January 31, 2017

















  • Polyunsaturated fats include omega-6 and omega-3 fatty acids

  • Omega-3 and omega-6 fats are similar long, flexible molecules, but cannot be inter-converted

  • These polyunsaturated fats can be made into many types of important  molecules

  • The extra double bond of the omega-3 molecules gives them more flexibility.

  • These fats are stored in adipose and other tissue membranes, and the relative amount of omega 3 and 6 in our diet is reflected in our tissue.

  • Many studies suggest that the amount of omega-3 fat in the American diet is low when compared to the amount of omega six fat

  • Dietary omega-3 is often limited to seafood or mother’s milk, also in walnuts, leafy plants

  • The American diet is abundant in omega-6 fat, present in oil from corn, and soy as well as in poultry, beef, and pork fattened on these commodities.

  • In contrast, the Mediterranean or Japanese diet is abundant in Omega 3, which is commonly present in fish.  Because fatty fish is such a critical source  of the long-chain omega-3 fats, (EPA & DHA), fish consumption can be a good indicator of an individual’s omega-3 status.

  • However, fish such as tilapia that is raised in tanks and fed soy and corn is not considered a source of omega-3 fats…it is more like beef and chicken.





  • To understand the two very different effects that a diet with abundant omega six or with omega-3 fatty acids can have at  the molecular level, let's take a look at this diagram of cell membranes from Joe Hibbeln.

  • Here you can see how the cell membranes are different depending on the type of long polyunsaturated fat they are made of.

  • On the left the American diet has created a membrane with abundant omega six fats and shown in the red.

  • On the right you can see that the Mediterranean or Japanese diet with its abundant fish consumption has created a membrane that is full of omega-3 fats shown in aqua

  • The Japanese membrane, full of the  more flexible omega 3 allows membrane bound receptors to change their conformation more easily.

  • Here a signaling molecule, such as a neurotransmitter, stimulates a g protein coupled receptor, which in turn activates the enzyme phospholipase A2, which cleaves a fatty acid from the membrane. 

  • The fatty acid is then metabolized to signaling molecules such as prostaglandins.

  • In the American situation, on the left, a red Omega six fatty acid becomes a prostaglandin which goes on to cause increased inflammation.

  • Prostaglandins are the target for anti-inflammatory medicines such as aspirin.

  • On the right, the Mediterranean or Japanese membranes that are full of aqua omega-3 fatty acids give rise to products made out of omega-3 fatty acids, which are less inflammatory and produce less inflammatory response.

  • These differences in membrane composition might explain the differences in health outcomes between those populations that consume lots of fish and those that consume lots of omega six fats


  • You are probably aware that omega-3 fat has many effects, and they are critical for brain function:

    •  Neuro-immune interactions & cytokines

    • Microbiome and gut inflammation

    • Synaptic differentiation & density in cortex  

    • Autonomic control of heart

    • Receptor function / signal transduction

    • Neurotrophic factors                             

    • Cerebral blood flow                              

    • Gene expression

    • Omega-3 fat is also related to serotonin function.







This diagram from Joe Hibbelin illustrates the two distinct families of essential fatty acids, the omega- 3 in aqua and the omega-6 in purple.  

  • The physical properties of these fats are different and determined by the position of their double bonds - the locations of these bonds form the basis of their classification.

  • All mammals, including humans, lack the enzymes to introduce double bonds at these two positions.

  • Hence, each distinct family of fatty acid must be obtained in the diet, thus they are called essential fatty acids. 

  • The 22-carbon long omega-3 fatty acid DHA, common in fish, and the 20-carbon long omega-6 fatty acid, are major components of the brain.

  • These fats can be manufactured from dietary sources of shorter n-3 and n-6 fatty acids respectively. 

  • To understand how people could be deficient in DHA, let us look closely at the shorter, 18 carbon essential fatty acids at the top. 

  • Both the omeg-6 and the omega-3 fats compete for the same enzymes that can elongate them.

  • (Point to enzymes)

  • If we have abundant 18 carbon omega-3 fatty acids, then our bodies will be able to manufacture plenty of DHA, and our intake of fish will not be so critical.

  • However, the typical American eats an overwhelming amount of omega-6 fat, and these enzymes are overwhelmed with omega-6. 

  • This prevents the body from making enough of the long omega-3 fats, such as DHA.

  • The function of these enzymes is genetically determined, and recent studies suggest that for western European populations, this is especially important.




  • One of my projects at NIH was to measure the brain uptake of DHA, which we found to have a half-life of more than 2 years.

  • What makes this critical is that the effects of a diet deficient in n-3 fat will last for a decade or more before the effects of an adequate diet are fully manifest.

  • We need to keep this in mind when we are evaluating studies of DHA only a few months in length,

  • Nevertheless omega-3 fat can sometimes have a rapid effect.








  • This can perhaps be seen most definitively in this randomized double blind controlled study from Andrew Stoll at Harvard demonstrating the efficacy of fish oil in individuals with severe bipolar depression, most of who required multiple medications.  

  • In this survival analysis, you can see that subjects on placebo were much more likely to relapse, and require hospitalization. 

  • This trial was stopped early after three months because the oversight committee felt it was unethical not to provide fish oil to all the subjects.

  • There have been a number of meta-analyses of omega-3 fatty acids, and they are generally found to have a positive effect





Fish oil has also been used to treat violence and aggression in a number of double blind placebo controlled studies

  • Students given fish oil had lower hostility in laboratory tests under stressful conditions.

  • Another study was done with women with borderline personality; In this study, omega-three fatty acids caused a 75% reduction in physical and verbal outbursts.




  • Fish consumption can be used a surrogate marker for the amount of omega 3 in our bodies, and there is epidemiological data suggesting that this is important.

  •  Here is a slide from the American Journal of Psychiatry looking at fish consumption and rates of Bipolar Depression in a number of countries around the world.


  • This is is depression on the vertical axis, and this fish consumption on the horizontal axis The countries with high rates of bipolar depression have low fish consumption and countries with high fish consumption have low rates of depression.





  • So what are various groups recommending in regards to fish consumption for prevention?

  • The American Psychiatric Association recommends that patients with mood and impulse control disorders should consume 1000 milligrams/day of EPA+ DHA .

  • This requirement could be met by eating salmon or tuna several times a week.

  • However, the average American woman consumes much less, less than 70 mg a day.

  • Supplements containing less than 3,000 milligrams are generally recognized as safe by the FDA, and doses much higher than this have been used in many studies.

  • The simplest intervention is to encourage people to eat more fish, especially women and children.

  • Although there is a concern about mercury levels in some type of seafood, like Swordfish or pilot wale, it appears to me that these concerns are greatly exaggerated, especially considering the benefits of eating seafood.

  • There is no mercury in fish oil.

  • Side effects from fish oil are generally minor GI upsets.

  • Theoretically, fish oil can reduce the clotting time, but importantly, there are no published reports of any serious adverse effects resulting from taking fish oil.


  • In the future, we may find that we can achieve the same effects by lowering omega-6 fat.

  • The American diet is abundant in omega-6 fat, present in oil from corn, peanuts, and soy as well as in poultry, beef, and pork fattened on these commodities.

  • Soybean oil is a key source of omega 6 fat, and it use has increased dramatically over the last century. 

  • Over the last few decades, it appears that Americans have consumed much higher relative amounts omega six fat, and this is reflected in their tissue composition.

  • To counterbalance such a situation, the recommended daily intake of omega-3 fat should be higher or lower depending on the intake of omega-6 fats. 

  • There are algae derived forms of DHA which may have increasing importance to prevent over fishing

  • DHA can be microencapsulated and put in many foods, including milk and bread.

  • Chickens can be fed seaweeds or flax which has lots omega 3, and their eggs will have increased levels of omega-3 fats.

  • It turns out that Bison meat is also high in omega 3 fat.

  • Bison are obligatory grass feeders, and they cannot be fattened on corn and soybeans like regular beef cattle.


  • One recent study examined how patients with depression respond to the SSRI inhibitor paroxetine.

  • In this study, measurements were made of the amount of DHA in red blood cells and reported fish consumption.

  • The patients who were treated with paroxetine and did not eat fish or had low levels of DHA were less likely to respond to paroxetine.

  • The depressed patients who did improve had higher levels of DHA.


AJP in Advance (doi: 10.1176/appi.ajp.2016.15091228)


  • A meta-analysis was published looking at various nutraceuticals as adjunctive therapy in depression which gives strong support for adjunctive use of omega-3 with antidepressants for depression.

  • The results showed a moderate to strong affect in favor of omega-3 fatty acid use with antidepressants.




The dose of omega 3 in the study by Stoll was based on the dose which has been found to improve arthritis, and reduce inflammation :14 capsules daily, 6.2 g EPA & 3.4 g DHA). It is much higher that is commonly recommended as the normal daily intake, but there have been no problems in the medical literature with this higher dose after many years of using fish oil.  Cod liver oil, the prototype fish oil, has been in use for centuries for arthritis.  You can get 9.6 grams / day of omega 3 from many sources, and variety may be good. 


Below I have listed some sources of EPA and DHA I am familiar with.  There is lots of hype about particular brands, but as long as the product contains both EPA and DHA totaling about 10 grams, it is probably fine.  (Note- this is not the same as 10 grams of fish oil, which may include other oils besides the EPA and DHA)


I met the Carson’s years ago, and he and his wife have a good product.  This liquid seems easier to take…it is 1600mg in 1 tsp, so to treat Bipolar, someone would take one tablespoon twice a day.


To cover the taste, you can take it with black cherry syrup:


I met the Joar Opheim, guy that started this company, at a convention.  He is a real believer in his products, which have a great reputation.  This liquid, which as roughly similar concentration to that of Carson, is good tasting as it is, but as noted, you can add black cherry syrup to it too.


Of course, you can also get capsules that have the same amount of omega 3 in them, but you have to take a lot ( i.e. ~15 capsules /day) to get the dose in the study by Stoll (9.6 grams/day). 


For example, you could take 12 daily of these from Trader Joe’s….


You want to make sure the fish oil contains the total mg of DHA + EPA….that is what is important.  It maybe ok to take cod liver oil (it is cheaper) but it has a higher % of DHA to EPA; this ratio may be less mood elevating, so may be best someone with mania.  The higher % EPA oils may be more mood elevating, and there is the possibility that mania could be induced. 


You could also get more that 9.6 grams of EPA+DHA by eating 30 oz of salmon, anchovies or sardines daily for those who don’t like medicine.  I have a friend whose son had severe mental illness, and eventually switched to the real fish from oil and capsules…he has done well over more than two decades.


Let me know if this is helpful, or if you need more information or references.


 The story below was from a while back, but it illustrates the benefit for some folks…


Best regards




John Umhau MD MPH CPE      August 20, 2016


E mail:




…Fired from his job, rejected by his family, John Palma bounced in and out of jails and hospitals as he sank into severe, suicidal depression, returning always to the drug that destroyed him.

"I just did not want to talk to anyone, see anyone, have anything to do with people and their insults. My mind was so scattered, I couldn't really grasp what anyone was saying," said Palma, 30… 

Flagged as an addict least likely to succeed in his drug recovery program at the Salvation Army, Palma joined a small, unscientific medical experiment there, when counselors began slipping little pills in his food.  

Today, five months after taking daily high doses of omega-3 supplements, Palma has emerged from his depression to rejoin the world, his head clear, his brain back in operation. The fog has lifted, as he puts it.  

… Palma and his counselors are firmly convinced the omega-3s are the key to his unexpected success. 

"I just think more clearly now," Palma said. "Before, I couldn't read the AA book. It was very hard for me - I would have to read it over and over just to get it. And I can honestly pay attention to what people are saying. My family has noticed it - everyone has."

Around the Rehab Center, the staff joked about Palma, so dramatic were the changes in him after about six weeks of taking the fish oil supplements.  

"It was - oh my God - who is this new person?" said Paulina Castillo, the center's director of rehabilitation services.

Palma was one of three meth addicts with especially difficult mental health histories who have tried the omega-3s in the Salvation Army experiment.

"In all three, the omegas have made such a difference," said Castillo, noting that two, including Palma, have graduated.



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