Carbs and Serotonin, A Connection After All?

A few weeks ago in Do Carbs Keep You Sane, I reported from a couple papers that disagreed with the textbook theory that a high carb, low protein and low fat diet would increase tryptophan in the brain.  The Wurtmans from MIT have designed a whole pharmacologic diet around this theory, so it was interesting to read the rebuttal, especially since the rebuttal included data from Dr. Judith Wurtman's own papers.

In short, the theory goes that carbohydrate ingestion stimulates insulin production, which in turn causes protein to be driven out of the bloodstream and into the cells.  Tryptophan, the rarest amino acid in the diet and the precursor for serotonin, is mostly bound in the blood to another protein called albumin, which makes it immune to insulin's effects.  Therefore a carb bolus will increase the ratio of tryptophan to other amino acids competing for the same receptor, tryptophan shoots into the brain, and you get a nice hit of satiating, serenity-making serotonin.

If we follow the lines of this theory, a high protein diet will increase the amount of other amino acids and increase the competition for the receptor, leaving tryptophan a loser and the brain relatively "low" in serotonin.  Fat in the diet will also delay gastric emptying and lower the overall glycemic index, lowering the insulin response and therefore reducing the insulin mechanism for driving tryptophan into the brain.  Pretty simple.

Except in nutrition, nothing is ever simple.  Turns out this mechanism works a bit differently in rodents than in humans or other primates, and any natural food and even flour and potatoes should have too much protein for it to work in humans.  You can get this effect after a night's fast by eating or drinking something that is pure carbohydrate - such as marshmallows or lemonade.  Not exactly an evolutionary model.  In fact, in the primate models, the amount of tryptophan that made it into the brain depended on a higher amount of protein, not a lower amount with higher carbs.

But Mr. Jamie Scott sent me the Pubmed link for this paper a few weeks ago, and I certainly don't like to ignore papers, even if they tell a different story than the majority of the papers I had seen thus far:

High glycaemic index and glycaemic load meals increase the availability of tryptophan in healthy volunteers

Interesting study.  10 healthy human male university student volunteers are given several diets of varying macronutrient composition on different days.  The first meal was a high GI meal consisting of 768 calories of jasmine rise and a tomato pureee - this meal was 1.6% fat, 8% protein, and 90.4% carbohydrate.  The glycemic index of the meal was 117 and the glycemic load 200.  That's 171 grams of carbohydrate, in case you were wondering.  The other two "mixed macronutrient" meals served were lower in calories (about 457 each) of either a lower glycemic rice + or a high glycemic rice with a Lean Cuisine chicken.  (I kid you not).  The latter two meals were about 16% fat, 18% protein, and 66% carbohydrate give or take a rounding up or down, and each meal had 75 grams of carbohydrate.

(Okay, another hysterical sentence in this paper - each volunteer was tested with a standardized glucose drink to calculate glucose and insulin response to the different meals - the standard was the 75 grams of glucose bolus, and the figures were extrapolated to estimate the response to the 171 grams of carbohydrate meal because "it was considered unethical to give a glucose reference drink of 171.4g CHO.")

The results?  The young men found the two mixed macronutrient meals palatable, whereas the (double calorie) high carb, high GI meal was more satiating, but less palatable.  Sleepiness did not differ when measured immediately after the meal.

Only seven of the participants participated in all the blood draws, so only seven data sets were used for comparison of the ratio of tryptophan (TRY) to other "large neutral" amino acids (LNAA) in the study.  At baseline (which was fasting), the ratio did not differ between the subjects.  After the high carbohydrate, high GI meal, TRY:LNAA ratios increased by 23% and remained high for the next 8 hours.  The Lean Cuisine folks with the low GI rice had an increase in TRY:LNAA of about 8%, and the high GI Lean Cuisine folks had an increase in TRY:LNAA of 17%.

The high carbohydrate bolus in several studies brings out robust high insulin responses - several hundredfold percentage increases over baseline (in this study the increase in insulin was 650% over baseline).  In another study, plasma platelet serotonin levels were increased 3.5 fold after a similar high carb meal.  Of course, high amounts of serotonin floating around in your periphery may not be exactly good for you - it is thought the high levels of serotonin caused by the diet drug combination fen-phen caused the aortic calcification risk from those drugs and possibly the risk of increased pulmonary hypertension.

In other studies, there are interesting implications.  Recall that serotonin is the precursor for melatonin - in this rather recent study, a high carbohydrate, high GI meal (high GI rice, very very low fat) four hours before bedtime decreased sleep onset by 50% compared to those who consumed a low GI rice meal (also very low fat).

So it looks that you can increase tryptophan ratios in the periphery with high glycemic index meals, even with a more realistic macronutrient mix than jasmine rice and tomato puree.  Presumably this may increase tryptophan intake into the brain.  Tryptophan has several fates in the brain, serotonin being one, kynurenic another depending upon your state of inflammation and what drugs you may be on.  Once again we have one fragment of a hugely complex picture.

And, since this mechanism depends on insulin, if one is contending that a high carb "serotonin cure" diet is helpful for depression, one must take into account that people with severe hyperinsulinemia are more likely to be depressed than people without, not less (though there are other confounding factors - since inflammation is one, the high carb diet in an (inflamed) type II diabetic might lead to increases in kynurenic rather than serotonin, explaining the diffference… but you see there is way too much unknown to make any general prescription for high carb diets in this context.)