The problem with mucking about with our biochemistry is that you are never really sure what exactly is going to happen. For most substances there is a a range of acceptable amounts, though the best range may depend upon levels of something else (zinc and copper, for example, or vitamin D3 and A and K2).
Serotonin is a tricky one to figure out. Too high, and we get confusion, high blood pressure, and possibly even psychosis, aggression, stroke and death. Too low, and we get anxiety, violence, suicide, and insomnia. It is obviously important to keep the brain levels within a nice healthy range, and the moment we start changing things up (as with an SSRI like Prozac), the body starts changing the number of serotonin post-synaptic receptors. Homeostasis in a nutshell.
But serotonin has some natural rhythms that could be useful to understand. First off, there is a definite summer/winter variation. Meyer's group in Canada used a PET scan on 88 healthy drug-naive individuals, and found that the serotonin transporter that shuttles serotonin out of the brain was highest during the winter, and lowest during the summer. The researchers felt that the most likely brain trigger to explain the variation was sunlight, though humidity also seemed to play a role (1). (Just reading the introduction to Jackson's Melancholia and Depression, and in the time of Hippocrates, 5th century B.C., melancholia was associated with black bile, autumn, and cold/dry weather).
Here in the northeastern US, there has already been a noticeable decrease in daylight compared to midsummer (humph. Back in Texas we would just be settling in for our second three months of summer). And, sure enough, the number of unhappy phone calls to my office has increased accordingly. This happens every single fall and spring with the changing light.
Why would our brains shuttle serotonin out for the winter? I don't know. Maybe it has to do with seasonal variations in food supply. Serotonin also signals satiety - perhaps we were better off eat more than we ought in the winter when we could get our hands on food, and it wasn't such an issue in the summer when food was likely more abundant. That's a wild guess, really. But I'm sure there's a reason.
There is also a carbohydrate/protein signal for serotonin. The actual mechanism is messy, but let's give it a whirl (2 - Thanks for the link, Jamie!).
If you recall, tryptophan is the dietary amino acid we need to make serotonin. The best source is meat, but when we eat meat, we get a mix of all kinds of amino acids, and since tryptophan is the least abundant, when it competes with all the other proteins for admission into the brain, it tends to lose out. So a high protein, low carbohydrate meal will leave your plasma full of tryptophan but your brain a little low.
Until you add some carbohydrate. Here's the messy part. Unlike some other amino acids, tryptophan is mostly carried around in the blood by another protein, albumin. Eat carbs - insulin is triggered, and proteins are taken out of the blood and pulled into the muscle. Except the mostly-bound tryptophan is immune to insulin's siren call. And the brain transporter for tryptophan doesn't care if tryptophan is bound to albumin or floating free. All the sudden, there is more tryptophan hanging out in the blood compared to the other amino acids, and tryptophan is first in line into the brain for once. From there, it is made into serotonin, and we feel good and relaxed and full and sleepy, at least for a couple of hours until the signal shuts off. Then we crave more carbohydrate.
So what does it all mean? Rob Faigin and others have postulated that having obscene amounts of sugar and carbohydrate over long periods of time can max out our serotonin machinery, leaving us unhappy, carb-craving, and depressed. Anti-low carb diet folks will claim that without carbohydrates, we will not get tryptophan into the brain and we will be depressed. Data has been mixed, with some studies showing high amounts of long term sugar consumption having no effect, some having quite a robust effect on aggression and mood, and there is also the rather infamous study of low carb diets showing more depression after two years (though the low carb diet group started off with twice as many people who were on antidepressant medication).
Some people try to bypass the whole thing and take 5-HTP, which is the immediate precursor to serotonin and can get into the brain pretty easily without the tryptophan insulin shenanigans. A couple of food-mood books recommend this strategy, others are against it - there have been only two acceptable trials of 5-HTP and the results were mixed. 5-HTP is not found in the food supply, so it may be safer to take l-tryptophan itself (it was banned in the US in 1990 due to contamination in the Japanese chemical plant that made it). 5-HTP should not be combined with migraine or antidepressant medication, or with too much vitamin B6. If you have a lot of vitamin B6 and supernatural amounts of 5-HTP in the liver, you can manufacture quite a bit of serotonin to be released into the bloodstream, and you risk giving yourself the symptoms of carcinoid syndrome. (Carcinoids are serotonin-secreting tumors and give you flushing, high blood pressure, and valve calcification. Phen-fen was a serotonin- related medicine too). Serotonin in the periphery cannot get into the brain - only 5-HTP and tryptophan can get into the brain.
Confused yet? Wait until you hear that there are seven subfamilies of serotonin receptors, with subtypes of each subfamily, all of which can be up or down-regulated depending on circumstance.
At the risk of being a hypocrite after yesterday's post, I do take some supplements myself. All are designed to more closely mimic an evolutionary milieu of nutrient-rich food and plenty of sunlight. In that vein I take vitamin D3, a mineral/multivitamin, omega 3 capsules depending on my food for the day, and extra magnesium, as the one issue I had with primal eating was cramps in my feet. Ouch! I haven't yet developed a taste for organ meats, which leaves me needing the multi and minerals, I'm sure. Now this is not what you should take, it is only what I take. Aside from those, I rely on food (grass fed beef, wild-caught Alaskan salmon, pastured or omega 3 eggs, organic poultry, pastured butter, ghee, extra virgin olive oil, coconut milk and oil, some fruit, and tons of vegetables from the local farm. Oh, and some macademia nuts, or the rare Larabar.) Some special paleo mironutrient extras include a sprinkle of dulse or kelp, and Celtic salt. Again - that is, for the most part, what I eat. You eat whatever you want :)
Thanks Emily! Even more clarification on a complicated topic. Will update my recent post to link to yours!ReplyDelete
Whilst I sympathise with you losing your light, it does mean that here at 45deg S, we are gaining light! Woohoo!!
I have tried 5HTP in the past - didn't do much for me that I noticed. And in those friends and clients who have tried it, they have all been female. This raises some questions in itself. Is this related to your previous post on women being more affected by the fructose malabsorption-related depression? Or could women be more prone to placebo-effect?
My supplement regime is similar to yours (NB: what I have figured out works personally for me and not for copycats to do just cos that's what a nutritionist prescribes himself). I take fish oil and vitamin D, iodine & selenium (NZ soils are very low in these minerals), and zinc and magnesium. Food-wise is easy - free range organic eggs, free range gluten free bacon, nuts such as almonds, pecans, and cashews, fruit of most kinds, lots of vegetables, New Zealand beef & lamb (which is all grassfed) (still coming to grips with organ meat myself - can do hearts and that's about it), I keep my carbs up when need be with yams, sweet potato, pumpkin, etc, and I use olive oil, coconut oil, and NZ butter as my main added fats. One thing I have done since going primal is to eat less fish. I am less concerned regarding omega-3 intake having cut down on omega-6 and I am very concerned regarding over-fishing (though most of NZ salmon is sustainably farmed in sea pens (not perfect, but better than other farming types).
Here's some more nitty gritty for the interested - 5-HTP comes in to the enzymatic pathway at the same place levodopa does, a treatment for parkinsons. They use the same aromatic amino acid decarboxylase enzyme (with B6) to become dopamine or serotonin. But ask any doctor if he/she would prescribe just levodopa - and he/she would say, no way, that would be a waste. Levodopa is almost always prescribed with carbidopa, a decarboxylase inhibitor in the periphery that is not absorbed into the CNS. Also, if you are on levodopa/carbidopa, you should be advised not to go whole hog on vitamin b6 for the same reason - dopamine can't get through the blood brain barrier either, just like serotonin. Theoretically you could prescribe carbidopa with 5-htp, but except in case of absolute tryptophan deficiency (anorexia, malnourishment, low stomach acid people (I'm going to look more into this), perhaps vegans, speculating more here but fructose malabsorbers eating fructose and fructans), adding more serotonin precursors to the picture may not help. Tryptophan can just as easily be made into kyurnetic, the inflammatory agent of doom in the brain. SSRIs intervene far enough along the pathway that they favor serotonin over kyurnetic, which may be the only reason they work. It's all about the BDNF,really, probably not the serotonin for most. I've been having some fun with serotonin, though, blogwise the last few days!ReplyDelete
Emily, another nice week of posts.ReplyDelete
do you track calls related to depression? just curious.
speaking of organ meats, just bought a beef heart to cook up for tuesday. Jennifer is not for it yet. me, love the stuff. all organs, any animal. was thinking that what i need to do is go out hunting and get me some fresh marrow.
this reminds me that when i order my 1/4 steer today i need to ask the rancher for all of the organs. yummy.
and lastly, i'm sure we'll have some serotonin syndrome in the icu this week. almost every time i attend i get one, usually a suicide attempt. good learning for the residents though. pretty boring for me anymore. never have understood taking all your psych pills in one go though.
keep up the good work as your blog gives me fun reading in the afternoon post rounds, before writing my notes.
Jamie - your placebo comment reminded me of a recent paper on borderline personality disorder and opiate dysregulation - I'm going to have to pull that out and do a post. Cool. Love the tag-team blogging!ReplyDelete
Dan - always good to hear from you on the front lines. Maybe one day we'll all get together and have some awful offal. Any plans to go to Aaron Blaisdell's evo med conference in August of '11? Looks like everyone who is anyone paleo will be there. Tell Jen I said hi!
Re: organ meatsReplyDelete
Emily, gah! I don't like them either! But, this is what has been working for us----I buy healthy grass fed beef liver, frozen. I slice it with a sharp knife when it is still firm and mostly frozen, into quarter to half inch thick slices. Those slices get portioned into bags and frozen.
When I made a dish conducive to hiding liver in it, I take out a bag, dice it into small pieces while it is still firm and mix it into whatever I'm making. It works great in seasoned dishes like chili, meatballs, meatzah, stews, taco meat, etc.
Easy, and no bad flashbacks of being forced to eat liver, straight, as a kid!
haha i love organ meats...all of them, absolutely my favorite over even bacon and chicken wings! this serotonin stuff is so interesting!!!!!!!! i take the same supplements. vita D, magnesium and fish oil. i try to KISS!ReplyDelete
the part about the protein having tryptophan and attaching to carb to enter the brain, hmm. our bodies are so incredibly complex. is there not serotonin relation with fat intake?
Obviously the mechanisms are pretty complicated, but I don't think that the dietary solutions are. They can't be. I don't know too much about this stuff, but I have a couple possible theories.ReplyDelete
In researching this stuff myself, the most compelling information (to me) is the anthropological data from Weston Price, Stefannson and others, which I read as saying that a diet composed of 90+% fatty meat (by calories) leads to perfect health. So I tend to look at everything through that lens. As such, I find it pretty impossible to believe that on such a diet tryptophan can't make it into the brain.
I've only recently found your blog, so I'm still digging through it, but I've always thought (though I don't quite remember where I got this idea) that at least part of the problem is the fat composition of the synapse. Could this be a contributing factor that is missed in this research? In other words, if someone is eating a high protein, low carb, low fat diet, could the problem be a lack of fat?
Excess protein in the diet gets converted to glucose via glyconeogenesis. I used to think this only occurred on an as needed basis, but in reading some of the recent stuff from Lex of the raw paleo forum, I'm not so sure anymore. If someone is eating a high protein diet, maybe it's having the same carbohydrate effect as a high carb diet.
The third possibility is that when your body is in ketosis some of these processes change and the brain's update of tryptophan is able to occur again by some alternative (and likely more efficient) mechanism. If someone's eating just enough carbohydrate to stay out of ketosis, I'd imagine it'd be enough to enable this brain uptake.
Hi Geoff - I agree - the brain is 60% fat so the change from omega 3 to omega 6 in the diet is huge, not to mention artificially lowering cholesterol may not be smart when it comes to the synapse. I discuss a lot of that throughout the blog. Here are a couple of posts that deal with cholesterol more explicitly:ReplyDelete
I agree with you - I consider a carefully researched evolutionary style diet to be a safe fall-back position, using the knowledge that other healthy cultures ate that way and thrived. From there we can figure out what neolithic, practical things are safe and good for us, and what paleo things might not be so good.
I'm not sure how important the carb/serotonin thing is. I'm not aware of any relationship with fat, Malpaz, but I'll look that up explicitly. I do know that our ancestors undoubtedly spent a lot of time in ketosis, and it is doubtful they all became horrifically depressed and suicidal, or else not much would be accomplished, and the babies wouldn't have been tended to, and their genes would not have been passed forward. I wonder if it is more obvious in our culture with the massive amounts of sugar. And I do tend to think it is more of an issue with some women, and perhaps diabetic men. They are the only ones who tell me they crave crave crave sweets.
Emily & GeoffReplyDelete
A Cambridge linguist is going to Northern Greenland to record language and culture; living and EATING local. I wonder will someone report on his reactions to hi-fat diet as was done with Stefansson ? I sent him a polite e-mail on that subject, but am not expecting a reply!
Let us know if he drops you a note!ReplyDelete
I am trying to figure out how important carbs are in the brain's uptake of tryptophan. Many assert that you need carbs to boost insulin, which causes peripheral uptake of amino acids and leaves albumin bound trp alone to be taken up by the brain. This makes sense, sure.
However, after looking into the insulin index of high protein foods, it looks like they also cause the release of a fair bit of insulin. At the same time, proteins cause secretion of glucagon, which raises blood sugar. A little burst of blood sugar via glucagon means more insulin, I assume. So, it seems like the combination of the insulin released in response to proteins themselves along with the sugar boost via glucagon will cue the periphery to take up amino acids. The raise in blood sugar from glucagon allows the liver to take up amino acids and turn them to glucose, while leaving albumin bound trp alone. The liver makes glucose even in the void of carb consumption.
So, if I choose to eschew grains and avoid the possible nasty effects of the weird proteins they contain, and rely on getting carbs from things like sweet potatoes, squash, carrots, etc., while eating quality meat and high fat dairy, am I really robbing my brain of a steady supply of tryptophan? I don't think so. What is your take?
A few comments from a Registered Dietician if I may! Love your explanation! On the fat note, it is important to know that fats influence the cell membrane integrity of all cell in the body so the more good, fluid, natural plant fat we include the more likely all these good things are going to be able to get into cells - remember that all this biochemistry takes place INSIDE the cell. Secondly, a comment, I have been practicing for approximately 17yrs and have taught my patients with great success the combination of carb, protein and fat in order to ensure better serotonin manufacture - I do also include Niacin as a supplement since during stress tryptophan is shunted by cortisol into a stress management pathway which uses tryptophan to make niacin to "cope"with stress and since there is limited tryphtophan relative to other amino acids in protein the effect can be a reduction in serotonin production and hence appetite increase, sleep issues, irritable bowel syndrome etc etcReplyDelete
Does sunlight boost serotonin simply by suppressing melatonin? Melatonin is created by burning serotonin. If so, can you get the same effects just by looking at an artificial light, like a computer screen, or a light therapy device? What of simply being in a room with windows.ReplyDelete
In saying that, if windows were okay then why do light therapy devices increase serotonin. Likewise there are studies that correlate the luminosity of the sun with serotonin. (3) I know you get more light through sunlight then sitting indoors, or in front of a computer. (1), (2)
Your first sentence says it all, Emily. Serotonin is a two-headed metabolite, as many are: too much is just as bad as too little. Formulation is also important, and here I am talking about the omega-3 fatty acids. In fish they occur as triglycerides (i.e., the fatty acids DHA and EPA are attached to a glycerine backbone). An article in the Proceedings of the National Academy of Sciences (http://www.pnas.org/content/early/2013/02/27/1221997110.abstract) concludes that DHA ethyl ester "antagonizes" the action of DHA and does not produce the same benefit as eating fish high in omega-3 fats. Most commercial formulations are as ethyl esters with the removal of DHA and EPA from the glycerine so they can be processed to a higher concentration. A few formulators add the DHA and EPA back to the triglyceride form.ReplyDelete