The problem with mucking about with our biochemistry is that we are never really sure what is going to happen. For most nutrients and chemicals there are a range of acceptable amounts, though the best range may depend upon levels of something else (zinc in toxic amounts can interfere with the absorption of copper with fatal consequences, for example).
Serotonin, made in our body, 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 such as Prozac), the body starts changing the number of serotonin post-synaptic receptors. Homeostasis in a nutshell.
But what is serotonin? Where does it come from, and how did we evolve to have it? Turns out that serotonin is nearly as old as the hills, and some of the simplest life forms have similar chemicals playing an important role in their biochemistry. Serotonin comes from a line of molecules who give off energy derived from the sun (1).
On planet Earth, much of the business of life occurs with chemical reactions driven by sunlight. The very first photosynthetic reactions occured with a molecule known as an "indole":
It's not obvious, but that molecule has lots of electrons whizzing around, and the atom at position "3" is extremely reactive and will lose electrons very easily. Add light to specific types of indoles, and energy will be created as hydrogen is released. It is theorized that this reaction first occurred on Earth 3 billion years ago. This energetic reaction was the beginning of light-based life.
Tryptophan is the dietary amino acid (protein) we must eat in order to make serotonin, and tryptophan also happens to be an indole. It is the most fluorescent amino acid under blacklight. Tryptophan absorbs light energy, and is a vital amino acid for photosynthesis in sea bacteria, algae, and plants. The process of photosynthesis creates oxygen from water, using the energy from the electrons whizzing around on tryptophan, among other things. This creation of oxygen by photosynthesis changed our planet's atmosphere and made our lives possible.
Plants evolved a specific energy factory within their cells called a chloroplast, whose function is to capture light for energy, and to create tryptophan. Chloroplasts are where chlorophyll lives. Tryptophan is also made in all primitive unicellular organisms and plant systems. Animals (like humans) do not make tryptophan and must obtain it through diet. The best source for humans is from the meat of other animals, though it can be difficult to get enough tryptophan into the brain, as it is the least abundant amino acid in muscle tissue, and it has to compete with all the other more abundant aromatic amino acids for the aromatic amino acid transporter. Everyone is waiting in the lobby for the elevator, and only a few can ride to the top at a time (remember this bit, as it we will come back to it shortly).
Serotonin is made from tryptophan only in mast cells and neurons. However, cells in every single organ have special uptake proteins to capture circulating serotonin from the blood.
Other molecules derived from tryptophan include melatonin (important in the sleep-wake cycle), psilocybin (the active molecule in psychogenic mushrooms), ergotamine, yohimbine (a traditional aphrodisiac), and LSD. Most of these compounds are active in the human brain because they can stimulate the serotonin receptor. A tryptophan-based compound called auxin affects cell growth in plants, enabling shoots and leaves to extend out towards the light.
In order to make serotonin, tryptophan has to go through a couple of enzymatic reactions. First, tryptophan hyrodxylase makes tryptophan into 5-HTP. Then another enzyme (using vitamin B6 and zinc) makes 5-HTP into serotonin. Serotonin is eventually degraded by MAO.
Tryptophan hydroxylase may be the oldest enzyme to attach oxygen to other molecules. Since oxygen is generally quite reactive and toxic biochemically, this was an early way to safely get rid of excess oxygen created by photosythesis in primitive organisms. The light receptors in the human (and other animal) retina are very similar to serotonin receptors and were first thought to evolve a billion years ago. Serotonin is the oldest neurotransmitter, and the original antioxidant. There are 20 different serotonin receptors in the human brain, and serotonin receptors are found in all animals, even sea urchins.
In other animals, serotonin is involved in swimming, stinging, feeding modulation, maturation, and social interaction. In general, it is thought of as a growth factor for animal brains. In humans, deficiency of serotonin is implicated in autism, Down's syndrome, anorexia, anxiety, depression, aggression, alcoholism, and seasonal affective disorder. Light therapy and serotonin-increasing medications are both effective treatments for depression that occurs with low levels of sunlight. Light exposure increases serotonin in humans, and serotonin levels are lowest in midwinter, and higher on bright days no matter what time of year. 10,000 lux light therapy decreases suicidal ideation in some folks.
Tryptophan is an important amino acid, most readily available from animal sources (vegetable sources such as pumpkin seeds contain phytic acid which may inhibit its absorption), and its many important derivative molecules work best with plenty of sunlight. Think of it as your own little bit of photosynthesis.
In the past several years, we have learned a bit more about the natural rhythms of serotonin, specifically the summer/winter variation. Meyer's group in Canada used a PET scan on 88 healthy drug-naive individuals, and found that levels of 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. (In the introduction to Jackson's classic textbook Melancholia and Depression, one will find that in the time of Hippocrates, 5th century B.C., melancholia was associated with black bile, autumn, and cold/dry weather).
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 eating more 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. Serotonin, the precursor for the sleep hormone melatonin, might not be needed quite as much in the winter time, when there is less light. These are guesses, really, but there must be a good reason.
There is also a carbohydrate/protein signal for serotonin. The actual mechanism is messy, but let's give it a whirl (2):
Once again, 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.
Then 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 on mood, whereas others show sugar and carbohydrate consumption having quite a robust effect on aggression and mood (3). There is also a rather infamous study of people on very low carb diets having more depression after a year than people on low fat diets - but the low carb diet group started off with twice as many people who were on antidepressant medication.
Seasonal variation, sunlight, sugar, and suicide - all linked somehow to serotonin. It seems to me that humans have thrived on all sorts of diets - from the high-fat Inuit (lots of periods of low light there!) to the high carbohydrate Kitavans. What those diets have in common is lots of real, nutrient-rich food, no processed food, no vegetable oils, and lots of fish. And while the Kitavans eat a lot of carbohydrate in the form of starchy vegetables, they don't eat much sugar. As far as I'm concerned, the jury is still out as to what macronutrient composition is absolutely optimal - it could be different season by season or person by person, if it matters at all. The most important thing is to get enough of all the raw building blocks. That is much easier to do if you avoid eating the junk.
Here's to health, sunlight, and serotonin.
A special thanks to paleo blogger Jamie Scott for links to many of the sources in this article.
More articles like this one at Evolutionary Psychiatry
Copyright Emily Deans, M.D.