It's Thanksgiving tomorrow and the question (of the title of this post) pops up on the internets again. See SciCurious and Janet for the latest local offerings.
Short answer: we don't know.
But there is endless speculation about it, each taking into account bits and pieces of information that we know about tryptophan and related physiology. The hypotheses tend to focus on:
a) Tryptophan itself, i.e., how it can get from food, through the intestine, through the bloodstream, to the brain and what it would do once there.
b) Serotonin, as a product of tryptophan metabolism, and how it can be produced (and where - in the brain or somewhere else) and what it would do once there.
I like to post and re-post, around this time of year, the third alternative, taking into account that serotonin is precursor of melatonin, that all the enzymatic machinery needed for transformation of tryptophan to melatonin operates in the intestine itself, that melatonin (unlike tryptophan) easily crosses the blood-brain barrier, and that melatonin does have some effect on sleepiness.
The posts (see the 2005, 2006 and 2007 versions) tend to elicit a lot of comments.
I am not claiming that this hypothesis is correct, just that it co-exists with other hypotheses that are just as untested as this one. Read it under the fold:
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Well, it's Thanksgiving tomorrow night so it's time to republish this post from last year, just in time for the ageless debate: does eating turkey meat make you sleepy? Some people say Yes, some people say No, and the debate can escalate into a big fight. The truth is - we do not know.
But for this hypothesis to be true, several things need to happen. In this post I look at the evidence for each of the those several things. Unfortunately, nobody has put all the elements together yet, and certainly not in a human. I am wondering...is there a simple easily-controlled experiment that people can do on Thursday night, then report to one collecting place (e.g., a blog) where someone can do the statistics on the data and finally lay the debate to rest? Any ideas?
Also, I will add the comments that the post originally received and I hope for new comments from people with relevant expertise. Is Trp Hxlse really a rate-limiting enzyme? If so, why gavaging chickens and rats with Try increases plasma melatonin? Is it different in humans? You tell me!
(originally posted on November 25, 2005)
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Right around Thanksgiving, it is quite usual to find articles like this one and this one that claim that eating turkey will not make you sleepy because tryptophan will be digested, that tryptophane levels in the brain will decrease in concentration due to amino-acid competition, or that eating turkey may even boost your mood through the rise in serotonin, though the dose may be too low.
What these authors do not know is that a number of papers have been published suggesting a different mechanism altogether, not dependent on tryptophan (or serotonin) getting released into the bloodstream and reaching the brain at all. Let's first review the biosynthetic pathway of melatonin. Here it is in a simplified shorthand:
The amino-acid tryptophan is a precursor of neurotransmitter serotonin which in turn is the precursor of hormone melatonin.
Not everyone knows that the complete enzymatic machinery for synthesis of melatonin is not active only in the pineal organ. It is also fully functional in the retina of the eye, in the Harderian gland (located in the ocular orbit just behind the eyeball), and in the intestine. After all, the GI tract possesses a large and complex semi-independent nervous system in which many of the same neurotransmitters and hormones are found as in the brain. Actually, more melatonin is produced in the intestine than in all the other sites combined.
Normally, intestinal melatonin plays a role in control of gut motility - peristalsis - and perhaps some other local functions. As usual, effects of serotonin and melatonin are opposite: whatever one stimulates, the other tends to inhibit.
In most species intestinal melatonin gets degraded within the intestine. In other words, little or no melatonin ever leaves the intestine and leaks into the bloodstream. Also, depending on the species, melatonin in the intestine is predominantly synthetized during the day, during the night, or continuously. In humans, it appears that some intestinal melatonin (not much, though) leaks into the blood at all times, and that most of the synthesis happens during the day.
The ability of the intestine to synthetize melatonin out of food tryptophan (described above) is the first link in the chain of our hypothesized mechanism.
The second link is, and that has been shown in rats and chickens, ability of extra tryptophan to promote synthesis of extra melatonin.
The third link, also demonstrated in rats and chickens, is that extra melatonin leaks from the intestine into the bloodstream even if it normally does not do so in that particular species.
The fourth link, also demonstrated experimentally, shows that melatonin secreted from the intestine does not in any way affect the levels of melatonin synthesis in other locations (pineal, eye).
Finally, it has long been known that increasing levels of melatonin in the bloodstream can phase-shift the circadian clock, place the phase into the night, and thus promote the feeling of sleepiness.
Now, as far as I know, nobody has done the complete study - all links in the chain - in any species, let alone humans. Still, as each link has been independently verified in one species or another, the whole hypothetical mechanism appears likely. Thus, until further research proves this wrong, you can tell your friends at dinner table this:
High levels of tryptophan in turkey meat and some other foods lead to increase in synthesis of melatonin in the intestine which results in more melatonin leaking from the GI tract into the bloodstream. Once in the blood, this extra melatonin phase-shifts the clock - your body thinks it is late at night and you feel sleepy as a consequence.
Furthermore, this shift of the clock will result in you being wide awake right after midnight - your body thinks it's waking-up time already - something that has been reported anecdotally.
Comments:
The Inoculated Mind said...
Interesting post about turkey, but I think there's a lot more going on than just the tryptophan. Many foods are high in tryptophan, some even higher than turkey. Swiss cheese and ham are particularly high, but no one talks about ham-related sleepiness (that I know of), or swiss cheese causing naps.
I did not know before I read your posts, the physiology of melatonin produced in the intestines, but I am curious about one thing: do the papers you mention in rats and chickens involve purified Trp, or food that is high in Trp? Because it's going to matter in how you can apply the research articles to the phenomenon in question.
I think the reason why the tryptophan myth is propagated by people is severalfold: First, we have the observation that the huge thanksgiving meal tends to make people tired. Second, while searching for an explanation, someone finds that turkey is high in Trp, and that Trp by itself induces sleepiness, and messes with the circadian rhythms. Third, it is a plausible scientifically-worded mechanism, and that by itself convinces some people. (Or convinces them to spread it as a what-if)
Fourth, and this is the most important, other explanations are often ignored. High-calorie (particularly high-carbohydrate) meals draw blood away from the brain for digestion, and people forget that they are drinking a known depressant - alcohol.
And finally, fifth, confirmations of the phenomenon are absent. Turkey sandwiches, ham and swiss cheese sandwiches, steaks, these things should also cause the same sleepiness on any other day. (Not to mention Christmas turkey dinners) But high-calorie meals have been found to cause sleepiness outside of thanksgiving, which is an important point that needs to be made.
There's no doubt that Trp would have some effect, but the question should really be, how much effect would it have relative to the other factors involved? Your advice to people interested in an explanation on turkey-day should also include the other explanations.
coturnix said...
Well, there are so many other explanation, some of which are probably valid, I decided to highlight the one that is always missing from such discussions.
I do not deny that this is likely to be more complex, but I also do not like that this hypothesis is dismissed out of hand, probably due to people's unfamiliarity with the processes I described in this post. Thus, my focus on this possible mechanism, without in any way dismissing alternatives.
And yes, the tryptophan-loading experiments were done with large doses of pure Trp solutions administered directly into the stomach via gastric gavages.
Kim said...
Very interesting post!!! I am embarrassed to say that I had no idea that serotonin was a precurser of melatonin, nor did I know that melatonin was produced in the intestine.
Given my interest in using melatonin for sleep,I should know more about it.
I wonder how SSRI medications interact with OTC melatonin.
Dan Dright said...
Not to mention that the rate-limiting enzyme is tryptophan hydroxylase. Change this and you'll get a fluctuation that might be measurable, but add more tryptophan? You'll only see a difference up until the point you run out of Trp Hxlse and then it's gonna level off.
What I'm interested in is whether orally administered melatonin allows more precursors (tryptophan and serotonin) to stay in the bloodstream/cortex and can boost serotonin levels by limiting the amount that is used for melatonin.
To kim, above, I have some anecdotal evidence that melatonin can affect entrainment pretty welldepending upon time of dose in relation to current sleep cycle.
coturnix said...
Ah, there goes a pretty hypothesis...LOL!
The Inoculated Mind said...
Still, it was an interesting thought and I found out a few things I didn't know as well. :)
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So what I've been told is that the key step is the transport of tryptophan across the blood brain barrier. Tryptophan uses the aromatic amino acid transporter system and if there is a higher ratio of tryptophan in the blood stream with regards to other substrates ot the transporter (phenylalanine and tyrosine). One theory (not sure if this is proven) is that the brain monitors the levels of the other aromatic amino acids and thus increases the activity (or level) of the transporter. To get the proper CNS levels of tyrosine/phenylalanine more tryptophan is thus transported. Thus there is more substrate (tryptophan) for serotonin production in the brain. Serotonin levels then have profound effects on neurological activity. Now as for serotonin and melatonin produced outside of the CNS, I'm not sure that those molecules can cross the blood brain barrier.
J-Dog:
Don't forget the correlation of sleepiness and excessve BR.
Oh. Where BR = Boring Relatives.
cool article - i would add that turkey is not special in its content of tryptophan, with chicken having just about the same amount per 100 gram serving. I posted a few links to the commonly cited real causes of the 'turkey coma' on my page today too. i forgot this one: http://chemistry.about.com/library/weekly/aa110402a.htm
happy thanksgiving :)
Unlike Tryptophan, melatonin easily crosses the blood-brain barrier. That is why I think that focus on Try transporter misses the boat - Try gets converted into melatonin by the gut and more Try in food -> more Mel in blood -> nore Mel in the brain in a pretty straightforward way.
Don't forget the wine...
I think the mashed potatoes and pie make you sleepy, too.
But I'm not giving up my piece of pie just to be the control experiment.
Perhaps I can say that I am doing an experiment and just eat tons of turkey meat and not have any of that grass around it (potatoes, salads, etc.), plus no alcohol (I am not a drinker anyway). Then I measure sleep latency and compare it to the day before and the day after at the same time of day.
trey leach:
well i know that tryptophan does not make you sleepy but what about seratonin(a chimical that also makes you sleepy) but that is also in turkey or so i have heard
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Of course, the underlying assumption everyone is making is that turkey naturally contains tryptophan. Maybe it doesn't. Maybe it is the factory-farms that add d and l-tryptophan to the poultry feed, encouraging rapid growth. And maybe the excess transfers through the factory-farm meat into humans, who respond by falling asleep in front of the Thanksgiving Day football games not because they overate carbs (which they may have done), and not because of the natural tryptophan, (which there is none - it is a myth that turkey meat is high in tryptophan), but instead, they fell asleep because they were, in essence, drugged by the perverted levels ofo trypophan in the turkey meat. Eat natural grass-fed turkey, and eat as many carbs, and I promise you, everyone will be bright-eyed and bushy-tailed wondering why they're not all snoring. http://jn.nutrition.org/cgi/reprint/43/2/223.pdf