Friday, August 27, 2010

Ketogenic Diets and Bipolar Disorder 2

Yesterday I made a brief introduction to the topic of ketogenic diets and bipolar disorder.  Today I want to discuss some of the issues raised in that post a little more thoroughly.

First let's talk a bit about how nerves work.  It's pretty cool, really, but involves a little biochem and physics, so bear with me.  Now a picture, courtesy the US government and wikipedia:

Nerve impulses and signals travel along the nerve fibers via electricity.  How that happens is that the extracellular levels of ions and the intracellular levels of ions are maintained at a very different level.  Inside neurons, the sodium concentration is about 10mM, but outside, it is 130mM or more - rather like there are a bunch of balls stored in a container on top of a hill.  Open a little door on the side of the container, and the balls come pouring out and down the hill.  Potassium is the opposite - levels are very high inside the cells, and quite low outside (1).

Neurons have plasma membranes like other cells in our bodies.  Those membranes are somewhat like a tarp that has been oiled on both sides.  Charged ions such as sodium and potassium can't get through unless they go through special ion pumps that are located in the cell membranes.  The sodium pump, in fact, may use up to 50% of the energy in our brains (2)! 

The result of all these shenanigans is that our nerve cell membranes are left somewhat negatively charged (-75 mV, in fact).  The neurotransmitters (such as serotonin, norepinephrine, dopamine, acetylcholine, glutamate, GABA, etc.) work by changing these membrane potentials in various ways.  Neurotransmitters can open ion channels, allowing sodium to enter the cell and causing a wave of electrical impulse that travels along the neuron.  Neat!

When the electrical impulse (or "action potential") reaches the end of the neuron, the "presynaptic terminal,"  neurotransmitters are released into the space between the nerve cells, called the synapse.  At this part of the neuron, calcium is the important ion (though sodium plays a role too).  The electrical impulse (originally mediated by sodium at the dendrite) that traveled down the nerve causes extracellular calcium to pour into the cell, which then leads to the release of the neurotransmitters into the synapse, which then can affect communication with the next neuron.  Voila!  Your neurons have now sent messages to one another.  Yee haw.  The sodium and calcium membrane potential craziness can be set back to baseline by the transport of potassium, so everything is all set for a new signal to be sent. 

It's Friday.  I know.  But it's important to understand the above to some extent to understand why a ketogenic diet might change the ionic environment in our brains.

Before we get to a ketogenic diet, let's look at lithium, carbamazepine, and valproic acid (depakote), all medications that have anti-seizure and mood stabilizing properties.  Lithium is especially interesting, because, if you recall, it looks a lot like sodium, so much so that our kidneys can become confused.  Seems our brains can too.    In rats treated with lithium, the lithium displaces the intracellular sodium in the neurons, and overall sodium is decreased.  The changed sodium gradient may be central to the mood-stabilizing effects of lithium.  (You doctors out there will be squinting at me right now - hey, lithium isn't an anti-seizure med!  Well, actually, it used to be used as one.  Most psychiatrists will know that we can get away with somewhat lower doses of many medicines for mood control than neurologists need for seizures - an exception to this is depakote - sometimes.  Lithium can be horribly toxic at levels high enough needed to control seizures, so it is never used for seizures now.  But it does have anti-seizure potential.)  Carbamazepine is a little mysterious, but one of its effects is to definitely inhibit the voltage-sensitive sodium channels.  (Lamotrigine, another anti-seizure and mood stabilizing drug, does something very similar).  Valproic acid (depakote) has a whole load of actions, and can increase GABA, making it a pretty good anti-anxiety med.  Another thing it does is to decrease the rapid-fire ability of the spazziest neurons, probably by inhibiting the sodium channels.

Get the picture here?  All these meds can be life-saving if you have bad bipolar disorder or seizures, but they can all be pretty toxic and have a host of side effects.  But all of them work (effectively) as insulators in the brain, decreasing the ability of the neurons to send out out-of whack sodium messages leading to neurotoxic calcium overload.  This calcium overload is speculated to be the cause not only of seizures, but also migraines and bipolar symptoms, which is why anti-seizure meds can be used to treat all three conditions.

Enter the ketogenic diet.  Ketogenic diets (severely carbohydrate restricted diets) result in ketone bodies (made from fat) being used by the brain as fuel in lieu of glucose.  The ketone bodies, acetoacetate and beta-hydroxybutyrate, are acidic.  That simply means that there will be extra H+ protons hanging out, compared to a non-ketotic brain.  Well, protons can be pumped into neurons in exchange for sodium, acting a little bit like lithium.  And a few extra protons outside the cell do all sorts of interesting things, such as reduce the excitability of the neurons and reduce the activity of the excitatory neurotransmitters.  Protons seem to block the calcium channels at the NMDA receptors, for example (3).  GABA (the inhibitory neurotransmitter and anti-seizure also) is increased in the brain in ketogenic diets, along with many other neurotransmitter changes (4)

Sounds good!  Well, some intrepid doctors in Israel had a bipolar patient who didn't respond that well to medication, and after discussion with the patient and family, it was decided to try a ketogenic diet (5).  The patient fasted for 48 hours and began what is described as a "classic" ketogenic diet for two weeks.  Oddly, she didn't have any urinary ketones.  After two weeks, the doctors added MCT oil (coconut maybe?  It doesn't specify), which low-carbers will also know can induce a more reliable ketogenic state.  The patient was pretty gung-ho on the diet, and the doctors made note that her compliance was good for the month the diet was tried.  She showed no clinical improvement, no loss of weight, no urinary ketosis, and no changes in liver function.  Seems odd that she wouldn't get ketosis while fasting or on a strict ketogenic diet, but perhaps that's why it didn't work.  I'll discuss a second case below.

On the internet, one can find a number of anecdotes about people improving bipolar symptoms with ketogenic or low carb diets.  But, as I mentioned yesterday, there are absolutely no systematic scientific studies.  The last thing you would want to do is, all on your own, ditch your meds and try a home-made ketogenic diet without anyone's help.  Ketogenic diets can have pretty bad side effects - constipation, menstrual irregularities, elevated serum cholesterol (if you care) and triglycerides (not good), hemolytic anemia, elevated liver enzymes, kidney stones, and gall stones.  Up to 15% of kids on a ketogenic diet will get changes in the heart conduction which puts them at higher risk for death (again, this was thought to be mediated via selenium deficiency).  Valproic acid + ketogenic diet seemed to worsen the side effects (6).  Now some of these ketogenic diet studies were done at the height of the low-fat era, and likely designed by some pretty lipophobic nutritionists.  And, like Atkins, many of the original ketogenic diets will have no regard for the omega6:omega3 ratio.  Here's a case where Atkins made manic psychosis a lot worse - I wonder about that, as arachadonic acid (omega 6 metabolite) administration has also been shown to worsen psychosis.  In that case, the patient was on valproic acid also, and that may have been part of the problem.  A natural sort of ketogenic diet (think Inuit) would probably have a lot fewer of these complications and side effects.

But it makes you think, doesn't it?  Many of our ancestors probably spent many a winter in ketosis, and other times lack of food or long fasts would have brought on brief periods of ketone body use in the brain too.   Maybe our brains work better if we spend time in ketosis.  Speculation, of course, but not an unimportant question to research further.


  1. I AGREE with your conclusion. i dont think we shoudl live day in and day out in ketosis but theres no denying there were spans of seasonal ketosis induced in evolution. i wonder if they also suffered the BS swings, headaches etc that many people who go keto experience?
    also the side effects yo quote:

    "Ketogenic diets can have pretty bad side effects - constipation, menstrual irregularities, elevated serum cholesterol (if you care) and triglycerides (not good), hemolytic anemia, elevated liver enzymes, kidney stones, and gall stones. "

    is that with people eating real food or the 'typical' atkins keto with veg oil, mayo, bacon etc?

  2. I tend to think that for the most part people were essentially keto adapted at all times. Three square meals a day just aren't happening all that often, even in the summer. And the side effects of not being in ketosis when your blood sugar starts to dip are too severe to be managed with any kind of regularity. Could you imagine trying to go out and find food when you're experiencing the headaches, dizziness, stomach pains, etc that you get when you don't eat for 5 hours in glucose metabolism?

    It is my opinion that glucose metabolism is designed for times of famine, where having the ability to eat plants and convert over to glucose metabolism could prove to be a reproductive advantage over your peers. Fat metabolism is the default, not the backup.

    So yea, I find it hard to imagine that a low carb paleo diet, inducing ketosis, would not cure bipolar disorder. Ketone bodies should show up in the urine, and it may take more than a month, but I'd be very surprised if a proper very low carb paleo diet, high in fat, of real foods didn't work as a cure for anyone over the long term.

  3. Malpaz - I'm planning on looking more closely at the selenium angle when I get a chance, but I'm pretty sure they were more typical Atkins or something else, certainly not paleo ketogenic, or even Mediterranean ketogenic, which I think would be very similar to paleo.

  4. Geoff - I once participated in a discussion about Good Calories, Bad Calories on a doctor's internet forum. The whole book was summarily shot down on so many levels (as was the evolutionary perspective that underlies the book, though Taubes hadn't made the leap 100%), all by people who had obviously never read it and wouldn't care to. And shot down with disdain and vehemence. I knew then and there that it would take systematic, exhaustive, irrefutable research-based arguments and questions to ever get doctors to think about a new perspective and start helping humans out instead of medicating us so we die more slowly.

    So here I am.

    I have a mixed opinion about how much of our evolutionary history we spent in ketosis. There are HG groups that are pretty much 100% ketosis all the time, and others that would never be in ketosis, and at least physically, they seem perfectly healthy.

  5. Dr. Deans, I am delighted with your blog, and this article is of particular interest to me: I hesitate to mention this, since people (even professionals) often cease to take one seriously, but here goes: I am bipolar I.

    Here's my anecdote: this time last year, I was 100+ pounds overweight, with blood sugars just under pre-diabetic, sky-high triglycerides, no energy, on seroquel as my main mood stabilizer (at 52, I now tend more to mania than depression).

    I went on Chellam's "pre-diabetes" eating plan (no starches, lots of plants, lean meats) and lost 113 lbs. (I've gained a few pounds back, but of muscle--I go to the gym these days). Mood stabilization is vastly improved (family, friends shocked at the change), and co-morbid conditions (panic disorder, OCD, also Asperger's-to-high-functioning autistic) have greatly improved as well, so much so that my psychiatrist has put me on a subclinical dosage of the seroquel, and has cut my alprazolam XR by 1/3rd.

    Interestingly enough, Chellam's "pre-diabetes" eating plan is very "paleo." I feel even better these days, because I'm adding in more saturated fats, and taking cod liver oil. Something's happening. Most of my life has been of the "troubled with so much potential" variety; now, I actually have a life.

    Hope I'm not gushing too much. It's just that the change has been night and day for me. I'm wondering how many psychiatric conditions are caused (or at least exacerbated) by what amounts to our overfed malnutrition?

    Thanks for reading. I've subscribed to your feed.


  6. "GABA... is increased in the brain in ketogenic diets"

    This makes sense with my observations on taking GABA and it being less effective since being on a more paleo diet. I checked with my mate who also takes it on occasion and he said he didn't think it had been as effective since switching to a high fat diet.

    So, is GABA increased on a high fat diet, or is it just normalised? And if we accept that GABA normalises on a high fat diet, what is it about a low fat, high carb diet that decreases GABA and potentially increases anxiety levels in some?

  7. You know, I asked Stephan Guyenet if he knew anything from his emails with Staffan Lindeberg about the mental state of the Kitavans. He said they were preoccupied with worries about evil spirits. Now there are many cultural and sociological issues that would impact the mental health of a particular culture. But the Kitavans are the high carb paleo example. And apparently on the anxious side. Hmmm.

  8. Mark, I'm so glad you are doing so much better. Needless to say I think an evolutionary-style diet will help everything from tooth decay to gout to gray hair, and the more anecdotes (positive are great, but even the negative ones would obviously be important!), the better.

  9. Well, I'll add my comments to Mark's and make the sample size n=2 :).

    After I went very low carb (for weight loss; I was 220 pounds and desperate) in 2007 I found I was able to stop taking both Celexa and Depakote within about four months' time. I backed off the meds very slowly, after noticing that my moods seemed much more stable eating low-carb. The only backslide I experienced was a brief period when I re-introduced bread into my diet (I tried Kwasniewski's Optimal Diet for a while), and noticed a very quick return of depressive symptoms: crying jags, extreme fatigue, and persistent feelings of hopelessness. Switching from bread to potatoes relieved the symptoms somewhat, but not completely. After I returned to very-low-carb eating, I found my moods were once again stable and positive.

    A skeptic might say the symptoms were caused by the swift regaining of weight I experienced on the Optimal diet, but my own records show that my daily weight was unstable by several pounds for over a year and a half on VLC--before the Optimal diet experiment--and my moods didn't fluctuate with the scale then.

    This is a great blog, by the way. I've subscribed to your feed and am getting a lot out of your posts.

  10. What lowers GABA on carbs? My hunch is, glutamate. Gluten, for example, elevates serum glutamate sharply. It's likely that insulin does too. Glutamate and GABA are antagonists.
    Side effects of ketogenic diets?
    The high-fat ketogenic diet given to kids is too low in protein. Also, it's likely that trans-fats were used (it was designed, like basic Atkins, in the days of phobia about saturated fats). Hence the elevated LDL and lowered HDL - that's an effect of trans fats, not of natural fat or ketosis. Saturated fat protects the liver from alcoholic liver disease (vide Esteban Mezey); PUFAs and rabs fats would have amplified any pro-oxidant effect of the drugs (most, perhaps all kids on ketogenic diets in the situdies were still on some drugs; valproate causes selenium deficiency).
    As well as medium chain triglycerides, branched-chain amino acids produce ketone bodies and help to advance ketosis.
    BTW, ever tried niacinamide for bipolar? It's my treatment of choice for cyclothymia. Niacinamide increases sensitivity to GABA, to an extent comparable to diazepam, and normalises serotonin by preventing tryptophan degredation.

  11. I've never tried niacinamide for bipolar but I'll definitely investigate the mechanisms more closely. Thanks!

  12. Dr Abram Hoffer did a lot of early work on using niacin in psychiatry. He is a psychiatrist with a PhD in biochemistry.

  13. Thanks the information ... your article really great, because the contents of the article is very complete and that I had been looking directly related to neurotransmitters, neurotransmitters disease, and type-species such as dopamine, serotonin, glutamic acid, amino acids, aromatic L-amino acids, GABA and others. I am very pleased to visit your blog and would often visit.

  14. Thank you so much for this article!

    I was diagnosed with bipolar, anxiety disorder and due to weight gain (now 238lbs), diabetic.

    I have been severely limiting my carb intake, adding water, exercise, more fruits and fresh vegetables (via juicing/salads) in order to lose excess weight. I lost 4lbs in my first week. The first few days were difficult but I started to feel good, so I continued. The past 2 days have been a nightmare.

    My anxiety is out of control and my mood swings are off the charts. Even my cat refuses to come near me. I am starting to scare myself. On a whim, I searched for "low carb diet side effects on bipolar disorder" and came across your article. I am going to eat a PB&J sandwich before I go to bed and rest easy knowing that although I may be fat, I am not losing my mind.

    Thank you so much for your help!

  15. Whoknew - I think you might have run into what is called the "low carb flu" - a period of transition from being a glucose burner to being a fat-burner. It usually lasts a week or two at the most, which is a week or two too much is anxiety and mood swings are a problem, I would think. I was able to transition to a low carb eating pattern quite gradually, and I personally did not experience any low carb flu. At first I continued with starchy carbs for one meal a day. Of course with your diabetes you would need to keep a very close eye on your blood glucose and talk to your personal physician about adjusting your medications accordingly. In my case I have been able to drop to VLC days and even fasting without much change in mood or cravings as long as I eat enough. However, I still probably average a piece of fruit and a starchy carb or just a starchy carb daily (usually potatoes or sweet potatoes, but sometimes white rice or squash or turnips, those sorts of things). However, I am not trying to lose a lot of weight and my glucose is on the hypo-side rather than hyper.

    I think if I have anything solid to bring out of this blog, it is that there is mucho evidence that what we consume can have a huge effect on our brains. Food can be medicine or it can be anti-nutrients. Any transitions might bring out psychiatric symptoms, and if your brain is telling you "no way!" give it a rest and try things a little differently.

  16. Dear Dr. Deans,

    I am going to be MUCH more careful in the future about changing my eating habits. Now that I know what I am up against, it may be a little more difficult, but at the very least, I know what I am working with and against. Thank you again for your help!

    By the way, the PB&J sandwich was delicious and I felt soooooooooo much better!

  17. Dr Deans

    I can't tell you how delighted I am to stumble upon your blog and would like to add my n=1 experience for you.

    My history - my paternal grandmother was as diagnosed manic depressive 40 years (died in the late 70s) was unsuccessfully treated through that time including with electric shock treatments which she used to beg to be excused from (unsuccessfully alas). She was a type two diabetic later in life (probably earlier than ever recognised by the medics who saw her as a pyschiatric case rather than medical), her mother was injecting insulin diabetic.

    Her weight fluctuated massively over the years according to her bipolar state and she died aged 56 from heart issues due to the poorly control diabetes. She was post-natally severely depressed and hospitalized on both occasions. She was sectioned many times during her life.

    I have struggled with massive mood swings since my teens (now nearly 44) but in a high functioning way, become post-natally depressed after baby number 1 who was born 5 weeks early and big for term and hypo'd (I realise that now looking back with my new found knowledge).

    Pregnancy number 2 (this is 20 years ago in the UK) and a very switched on obstestrican looked at my history and glucose tested me at 29 weeks - off the scale, diet controlled until another 35 week delivery but this time a well baby. The first, my son was fine once his little system sorted the glucose problem!

    I was a vegetarian and latterly a high carbohydrate consuming endurance athlete and struggled with the bipolar through the following 18 years till I chanced upon GCBC read it in about 3 sittings (manic don't forget LOL!). It changed my life. No, it saved my life. Taubes is my hero.

    Cut out grains and sugar cold turkey (full range of detox symptoms for 36 hours) then have never felt better. Added meat to my diet and started to follow Mark's Primal system and then noticed that I no longer had the swings. After around 9 months I was sure enough to consider myself 'cured' but had no idea how or why. continued in next post

  18. continued

    Started researching avidly in the last few months and worked out that the insulin pathways were overloaded and that affected the up and down regulation of serotonin and dopamine and hey presto it all began to fall into place.

    I'm convinced bipolar is another form of metabolic disorder which explains the high correlation between bp sufferers and obesity and diabetes, it's just another facet of the same problem.

    "2009, the medical journal Psychiatric Services published findings showing that bipolar disorder can DOUBLE your risk of early death from a range of medical conditions - including those that can be controlled through diet and exercise. Their survey showed that

    1. 35% of people with bipolar disorder are obese. This is the highest percentage for any psychiatric illness.
    2. People with bipolar disorder are 3 times more likely to develop diabetes than are members of the general population.
    3. People with bipolar disorder are 1.5 - 2 times more likely to die from conditions such as heart disease, diabetes and stroke."

    I can't tell you what a relief it is to know it was a simple bio chemical imbalance from an inappropriate diet rather than my lack of will power or self control that many had me believe.

    Clearing the mental fog of bipolar has been extraordinary.

    This is the link that really convinced me and really made me see so many modern problems all flow for this same issue.

    'The One True Path' Jennifer Walsh

    So, I move in and out of ketosis I think, I eat about 60% from fat, 30% or so from protein and the balance is carbs from vegetables, some nuts, a little in the beef and very limited fruit - fruit does a number on me if I have much - that's down to the fructose and something going on in the liver but that's a whole other post! I feel most alive and clear headed when fasted.

    Hope this adds to your database and more power to you!

    Kelda Spratt

  19. I love your blog! Very interesting stuff with lots of people posting thoughtful comments.

    I'm curious too about the connection between thyroid disorders and bipolar. I have Hashimoto's Thryoiditis and Bipolar II. Makes sense in the metabolic scheme of things but I'm not really sure why. The Hashimoto's first manifested as Hypo, but--I swear--sometimes I get hyper with heart palpitations, anxiety, and dysphoria. This almost always happens in hot, humid weather. Last August was terrible (over 100 and extremely humid here in Maryland).

    Also, a somewhat unrelated question: I've heard over and over that Vitamin B is good for mood, but whenever I take it, I get very agitated, anxious, and have to stop within one day. What's with that?

  20. I realize this is an old-ish blog post, but I wanted to comment on this part:

    "The patient fasted for 48 hours and began what is described as a "classic" ketogenic diet for two weeks. Oddly, she didn't have any urinary ketones. After two weeks, the doctors added MCT oil (coconut maybe? It doesn't specify), which low-carbers will also know can induce a more reliable ketogenic state."

    Aren't ketones in urine only indicative of overproduction of ketones?

    It seems that when people get into ketogenesis for a while -- time length hugely variable by individual -- ketone production becomes more efficient and doesn't show in the urine.

  21. I am a 49 yr old woman, BP2 (mostly manic), with primary Cushings Disease (pituitary tumor), a adrenal tumor, and Hashimoto's thyroiditis (thank you menopause yet). Oh yes, all of the above also resulted in causing a benign LBBB-the heart is whacked out-with NO INFARCTION. I don't know if I actually go into ketosis, but when I spend time on a healty low carb diet (vegies, meat, low fat cheese, olive oil) everything balances, I sleep, and I don't spin out (mania turns into personality-per my loved ones). I stopped the BP meds-yuck!-but I take 20 mg of Celexa, 50 mcg of levothryroxine, and 50 mg of Aldactone. Emily, I don't know where you are now or what you are doing, but thank you for writing this post back in 2010. I have spent time experimenting on myself and looking at the whoe serotonin, dopamine, acetylcholine, GABA lack of balance and how it affects my own personality.

  22. I'm curious if whether Sodium is actually harmful to someone that has OCD as I notice a huge change if I uptake my sodium levels and how bad my ocd is the following hour/night.
    I'm on a ketosis as grains and carbs have been shown (in separate analyses) to have huge effects negatively on the brain.
    I feel great on ketosis when I exclude as much sodium as possible.
    Almost feel cured.

  23. Great post and comments. I've had the diagnosis of BP 1 with comorbidity. I'm also autoimmune with Lyme disease and a history of seizures. I follow a strict paleo diet and recently transitioned into ketosis. No more seizures, much less brain fog, and my health has really improved around the autoimmune issues.

    However, my sleep is still inadequate and inconsistent. I've been feeling wired and irritable. I've had a flux of creative ideas that can be overwhelming. It had been a long time since I'd had this symptoms, as I'd stabilized on a whole foods diet, but now I'm thinking "oh yeah, this could be mania!"

    I'm wondering if this is part of the transition period for me. It seems ketosis helps many and I've also read the article about the man who had a psychotic relapse on VLC.

    I've definitely lost my sense of grounded calm. I'm fidgety and rushed feeling. Perhaps it's the degree of ketosis that matters. I wanted to share my experience with this diet. I've been medication free for years, use high MTC oils, current macros: 12% carb, 14% protein, 74% fat. I require electrolyte supplementation and am starting to experience gallbladder congestion. I'm working closing with my doctors.

    I hope adding my experience helps.


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