Huberman notes: Major Depression

Harpreet Vishnoi
11 min readApr 19, 2023

Notes of Huberman’s video on depression.

Photo by Adrian Swancar on Unsplash

Major Depression or clinical depression characterised by persistently depressed mood or loss of interest in activities, causing significant impairment in daily life.

Usually there is an imbalance of 3 neurotransmitters:

  1. Norepinephrine and epinephrine
  2. Dopamine
  3. Serotonin

These neurotransmitters can be tried balancing out using some supplements and change in lifestyle which can reduce the intensity of depression.

Ways to cope up with Depression

  1. 8 hours of sleep. REM sleep is disrupted in depression still getting 8 hours of sleep at night can help regularize neurotransmitters.
  2. Take cold showers everyday to release norepinephrine and epinephrine in your brain and body.
  3. 1–2 gm of EPA which can be found in omega3 supplements.
  4. Exercise for 30 minutes everyday. Mix aerobic and resistance training.
  5. 3–5gm of creatine monohydrate.
  6. Fermented foods like yogurt, curd, etc.
  7. Reduce or no high intensity dopaminergic activities like computer games, social media (Instagram, Facebook, dating apps) and substance abuse (alcohol, weed, drugs, etc).

Detailed Notes

300 million suffer from this.

Anhedonia: Lack of ability to enjoy things. People stop enjoying sex, food, and social interactions which people liked before. When we do high dopamine inducing activity, it is followed by a high pain since our reward pain pathway balances out. In order to get the same dopaminergic hit, we overdo the pleasure thus falling in a spiral loop. This can also induce addictions.

SSRIs (Prozac, Zoloft, etc.): Selective Serotonin Reuptake Inhibitors: Selective Serotonin Re-Uptake Inhibitors prevent serotonin from being wiped up from the synapse after two neurons talk to one another.The more typical names or more generic names are things like fluoxetine, when people take those, more serotonin hangs out in the synapse and is able to be taken up by the neuron on the opposite side because of this selective re-uptake inhibition. It prevents the clearance of serotonin from the synapse and thereby more serotonin can have an effect. So SSRIs don’t increase the total amount of serotonin in the brain. They change how effective the serotonin that’s already in the brain is at changing the activity of neurons

Norepinephrine, dopamine, and serotonin that relate to and can adjust the symptoms of depression.

Epinephrin or norepinephrine is thought to relate to the so-called psychomotor defects, sometimes called psychomotor retardation. This is the lethargy, this is the exhaustion, this is the inability to get out of bed in the morning.

Dopamine is thought to relate to the anhedonia, or I should say lack of dopamine in depressive patients is thought to lead to the anhedonia. The lack of ability to experience pleasure. Dopamine does not directly impact mood, but can affect motivation and feelings of pleasure.

And serotonin is thought to relate to the grief, the guilt, some of the more cognitive or more emotional aspects of depression. Low serotonin leads to guilt. Serotonin is a neurotransmitter that plays a large role in positive mood and happy feelings.

20% of people that have major depression have low thyroid hormone. Thyroid hormone is related to metabolism. Oftentimes we think about thyroid is only related to having a fast metabolism, but thyroid is related to all forms of metabolism, including our ability to synthesize new tissues like protein and repair injuries. 20% of people with major depression are hypo thyroidal. And that leads to low energy, low metabolism in the brain and body. And there’s a condition called Hashimoto’s, which is essentially low thyroid output.

Who carry particular copies of genes, what they call polymorphisms, in particular of a gene called 5HTTLPR, which is a serotonin transporter. So this is a gene that controls or regulates how much serotonin is available in the brain.

If you get into a very cold shower, you take an ice bath, you will release norepinephrine and epinephrine in your brain and body. Lack of them (This is the lethargy, this is the exhaustion, this is the inability to get out of bed in the morning)

Will exercise help? Well, if you go out for a run, you’re going to increase the amount of norepinephrine in your body. If you enjoy that run, it’s likely that you’ll increase the levels of dopamine and probably serotonin in your brain and body as well. Will that cure your depression?

Brain Inflammation & Mental State: Cytokines, Prostaglandins

And I’m not just going to tell you to get sunlight in your eyes and to get a good night’s sleep, although I think everybody should do that on a regular basis. There’s growing evidence now that many forms of major depression, if not all of them, relate to excessive inflammation. Now inflammation plays an important role in wound healing. It is a positive aspect of our immune system. Our ability to combat wounds, combat illnesses, et cetera, but inflammation gone unchecked, inflammation that lasts too long, or is of too high amplitude, meaning too many anti-inflammatory or inflammatory cytokines and things of that sort in the body is bad.And that if we want to control depression, or limit or eliminate depression, that focusing on reducing inflammation and its associated pathways is a really good thing to do.

Essential Fatty Acids (Omega-3, EPAs: Eicosapentaenoic Acid)

Several quality peer reviewed studies now to reduce inflammation and to relieve some, and in some cases, all of the symptoms of major depression. One of those approaches is to increase our intake of so-called EPAs or Essential Fatty Acids. There’s now a very long list of papers in quality peer review journals showing that when people ingest a certain level of EPA omega-3 fatty acids, the relief from depressive symptoms matches the SSRIs. That’s incredible, right? EPA variety of omega-3s, can lower the effective dose of things like SSRIs. Meaning if we require a 50 milligram or 40 milligram dose of fluoxetine, that one can get by on a lower dose and thereby perhaps not experience as many or as severe side effects by taking or supplementing with EPAs. Now, the threshold level seems to be about one gram, 1000 milligrams of EPA. So you will sometimes see on a bottle of krill oil or fish oil or any other source, even plant source or other source of EPA that it’s 1000 milligrams or 1200 milligram. 1000 milligrams or 2000 milligrams of EPA, there does seem to be some substantial relief for many people, should emphasize many, not all,

How EPAs Help Offset Depression: Serotonin Synthesis, Kynurenine, Quinolinic Acid: Well, it turns out that these inflammatory cytokines impact neurons and the circuits of the brain that relate to things like serotonin, dopamine, and norepinephrine. These inflammatory cytokines act in a variety of different ways, but they mainly act to inhibit the release of serotonin, norepinephrine, and dopamine, or the synthesis of serotonin, norepinephrine and dopamine. And I’ll give you one example of how EPAs can positively impact this process. Dopamine also called 5HT, essentially derives from a precursor called tryptophan. Tryptophan arrives into our system through our diet, okay, tryptophan is an amino acid. Tryptophan is found in Turkey, it’s found in carbohydrates. And that should therefore raise the idea, hmm, I wonder if one of the reasons why people who are depressed have such an appetite for carbohydrate late in foods is because they’re trying to get more tryptophan, and therefore more serotonin. And indeed that’s the case. Tryptophan is eventually converted into serotonin. However, if there’s excessive amounts of inflammation, these inflammatory cytokines cause tryptophan to not be converted so much into serotonin, but to be diverted down a different pathway. The pathway involves something called IDO, Indoleamine, which converts tryptophan into kynurenine. Kynurenine actually acts as a neurotoxin by way of converting into something called quinolinic acid. And quinolinic acid is pro depressive. So if that seems like a complicated biochemical pathway, what’s basically happening here is that the tryptophan that normally would be made into serotonin, under conditions of inflammation is being diverted into a neurotoxic pathway. And ingestion of EPAs, because it limits these inflammatory cytokines, things like IL-6, C-reactive protein, et cetera, can cause more of the tryptophan that one ingests.

Increased Quinolinic correlates with depression. Link

“The prefrontal cortices in the post-mortem brains of patients with major depression and bipolar depression contain increased quinolinic acid immunoreactivity compared to the brains of patients never having had depression.[14] The fact that NMDA receptor antagonists possess antidepressant properties suggests that increased levels of quinolinic acid in patients with depression may overactivate NMDA receptors.[11] By inducing increased levels of quinolinic acid in the cerebral spinal fluid with interferon α, researchers have demonstrated that increased quinolinic acid levels correlate with increased depressive symptoms”


“Quinolinic acid is an excitotoxin in the CNS. It reaches pathological levels in response to inflammation in the brain, which activates resident microglia and macrophages. High levels of quinolinic acid can lead to hindered neuronal function or even apoptotic death.[10] Quinolinic acid produces its toxic effect through several mechanisms, primarily as its function as an NMDA receptor agonist, which triggers a chain of deleterious effects, but also through lipid peroxidation, and cytoskeletal destabilization.[10] The gliotoxic effects of quinolinic acid further amplify the inflammatory response. Quinolinic acid affects neurons located mainly in the hippocampus, striatum, and neocortex, due to the selectivity toward quinolinic acid by the specific NMDA receptors residing in those regions.[10]

When inflammation occurs, quinolinic acid is produced in excessive levels through the kynurenine pathway. This leads to over excitation of the NMDA receptor, which results in an influx of Ca2+ into the neuron. High levels of Ca2+ in the neuron trigger an activation of destructive enzymatic pathways including protein kinases, phospholipases, NO synthase, and proteases.[13] These enzymes will degenerate crucial proteins in the cell and increase NO levels, leading to an apoptotic response by the cell, which results in cell death.

In normal cell conditions, astrocytes in the neuron will provide a glutamate–glutamine cycle, which results in reuptake of glutamate from the synapse into the pre-synaptic cell to be recycled, keeping glutamate from accumulating to lethal levels inside the synapse. At high concentrations, quinolinic acid inhibits glutamine synthetase, a critical enzyme in the glutamate–glutamine cycle. In addition, It can also promote glutamate release and block its reuptake by astrocytes. All three of these actions result in increased levels of glutamate activity that could be neurotoxic.[10]

This results in a loss of function of the cycle, and results in an accumulation of glutamate. This glutamate further stimulates the NMDA receptors, thus acting synergistically with quinolinic acid to increase its neurotoxic effect by increasing the levels of glutamate, as well as inhibiting its uptake. In this way, quinolinic acid self-potentiates its own toxicity.[10] Furthermore, quinolinic acid results in changes of the biochemistry and structure of the astrocytes themselves, resulting in an apoptotic response. A loss of astrocytes results in a pro-inflammatory effect, further increasing the initial inflammatory response which initiates quinolinic acid production.[10]

How Exercise Offsets Depression:

Exercise, it turns out, also has a positive effect on the tryptophan to serotonin conversion pathway. And the way it does it is really interesting. You now know that tryptophan can either be converted into serotonin or it can be converted into this neurotoxin(Quinolinic), which is a bad thing. Exercise, the activation of the muscles through rhythmic repeated use, in particular aerobic exercise, but also resistance training has been shown to do this to some extent, tends to sequester or shuttle the contouring into the muscle so that it isn’t converted into this neurotoxin that is pro depression, okay?

EPA by ingesting particular food sources, you certainly can do it through food, you don’t have to supplement, but it’s easier to do with supplements, that doing that will limit the inflammation that diverts tryptophan into this neurotoxic pathway

And exercise as well, augments this conversion of tryptophan into serotonin because it takes this thing that would potentially be a neurotoxin and it sequesters it, it pulls it away so that it can’t actually go have its pro depressive effects. So you’ve got multiple steps here.


“Physical exercise has emerged as an alternative treatment for patients with depressive disorder. Recent animal studies show that exercise protects from depression by increased skeletal muscle kynurenine aminotransferase (KAT) expression which shifts the kynurenine metabolism away from the neurotoxic kynurenine (KYN) to the production of kynurenic acid (KYNA). In the present study, we investigated the effect of exercise on kynurenine metabolism in humans. KAT gene and protein expression was increased in the muscles of endurance-trained subjects compared with untrained subjects. Endurance exercise caused an increase in plasma KYNA within the first hour after exercise. In contrast, a bout of high-intensity eccentric exercise did not lead to increased plasma KYNA concentration. Our results show that regular endurance exercise causes adaptations in kynurenine metabolism which can have implications for exercise recommendations for patients with depressive disorder.”


“The N-methyl-D-aspartate (NMDA) receptor is a receptor of glutamate, the primary excitatory neurotransmitter in the human brain. It plays an integral role in synaptic plasticity, which is a neuronal mechanism believed to be the basis of memory formation.”

Creatine Monohydrate, Forebrain Function & NMDA receptors*

creatine can draw more water into muscles and can increase power output from muscles. So it’s something that does indeed work. There have been debates about whether or not it’s unhealthy for the kidneys to take long-term creatine, supplementation at high doses.

phosphocreatine system in the brain, and that phosphocreatine system has everything to do with the dialogue between neurons and these other cell types called, glial, and glial comprise several cell types, microglia, astrocytes, et cetera, but the foster creatine system in the forebrain in particular, in the front of our brain, has been shown to be involved in regulation of mood and some of the reward pathways as well as in depression.

Creatine monohydrate. The American Journal of Psychiatry in 2012, published a study, which was a randomized, double blind placebo controlled trial of oral creatine monohydrate. And what it found is that it could augment or enhance the response to a selective serotonin re-uptake inhibitor, in particular, in women with major depressive disorder. So like EPA, creatine supplementation seems to either lower the required dose of SSRI that’s required to treat depression, or can improve the effectiveness of a given dose of SSR.

are pretty reasonable for most people, anywhere from three grams to five grams, sometimes up to as many 10 grams per day of creatine. Many of these also were shown to increase activity of this phosphocreatine system in the forebrain, and some show a relationship between that phosphocreatine system and a particular category of receptors in the brain called the NMDA receptor, N-methyl D-aspartate receptor.

And that increases in the activity of the forebrain phosphocreatine system relate to changes in the way the NMDA receptors function and may lead to some of the plasticity, the changes in neural circuits that underlie the shift from negative mood and affect to positive mood


Don’t overpower your dopaminergic pathways using activities or compounds. At depression was probably triggered by an overindulgence in video games and other highly dopaminergic activities to the point where those activities eventually were countered by the pain balance that Dr. Anna Lembke described. And he now has to do those activities repeatedly and for many, many hours each day, just to feel okay, not even to derive pleasure from them. And worse, many other activities, practically all other activities have lost their zest, they’ve lost their excitement and his sense of pleasure for them. And so there’s a really active campaign now to reset that system. So, number one, don’t overwhelm your pleasure centers either through activities or compounds. Might seem counterintuitive, but you’re setting yourself up for anhedonia and depression if you do that.

Mind your extreme highs and extreme lows. Anything that is a lot of fun can make your pleasure pain balance tilted.

But if you do feel like you need to reset that system, it really does seem like a 30 day complete detox from whatever activity or substance that is. And ideally it doesn’t continue after that 30 days, especially in conditions of drugs of abuse.

Note: The information provided is just notes and is not medical advice, nor should it be taken or applied as a replacement for medical advice.



Harpreet Vishnoi

Carnegie Mellon University| Product Manager | AI Developer