Thursday, December 16, 2010

Scratchy

Purdue University and its mice hit the nutrition news this week with the work of Dr. Joseph Garner and his team. Their paper, "Nutritional up-regulation of serotonin paradoxically induces compulsive behavior" was published in Nutritional Neuroscience, and prompted several reports and tweets rather like this one. Jad supplied me with a links in the comments to That Tapeworm Ate Your Depression, and Jamie emailed me the abstract as well. No one was going to let Mark Sisson get the jump on me this time!

And, to be sure, this paper and the work are pretty neat. As far as I know, it may be the only paper showing a definitive development of psychopathology with an adjustment of diet. So that's a big deal!

A little background - serotonin is a neurotransmitter in part responsible for calm, happiness, and whatever the opposite of wanting to kill yourself is - contentment and serenity with living in your own skin, I would say. I talked about serotonin in several blog posts:

The Evolution of Serotonin
More About Sunlight, Food, and Serotonin

As did Jamie:
Midwinter Blues
More Serotonin
Brain Dump on Serotonin


It is common knowledge that eating carbs will increase serotonin levels in the brain. Basically, carbohydrates increase the brain's ability to import tryptophan, the amino acid precursor to serotonin, through the blood brain barrier. It shouldn't surprise you that eating tryptophan can also increase the transport of tryptophan through the blood brain barrier. Well, Dr. Garner and team searched the literature and quantified the whole thing, and figured out that if one increases carbohydrate:protein ratio a certain amount and increases tryptophan a certain amount, serotonin creation in the brain goes lickety split, zoom zoom - and if you do that, hey, maybe you get a calm happy la-la land of serotonin peace coma, rather like Thanksgiving afternoon after turkey, mashed potatoes, and pie.

Instead he got scratchy mice. But I'm skipping to the end. Enter the mice - happy mice in their standard cages on their standard mice chow control diet or treatment diet, in a double-blinded (actually, they only called it blinded, as maybe the mice knew, but couldn't tell anyone) crossover trial.

Read about the control diet and try not to gag too much:


Casein 24%
Soybean Oil 10%
Cornstarch 52.3%
Sucrose 5%
Fiber (cellulose) 4%
Vitamin and mineral mix
Choline 0.2%

Overall it was 24% protein and 57.3% carbohydrate, and only 10% fat, mostly polyunsaturated omega 6 vegetable oils. Kind of the USDA dream diet, really - skim milk derivative and vitamin-enriched low sugar corn cereal, kids! (It is noted that all the mice gained weight when allowed to eat ad libitum during this experiment, though the treatment mice gained more than the controls).

The treatment diet had an increased carbohydrate to protein ratio with a little extra tryptophan, and a big bolus of sugar in the form of dextrose (which is two glucose molecules hooked together - or not, it is just glucose molecules. Thank you Jim, maltose, not dextrose, is glucose-glucose)

Casein 12%
Methionine 0.4%
Tryptophan 0.9%
Soybean Oil 10%
Cornstarch 30%
Dextrose 33%
Sucrose 5%
Fiber (cellulose) 4%
Vitamin and mineral mix
Choline 0.2%

These mice have a little issue, in that they engage in behavior called "barbering." Meaning they pull out their own hair and the hair of their cage mates (they pull out their own hair in a particular pattern, and cage mates in a different pattern, so the hair-pulling can be differentiated. Humans with a rather common (3-4% of women) behavior called trichotillomania also compulsively twist hair until breaking and pull out hair, eyebrows, and eyelashes. It is thought that trichotillomania is due to a serotonin deficiency, so it would make sense to test this hypothesis by using a mouse model and a diet designed to increase serotonin in the brain.

So after the mice were fed their diets, and the amount of barbering was measured, and the amount of scratching was measured during a "spray test," and then the mice were decapitated, the brains were put on ice and eventually homogenized and analyzed for serotonin and other neurotransmitter amounts.

As expected, treatment diet increased whole brain metabolites of serotonin and decreased the ratio of serotonin to the metabolite - consistent with increased serotonin synthesis and metabolism. Dopamine metabolites were also reduced, consistent with the general principle that when serotonin is increased, dopamine is suppressed.

However, the treatment diet, which definitely increased serotonin turnover, actually increased barbering behavior. Scratching scores were doubled. In addition, a deadly skin infection seemed to plague the treatment mice, especially the female mice. Basically, a diet low in protein and fat and high in sugar led to hair-pulling, scratching, and death via skin infection in this mouse model of trichotillomania.

So, what the heck is going on? If trichotillomania is caused by low serotonin, why would increasing serotonin metabolism cause more picking? SSRIs, which also affect serotonin, are used to treat trichotillomania. However, any psychiatrist in practice will know that SSRIs can also induce skin-picking behavior in vulnerable individuals that will go away once the SSRI is withdrawn.

Skin-picking and grooming are basic primate behaviors. Observe any group of monkeys or chimps and they seem to spend a lot of time grooming each other. These activities are thought to be mediated by serotonin. High amounts of dopamine can also cause compulsive tapping (as in OCD or autism) and tic behaviors. It is interesting that women, who seem to be more vulnerable to serotonin pathology, are four times as likely to have trichotillomania as men, but men, who are more vulnerable to dopamine pathology, have much higher rates of tapping and tics.

I conceptualize serotonin and dopamine levels in the brains as see-saws. Sometimes pushing the see-saw one way with diet or a pharmacologic agent will result in the see-saw becoming balanced, sometimes pushing it will unbalance it further. So some folks with trichotillomania will improve with an SSRI, and other folks with no picking problems will start to pick when given an SSRI. And these mice, apparently, do not do well with increased serotonin turnover. Of course one has to wonder what such a diet would do to our psychopathology.

More on the neurobiology of compulsions and trichotillomania in the next post. If I get through the articles. Reading about trichotillomania always makes me itch.


12 comments:

  1. The control diet sure sounds like my childhood diet, except I had a lot more wheat in the form of bread, pasta, breakfast cereal and not as much corn. I remember always being fidgety, tapping my fingers and feet a lot, and going through bouts of facial ticks. Hmm...it's all starting to make sense. I'm actually a little surprised that a large increase in glucose caused the scratching and hair pulling. I would have guessed it was an increase in fructose that would have been responsible. A high starch diet (e.g., Kitavans) seems to be well handled by humans so long as the starches are from tubers which break down into glucose.

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  2. I thought for sure when I read the news reports about 8x the sugar that it was sucrose - but no - glucose - and the study confirmed the increased serotonin turnover by checking the actual brains.

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  3. Hi Emily,

    I've been looking at this one also, see http://perfecthealthdiet.com/?p=1479. Please pay no mind to the psychiatrist-skepticism! Doesn't apply to you.

    I'm looking forward to your thoughts.

    Best, Paul

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  4. That's what they all say, Dr. Jaminet.

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  5. Very interesting. Did you intend the title as a reference to the Simpson's characters Itchy and Scratchy? No credit unless it was intentional ...

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  6. "dextrose (which is two glucose molecules hooked together)"

    That would be maltose. Dextrose is a single glucose molecule.

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  7. Oh, absolutely right. I hate it when I mess up silly things.

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  8. Todd, I did originally title the post "itchy and scratchy" as a matter of fact ;)

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  9. For dietary mention, I once got a book on Sesame. All about sesame.

    Said it's the highest source of L-Tryptophan of any vegetables. It was also near the top on protein.

    Alas- Open Sesame !

    no, really though, if you're after dietary loading up on Serotonin ? Don't forget about Sesame or tahini (ground sesame).

    For an interesting note ? Hummus ? made with Garbanzo beans ? I recall reading Garbanzo beans are high in levodopa.

    Bottom line, here is Hummus ? My view ? Offering a plethora of neurotransmitter support. I am convinced diet is CRITICAL in neurophysiological health, far more influencing than ANY Eli Lilly product.

    I find it interesting to learn that a small percentage of people ? can not absorb folate at ALL in their intestines, and some 50% of all people have trouble absording it.

    I recently found 5-Methyl tetrahydrofolate) -- 60 Vegetarian Capsules, you can find it - I can't promote any website it will detract from my point, heh, I have it on my wishlist, but I can't afford the $15.65, but I am want this for a methyl donor purpose in my own regiment I'm exploring. But I bring this up because I'd think 50% of people not absorbing folate WELL at all ? is a SERIOUS deficit. Who knows, maybe the 'feel good' nature of dopamine ? is tied into having the 5-Methyl tetrahydrofolate around.

    Ending up to realize I should get the 5MTHF ? Took a while after a good long evening of reading one article after another.

    I also recall reading some percentage of people- MOSTLY Middle Eastern lack this CytoChrome P450 enzymes, as in COMPLETELY lack it, I wrote a genetics expert who specializes in this, and he said they see typically 1 in 300,000 patients with this disorder - I'd think it's higher, I wrote saying, hey, shouldn't EVERYONE take this test before being given anything ? even a diphenhydramine ? I mean, imagine someone taking Nortryptaline having that condition, or Abilify, sure, they really could take 1/10th the capsule and save on bills ! (Eli Lilly wouldn't like that though, that cuts into profits), but I suspect before doing ANY studies on who takes this, and what happens ? I think there should be a BAR set - a STANDARD genetics clearing house on the data to make sure no one or no animals in any study ? comes in with a genetic bias.

    I learned that the FDA is requiring as of recent ? Such a test now for certaine drugs that would be broken down by Cyto P450, me ? I think EVERYONE should be tested for known genetic cicrumstances, even a Benadryl could cause someone harm if you're one of the unlucky ones. Maybe in time... Let's hope.

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  10. Looks like Gustav Jung's promotion of Intuition over intellect is on again:

    http://www.bioportfolio.com/resources/trial/73908/Trd-2-A-Study-Of-6-s-5-mthf-Among-Selective-Serotonin.html

    Looks like Mass Gen has an ongoing study on 5MTHF.

    Gee, I only wanted it because it was a decent methyl donor, I just read such nasty business about Homecysteine, from meats and cheeses, even to Alzheimer's possibly being caused by too much Homecysteine because we supposedly progressively lack methyl donors in aging. Me? When I see ANYTHING that changes as we age? I like to start examining, is it a casual factor ? or effect of something else, or is the effect of one thing, a cause of another... Seems I may be looking at biochemistry as a hierarchy - all wrong, I'm guessing the winning game of chess each time is through a careful process involving many thought processes/ analog to understanding MANY chemical pathways working together. I once read in my arm chair studies - heh, that serotonin actually plays over 100 roles in the body, MOST in the intestines involved with messaging about food, same molecule ? yet so many uses in different contexts. Seeking too high or too low of a neurotransmitter might be like an English paper being returned and graded down because it had too many vowels.

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  11. Sometimes one can seek to increase serotonic ? But I do say- IF the receptors are not - how shall we say ? as receptive as they COULD BE? amplifying THAT is probably a better path, or restoring that- and to that ?

    One of my favorite articles of all time - on neuronal regrowth ?

    http://genedynamics.bme.ufl.edu/Pubs/assets/Ying_ogle_07.pdf

    As well as increasing S1a at the least. Sure it's not all of them, but hey - it's a start.

    All form Curcumin -

    I was reading an article about a village in India with high curcumin intake and very low AHD.

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  12. I noticed in the artlce above, Emily you have:

    "I conceptualize serotonin and dopamine levels in the brains as see-saws. "

    The key word See Saw triggered a memory of something I Read a LOOOONNNG time ago, but it's always stuck out to me. It was in a rather academic resource someone had, I had just picked it up thinking, sheesh, I can't comprehend this, but seeking a challenge I recall this literal see-saw diagram that showed AcH with Dopamine DO have a see-saw relationship, to which I once thought, hey - if you decrease Dopamine ? I bet you could increase AcH - I've learned with AHD ? it doesn't work this way. I think it was Germany or Russia where that research didn't pan out.

    BUT - I went to print.google.com to see if I could find a medical textbook that had these terms to share with you that INDEED, there REALLY IS a relationship between dopamine and AcH -

    http://books.google.com/books?id=U7J4ls49HkIC&pg=PA52&dq=acetylcholine+dopamine+see+saw&hl=en&ei=17wRTbvbBYOglAei38i6BQ&sa=X&oi=book_result&ct=result&resnum=3&ved=0CDMQ6AEwAg#v=onepage&q&f=false

    It's on page 52, it may or may not come up, print.google.com is like that, I read some books by logging in with other IP's because I can't afford to buy them, but it serves up different pages usually if you do it right.

    3 weeks from now ? Some article will be out saying that's all wrong ! lol

    One thing for sure, SHARP chemistry skills I think can lead the way out of this dark tunnel. I don't have those, but I intuit having a solid grasp of chemistry - DEEP grasp is probably critical in understanding neuropsychiatry. First thing I'd do as a doctor with EVERY patient though is have a genetic screening performed to check for P450 problems, and other known genetic dispositions.


    A friend of mine got his Masters in Chemistry, then ? became a pharmacist. Now, THERE is someone who will understand and even probably catch something that software might otherwise overlook. I REACH for that ? but my oh my - I find chemistry SO abstract at times, I usually have to just start accepting abstract models, abstract terms, and I try to remember, that what I may be trying to grasp in 30 minutes may have taken thousands of people researching for decades or years prior.

    The pre-requisites required to advance from all of the labors of the past are sometimes more burdening in perception I do say, than any foreseeable benefits, but it's only AFTER seeing the -kines so often or the -folates, or the tetra- or Hydro- prefixes and PLENTY of free thinking to 'conceptualize' I think do breakthroughs come about. I think intuition is the breadwinner in the end for innovation, the intellectual aspects are merely backup ! heh- just my take.

    What I was trying to say earlier is, I think there is a great synergestic relationship for the neurotransmitters more so of value than any by themselves. But molecular chemistry ULTIMATELY comes down to really understanding the atomic elements. For me - JUST figuring out what is analagous to molecular and what is the analog to atomic in regards to neurotransmitters is seemingly ? impossible ! heh.

    But again, when I see things over and over and over such as - methyl donors decrease as we age, I can't help but think, I should explore supplementing those, AND also explore finding out WHY that is, and reach for an upstream solution. Seems there is ALWAYS an upstream solution.

    One of my childhood fascinations was following streams until you couldn't tell where they came from - I sometimes feel that way in seeking to understand domains that require an expertise which I know is out of my reach, alas ! Why it's so good to communicate and learn with and from others, to teach and be taught... ALAS a BLOG such as yours Dr. Deans.

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