals from their emotions. He emphasizes that it is still an experimental treatment but shows promising results in providing relief from symptoms without the need for ongoing treatments.+
Brain Plasticity:Andrew discusses the concept of brain plasticity and how it can be used to alleviate symptoms of depression. He also talks about the use of experimental therapies and drugs in treating depression and the importance of being cautious when discussing them.+
Ketamine and Neuroplasticity:Andrew discusses how ketamine can rapidly relieve depressive symptoms by increasing spines on neurons in the prefrontal cortex, leading to changes in circuit function and neuroplasticity. This suggests that drugs used in a therapeutic context may be increasing neuroplasticity and changing neurocircuits in the forebrain.+
Distancing from Depression:Andrew discusses the use of ketamine as a treatment for severe depression, particularly for those who struggle with delusional anti-self confabulation. He suggests that ketamine can help individuals distance themselves from negative emotions and experiences, which can lead to positive therapeutic outcomes.+

20. Psychedelics for Depression

Psychedelics for Depression:Andrew discusses the use of psilocybin, a psychedelic compound, for treating major depressive disorder. Psilocybin mainly works on the serotonin 5H2A receptor and has the capacity to rewire neural circuits and alleviate depression. The work being done is in university settings, university hospitals, by scientists and psychiatrists, and these are clinical studies, clinical trials, leading to peer-reviewed data.+
Psilocybin's Antidepressant Effects:Andrew discusses a recent study on the effects of psilocybin-assisted therapy on major depressive disorder. The study showed significant improvement in mood and relief from depressive symptoms in 50-70% of subjects who received psilocybin treatment, pointing towards psilocybin becoming a treatment for various forms of depression.+
Psilocybin Journeys:Andrew discusses with Matthew Johnson the impact of psilocybin journeys on depression. Despite the varied experiences of people on the drug, it seems to rewire neural circuitry in a common way, leading to relief from depressive symptoms.+
Ketamine's Impact:Andrew explains how ketamine impacts the brain by activating the serotonin system and 5HT1A receptor in layer five of the cortex. This activation allows for broader lateral connections between brain areas, which can help individuals see new opportunities and optimism in the future.+
Psychedelic Treatments:Andrew discusses the legality and clinical studies of psilocybin and ketamine for treating major depression. Psilocybin has shown to provide relief for depressive symptoms through high amplitude sessions in a controlled setting, while ketamine dissociates from negative experiences during sessions with a psychiatrist. The future of psychedelics in legislature is likely to shift in the future.+

21. Nutrition and Ketogenic Diet

Nutrition and Depression:Andrew discusses how nutrition, particularly the ingestion of carbohydrates and tryptophan-rich meats, can be a form of self-medication for depression. He also explores the potential benefits of the ketogenic diet in maintaining euthymia for people with major depressive disorder and manic depression.+
Ketogenic Diet Benefits:Andrew discusses how the ketogenic diet can be beneficial for treating epilepsy by increasing GABA transmission in the brain. He also explains how it can have positive effects on people with major depressive disorders who don't respond to classic antidepressants.+

22. Summary of Protocols Covered

Overcoming Depression:Andrew discusses the neurochemistry of depression and shares tools to overcome it, including not overwhelming the pleasure system, resetting the system through a 30-day detox, and pursuing noradrenaline-inducing activities like exercise and cold showers.+
Mood-Boosting Techniques:Andrew discusses various techniques to boost mood, including cold showers, regular exercise, and EPA intake. He also mentions the benefits of fermented foods and creatine. Lastly, he talks about prescription compounds and ketosis as potential sources of relief from depression.+

23. Support & Additional Resources

Andrew shares ways to support the podcast and offers a discount on supplements he recommends. offers high-quality supplements with a 20% discount for listeners.+