I'm really falling behind my stack of papers. Fortunately, life is good and busy, and there are always new, catchy songs to listen to:
The Temper Trap: Fader
That song really puts a spring in my step. Rather like a strong cup of coffee. Full disclosure - more of a tea person, but I've been known to drink a cup of joe every now and again. Maybe I ought to drink a bit more… the evidence is mixed, frankly. And certainly I can't tell you how many times I've had patients complain of insomnia, only to find out they are drinking 6 large iced coffees a day, or 12 Mountain Dews (no matter how much I exercise, I don't seem to be able to take this weight off, doctor…).
But what does the research say about, say, depression and coffee? A brand spanking new piece of epidemiology from the Nurses' Health Study was published in the Archives of Internal Medicine this month - Coffee, Caffeine, and Risk of Depression Among Women.
Some facts from the article - 80% of the caffeine in the world is consumed as coffee. Interesting. Prospective studies of men and caffeine use showed a strong inverse association between coffee drinking and depression, with no association for tea or cola. Three cohort studies showed an inverse relationship between coffee consumption and suicide (though in a Finish study, there was a J-shaped curve with both very high (>7 cups of coffee daily) and low consumption of coffee seemingly less protective than moderate amounts.)
So, in the Nurses' Health Study (following 121,700 American female nurses starting in 1976), women filled out questionnaires every two years. 97,000 filled out questionnaires in 1996, 98, or 2000, and those with no history of depression at that time (50,739 women) (those with unknown history were excluded) were followed over the next decade.
Regular coffee drinkers in this cohort were more likely to be smokers, drinkers, and not go to church! They also tended to have lower rates of diabetes and obesity. Average consumption for the whole group was about 1&1/2 cups of coffee a day.
Among the 51,000 women, about 2600 developed clinical depression in the 10 year period. There was a dose dependent, inverse relationship between the amount of coffee consumed and the risk of developing depression over the years. When covariates (such as age, health, smoking, divorces, etc. etc.) were all adjusted for, the inverse relationship became even stronger! No associations were found between tea consumption, chocolate consumption, decaf coffee, or soda consumption and depression.
So what's up? Is coffee an antidepressant?
I Know What I Am: Band of Skulls
Well, maybe. This is no randomized controlled trial, so causation cannot be determined, but caffeine (1,3,7-trimethylxanthine) antagonizes the adenosine A2A receptor. This is thought to have pro-dopamine effects. By taking out adenosine, we might also be affecting the transmission of norepinephrine and serotonin, both known targets of antidepressant medicines.
Since coffee is known to cause insomnia and anxiety, both features of depression, a weakness of the study is that women prone to insomnia and anxiety might limit their intake of coffee, thus biasing the results so that women who can tolerate a truckload of coffee also happen to be the ones less prone to depression.
But… all told, it seems that this study is another notch in coffee's bedpost. Though less than 8 cups a day seems prudent. And I really can't recommend Mountain Dew :)
Thursday, September 29, 2011
Saturday, September 24, 2011
Anger and Serotonin
My buddy Jamie Scott is a research machine. It's all I can do to keep up with the interesting papers and links he emails my direction. Today's article is yet another one we owe to his sharp eye. He also has brand new digs at a wordpress blog (*brief moment of jealousy*) - so edit/add him to your blogroll and check it out:
Some music - I rather adore the Yeah Yeah Yeahs. Here's an oldie but a goodie: Gold Lion (right click to open in new tab). Favorite comment on youtube: "i think I just got whiplash rocking out to this song" [sic].
Want something a bit more classical? How about a Chopin Nocturne played by none other than Rachmaninoff from 1927? (You will not be rocking out, but it is quite lovely).
The paper is in Biological Psychiatry: Effects of Acute Tryptophan Depletion on Prefrontal-Amygdala Connectivity While Viewing Facial Signals of
It's kinda cool. Involves humans, which is always a plus. It is one of those "view angry faces whilst in a functional MRI machine" which has some limitations, but it is pretty much the only way to see what's going on in real time in the old noggin, seeing as how it's rather awkward to test gene expression and neurotransmitter levels other ways without decapitation (not likely to pass the institutional review board any time soon, unless you were unfortunate enough to be born as a research rodent). (Random aside - Andrew tweeted this REAL MIND READING finding yesterday. Wow.)
How many segues is that? Welcome to my left-handed, small child-raising brain. As we know, depletions in serotonin, especially in a particular communication circuit between the frontal lobes (the policeman) and the amygdala (the emotional/rage center of the brain) leads to anger and aggressive behaviors. Now, there are some people who are just aggressive altogether - I'm thinking Drew Barrymore's boyfriend in one of the Charlie's Angels movies. We're not talking about that. We're talking about impulsive aggression. All the sudden, you just want to jump out of your car and strangle the other driver who cut you off (please don't do this). Impulsive aggression can be unexpected and very scary, and can certainly ruin lives.
So what if it happens just because you forgot to eat your banana this morning??? Oh, don't worry, we are likely more resilient than all that… but in an experimental setting, one can pretty much abolish serotonin via a weird laboratory tryptophan-depleting drink. Then you get into an MRI machine. Then you look at pictures of angry faces (if I were running this experiment, I would pipe in some hard core metal, and not one of Chopin's Nocturnes). Of course, I read A Clockwork Orange in high school. The tryptophan-depleting drink significantly reduced both plasma tryptophan levels (remember, tryptophan is the precursor to serotonin) and the ratio of tryptophan to other long-chain neutral amino acids (remember, tryptophan competes with these other amino acids for entrance into the brain).
In the end, the reactions of the tryptophan-depleted individuals to the angry faces vs. controls was statistically significant. Tryptophan-depleted folks had a higher response to the angry faces within the amygdala (the rage/anger part of the brain) compared to controls, and compared to the response to neutral faces. These findings would suggest that, as suspected, serotonin helps you chill out and assess the situation when faced with an angry hoarde.
Between the mind reading and the availability of a rapid acting tryptophan-depleting anger drink that will affect our aggressive reactions, I'm a little worried about the future of our free will. But I'll try to eat some protein, micronutrients, a banana, and put my trust in the incompetence of bureaucracy in order to be less paranoid.
Friday, September 23, 2011
Carbohydrates, Gut and Autism
If you haven't already, go read the latest Psychology Today post about Alzheimer's and High Blood Sugar and Alzheimer's and Omega3s. Page views on my Psychology Today posts help support the paper, toner, textbook, and time that goes into Evolutionary Psychiatry.
Jamie sent me this link from PLOS1 (which, admittedly, is not the Rolls Royce of journals, but does have some interesting stuff every now and again):
Hmm. The text is very large and doesn't seem amenable to editing. One more reason to move over to wordpress…
So y'all have heard of the GAPS diet, right? Natasha Campbell-Mcbride is a doctor who had a kid with autism. I haven't read her book yet, but the general theory is that folks with certain issues with gut microbiota and carbohydrate malabsorption will end up with psychological/psychiatric symptoms, including autism. Dr. Campbell-McBride had great success with this approach, as, apparently, do many others.
In this PLOS1 paper, patients with autism and patients with GI disturbances were examined for different carbohydrate malabsorption.
Kids with autism often have gastrointestinal problems (survey studies report comorbidities of 9-91%, which isn't all that useful a percentage spread, but certainly given clinical experience and thinking about autistic kids I know in the community, higher seems more likely than lower). Pathologic findings of gut issues in autistic kids include gastritis, esophagitis, inflammatory markers at the gut lining, gut lymphatic system hyperplasia, increased intestinal permeability, abnormal gut microbiota findings, increased enzyme secretion, and carbohydrate malabsorption. Indeed, autistic children with severe gastrointestinal symptoms are more likely to have severe autistic symptoms (1).
So what happens if you don't have efficient digestion of disaccharides, for example, for whatever reason (damage to gut, unlucky genes, other illness)? Well, any carbohydrate that goes undigested will float down and feed the hungry masses of gut bacteria. This feeding can result in bloating, discomfort, diarrhea, and proliferation of pathogenic bacteria, which can presumably affect both inflammation and behavior.
The researchers from the latest studies biopsied the intestines of autistic children with gastrointestinal symptoms (AUT-GI), finding the following (among other things:)
When there is a devastating illness with only supportive treatment, a harmless intervention, such as adjusting the types of carbohydrates in the diet (this will not be a completely "paleo" intervention - sweet potatoes, for example, are off limits on GAPS I believe - I will post some more when I get the book), seems to be an approach that ought to be supported and attempted. Sure, it might not help everyone, but what is there to lose?
Jamie sent me this link from PLOS1 (which, admittedly, is not the Rolls Royce of journals, but does have some interesting stuff every now and again):
Impaired Carbohydrate Digestion and Transport and Mucosal Dysbiosis in the Intestines of Children with Autism and Gastrointestinal Disturbances
Hmm. The text is very large and doesn't seem amenable to editing. One more reason to move over to wordpress…
So y'all have heard of the GAPS diet, right? Natasha Campbell-Mcbride is a doctor who had a kid with autism. I haven't read her book yet, but the general theory is that folks with certain issues with gut microbiota and carbohydrate malabsorption will end up with psychological/psychiatric symptoms, including autism. Dr. Campbell-McBride had great success with this approach, as, apparently, do many others.
In this PLOS1 paper, patients with autism and patients with GI disturbances were examined for different carbohydrate malabsorption.
Kids with autism often have gastrointestinal problems (survey studies report comorbidities of 9-91%, which isn't all that useful a percentage spread, but certainly given clinical experience and thinking about autistic kids I know in the community, higher seems more likely than lower). Pathologic findings of gut issues in autistic kids include gastritis, esophagitis, inflammatory markers at the gut lining, gut lymphatic system hyperplasia, increased intestinal permeability, abnormal gut microbiota findings, increased enzyme secretion, and carbohydrate malabsorption. Indeed, autistic children with severe gastrointestinal symptoms are more likely to have severe autistic symptoms (1).
So what happens if you don't have efficient digestion of disaccharides, for example, for whatever reason (damage to gut, unlucky genes, other illness)? Well, any carbohydrate that goes undigested will float down and feed the hungry masses of gut bacteria. This feeding can result in bloating, discomfort, diarrhea, and proliferation of pathogenic bacteria, which can presumably affect both inflammation and behavior.
The researchers from the latest studies biopsied the intestines of autistic children with gastrointestinal symptoms (AUT-GI), finding the following (among other things:)
Pyrosequencing analysis of mucoepithelial bacteria revealed significant multicomponent dysbiosis in AUT-GI children, including decreased levels of Bacteroidetes, an increase in the Firmicute/Bacteroidete ratio, increased cumulative levels of Firmicutes and Proteobacteria, and increased levels of bacteria in the class Betaproteobacteria...
Metabolic interactions between intestinal microflora and their hosts are only beginning to be understood. Nonetheless, there is already abundant evidence that microflora can have system-wide effects and influence immune responses, brain development and behavior.
When there is a devastating illness with only supportive treatment, a harmless intervention, such as adjusting the types of carbohydrates in the diet (this will not be a completely "paleo" intervention - sweet potatoes, for example, are off limits on GAPS I believe - I will post some more when I get the book), seems to be an approach that ought to be supported and attempted. Sure, it might not help everyone, but what is there to lose?
Saturday, September 17, 2011
Interesting Findings in Eating Disorders and Alzheimer's
First off, everyone take a couple of hours and hop on over to Robb Wolf's blog and listen to his podcast with Dr. Kurt Harris. As usual, Kurt pulls it all together with fun and flair and a hefty serving of common sense. He gives me and my blog a few mentions, which is very much appreciated, as always :)
I've been anticipating excitement hunting down a couple of papers that came out in the last couple of weeks - the first one: An Update on Hospitalizations for Eating Disorders, 1999-2009. As expected from a statistical brief, there is little there besides the numbers - so it is not all that exciting. Overall, eating disorders as a primary or secondary diagnoses have increased 24% in that period, cost of hospitalizations have increased 29%, and hospitalizations for children under 12 have increased 72%, and for people 45-65 88%, and for men 53%. Weirdly, hospitalizations for pica (compulsively eating non-food items, such as dirt or soap or whatever) have increased 93% but are still rather unusual. If you look at eating disorders as a "principal" diagnosis only, the number has actually fallen 1.8%, and I've seen some funny headlines as a result - "eating disorder hospitalizations fall, but pica hospitalizations double."
An important caveat is that these numbers are generated from billing codes. If someone comes to see me at the office, I am obligated (if I want to be paid by the insurance company) to generate a code based on a DSMIV diagnosis that I put on a billing form. The same is true for inpatient hospitalizations. And in the past 13 years, a number of states and the federal government have issued rules to prevent insurance companies from rejecting paying for psychiatric diagnoses that are so-called "biologic." This change is a part of the mental health parity act. "Biologic" diagnoses vary from state to state depending upon the laws, and even depending upon the insurance company, but generally include major depressive disorder, bipolar disorder, schizophrenia, etc. Sometimes anxiety disorders are not included. Addiction used to be not included, now it is I believe, and often autism and eating disorders are not included. Therefore if I am a doctor who would like to get paid and not have patients stuck with bills when they pay their insurance premiums, and someone meets criteria for major depressive disorder (MDD) AND an eating disorder (which in the inpatient world will very often be the case), the MDD will always be the "principal" diagnosis to avoid issues down the line. I know that anorexia is often more likely to be covered for inpatient care than bulimia, depending upon the medical status of the patient… in short, the overall trend of primary and secondary diagnoses and increase in men and children and older people I find very interesting more than the drop in "principal" diagnosis.
It is actually rather difficult and getting more difficult all the time to be hospitalized for psychiatric disorders in general. For the most part you must be an obvious imminent risk to self or others or completely unable to care for yourself in order to get a bed, which are in scarce supply. In 1999 it was easier to get the slightly less ill hospitalized. So with this background, I find it rather remarkable the eating disorder hospitalizations have increased to such a degree. Binge eating rarely results in psychiatric hospitalization, and outpatient rates of binge eating and bulimia are rising also (though inpatient bulimia hospitalization dropped - the severe cases are often readily managed in intensive outpatient day programs nowadays, however.) As obesity has also increased over the same period of time, I can't help but suspect the two trends are related, but I can't prove it.
The second article I was excited to hear about is probably a watershed paper in the treatment of Alzheimer's dementia: Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment. This paper discusses a pilot trial of 104 adults with amnestic mild cognitive impairment or Alzheimer's disease vs controls with a couple of doses of intranasal insulin.
Why intranasal? None of the subjects had diabetes, and obviously systemic insulin could cause dangerous hypoglycemia. The intranasal dose goes pretty much straight to the central nervous system via the olfactory and trigeminal nerve perivascular channels, and none of the subjects had hypoglycemia during the trial.
Why insulin? Well, as I've discussed at great length (I really ought to repost some of those dementia articles up on Psychology Today…), there are very clear issues with the ability of a dementing brain to metabolize glucose (the example in that article is Parkinson's disease, but the principle is very similar for Alzheimer's). This problem results in inefficient use of energy, free radical generation, and neuronal toxicity and death. There are several ways to (theoretically) improve this issue - one of them is to use a therapeutic ketogenic diet. The other way is to jack up insulin in the central nervous system to improve the ability of the cells to pull in and utilize glucose, theoretically. In addition, insulin seems to have an effect on amyloid-beta peptides that may protect the neurons, and insulin and insulin activity are generally low in the CNS of folks with dementia (though hyperinsulinemia with insulin resistance seems to be a long-term risk factor for developing Alzheimer's dementia eventually).
My question is - and this is highly speculative - without improving the energetics, does jacking up the insulin help in the short term but hasten the problems in the long term? No long term studies have been done. In the absence of insulin resistance and with insulin in the CNS low already, perhaps not? I'll have to think a little more on that one.
I've been anticipating excitement hunting down a couple of papers that came out in the last couple of weeks - the first one: An Update on Hospitalizations for Eating Disorders, 1999-2009. As expected from a statistical brief, there is little there besides the numbers - so it is not all that exciting. Overall, eating disorders as a primary or secondary diagnoses have increased 24% in that period, cost of hospitalizations have increased 29%, and hospitalizations for children under 12 have increased 72%, and for people 45-65 88%, and for men 53%. Weirdly, hospitalizations for pica (compulsively eating non-food items, such as dirt or soap or whatever) have increased 93% but are still rather unusual. If you look at eating disorders as a "principal" diagnosis only, the number has actually fallen 1.8%, and I've seen some funny headlines as a result - "eating disorder hospitalizations fall, but pica hospitalizations double."
An important caveat is that these numbers are generated from billing codes. If someone comes to see me at the office, I am obligated (if I want to be paid by the insurance company) to generate a code based on a DSMIV diagnosis that I put on a billing form. The same is true for inpatient hospitalizations. And in the past 13 years, a number of states and the federal government have issued rules to prevent insurance companies from rejecting paying for psychiatric diagnoses that are so-called "biologic." This change is a part of the mental health parity act. "Biologic" diagnoses vary from state to state depending upon the laws, and even depending upon the insurance company, but generally include major depressive disorder, bipolar disorder, schizophrenia, etc. Sometimes anxiety disorders are not included. Addiction used to be not included, now it is I believe, and often autism and eating disorders are not included. Therefore if I am a doctor who would like to get paid and not have patients stuck with bills when they pay their insurance premiums, and someone meets criteria for major depressive disorder (MDD) AND an eating disorder (which in the inpatient world will very often be the case), the MDD will always be the "principal" diagnosis to avoid issues down the line. I know that anorexia is often more likely to be covered for inpatient care than bulimia, depending upon the medical status of the patient… in short, the overall trend of primary and secondary diagnoses and increase in men and children and older people I find very interesting more than the drop in "principal" diagnosis.
It is actually rather difficult and getting more difficult all the time to be hospitalized for psychiatric disorders in general. For the most part you must be an obvious imminent risk to self or others or completely unable to care for yourself in order to get a bed, which are in scarce supply. In 1999 it was easier to get the slightly less ill hospitalized. So with this background, I find it rather remarkable the eating disorder hospitalizations have increased to such a degree. Binge eating rarely results in psychiatric hospitalization, and outpatient rates of binge eating and bulimia are rising also (though inpatient bulimia hospitalization dropped - the severe cases are often readily managed in intensive outpatient day programs nowadays, however.) As obesity has also increased over the same period of time, I can't help but suspect the two trends are related, but I can't prove it.
The second article I was excited to hear about is probably a watershed paper in the treatment of Alzheimer's dementia: Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment. This paper discusses a pilot trial of 104 adults with amnestic mild cognitive impairment or Alzheimer's disease vs controls with a couple of doses of intranasal insulin.
Why intranasal? None of the subjects had diabetes, and obviously systemic insulin could cause dangerous hypoglycemia. The intranasal dose goes pretty much straight to the central nervous system via the olfactory and trigeminal nerve perivascular channels, and none of the subjects had hypoglycemia during the trial.
Why insulin? Well, as I've discussed at great length (I really ought to repost some of those dementia articles up on Psychology Today…), there are very clear issues with the ability of a dementing brain to metabolize glucose (the example in that article is Parkinson's disease, but the principle is very similar for Alzheimer's). This problem results in inefficient use of energy, free radical generation, and neuronal toxicity and death. There are several ways to (theoretically) improve this issue - one of them is to use a therapeutic ketogenic diet. The other way is to jack up insulin in the central nervous system to improve the ability of the cells to pull in and utilize glucose, theoretically. In addition, insulin seems to have an effect on amyloid-beta peptides that may protect the neurons, and insulin and insulin activity are generally low in the CNS of folks with dementia (though hyperinsulinemia with insulin resistance seems to be a long-term risk factor for developing Alzheimer's dementia eventually).
My question is - and this is highly speculative - without improving the energetics, does jacking up the insulin help in the short term but hasten the problems in the long term? No long term studies have been done. In the absence of insulin resistance and with insulin in the CNS low already, perhaps not? I'll have to think a little more on that one.
Thursday, September 15, 2011
Back to School Again
I've started teaching my small section of the introduction to psychiatry class for the medical students again, which has added a measure of increased chaos to the week. Not always a bad thing. However, blogging frequency may diminish for the fall (but who knows - depends upon what I see that interests me, and the class time for the lectures I don't teach does give me time to catch up on some journals, as I'm not taking a test at the end of the semester, I don't always need to pay attention…)
A few weeks ago I recorded a podcast with Superhuman Armi Legge and Bulletproof Exec Dave Asprey. Here is the podcast, so enjoy! I'm not entirely certain I am a paleo "brain hacker" - I'm more into emulating the evolutionary milieu(™)* than throwing MCT oil and butter into coffee for a kickin' breakfast, but that could be my likely dairy intolerance talking. We all share enthusiasm and interest in human health - the search for optimization of human health and performance is preliminary but intriguing. Thanks for the opportunity, Armi and Dave! Very happy to be on your podcast.
I also have another post up on Psychology Today about vitamin D, birth weight, and schizophrenia. All clicks are very helpful and help me finance my textbook addiction.
A few interesting articles in the queue - stay tuned for brand new posts. In the mean time, here's a boppin' rock tune (can't get enough of it):
Brooklyn is Burning by Head Automatica
*lovin' Kurt Harris's new picture.
A few weeks ago I recorded a podcast with Superhuman Armi Legge and Bulletproof Exec Dave Asprey. Here is the podcast, so enjoy! I'm not entirely certain I am a paleo "brain hacker" - I'm more into emulating the evolutionary milieu(™)* than throwing MCT oil and butter into coffee for a kickin' breakfast, but that could be my likely dairy intolerance talking. We all share enthusiasm and interest in human health - the search for optimization of human health and performance is preliminary but intriguing. Thanks for the opportunity, Armi and Dave! Very happy to be on your podcast.
I also have another post up on Psychology Today about vitamin D, birth weight, and schizophrenia. All clicks are very helpful and help me finance my textbook addiction.
A few interesting articles in the queue - stay tuned for brand new posts. In the mean time, here's a boppin' rock tune (can't get enough of it):
Brooklyn is Burning by Head Automatica
*lovin' Kurt Harris's new picture.
Sunday, September 11, 2011
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.)
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.)
Friday, September 9, 2011
Anger and Homocysteine (A Folate Cycle Ditty)
Happy Friday! I actually have a whole stack of interesting papers from email and links (as usual) - Paleo Wunderkind Jamie Scott sent me an email about homocysteine and anger earlier this week, and the papers are pretty cool.
Quick and catchy brand new tune by Girls - Honey Bunny (right click to open in new tab)
All right. Homocysteine. If you recall, in protein we eat an amino acid named methionine. Methionine plus various derivatives of the B vitamins, including folic acid vitamin B6 and vitamin B12 helps us make all sorts of stuff from other proteins like DNA, neurotransmitters, etc. Lots of important stuff. Homocysteine is an intermediate in the pathway, that is supposed to be recycled back into methionine (see this diagram) so that the cycle can begin again. Older people and men are likely to have higher homocysteine. Older folks also tend to eat less B vitamins. And folks with hyperinsulinemia are also more likely to have high homocysteine (if you really want your mind blown, check out this anonymous commenter who sounds and awful lot like Dr. K on my latest Psychology Today post linking insulin, homocysteine, selenium, B vitamins, choline, NAC and basically all the pathology of disease in Western Civilization.) Those who are obese are also more likely to have high homocysteine (in some studies but not in others), even with normal serum B6, B12, and folate levels (3).
If you don't have all the B vitamins in the right amounts, or if you are on medications that change the effectiveness of the enzymes in this pathway, or if you are one of 10% of of folks genetically deficient in the MTHFR enzyme, you will end up with extra homocysteine hanging about. And that, my friends, is not good. It's a bit murky, but homocysteine is thought to do all sorts of bad things, like stiffen arteries and increase the proliferation of smooth muscle cells leading to high blood pressure and increased risk of stroke. Homocysteine is also thought to be associated with joint and cartilage stiffness, weak bones, and is probably directly neurotoxic. High homocysteine is associated with increased risk of heart attacks both in baseline healthy folks and in people with previous heart disease, and it is thought to directly damage the blood vessel endothelium and is also probably prothrombic (2). High homocysteine (indicative of an inefficient folate cycle) (the actual level that is high is greater or equal to 11.3 micromol/L, in case you were wondering) means may be low in SAMe. SAMe (as we discussed earlier) is needed in the brain to make many neurotransmitters.
Over the years, high homocysteine has also been associated with anger (1). In fact, each 10 point increase in the Hostility and Hostility Direction Questionnaire is associated with a 2.9 micromol/L increase in homocysteine. Women under psychologic stress have higher levels of homocysteine also. Homocysteine has been investigated a number of times with respect to major depressive disorder, and it was found that only those with the disorder who also have anger attacks (approximately 40%) had significantly higher levels of homocysteine.
Anger on its own is also highly correlated with risk of heart attack. In one study of Koreans getting treatment for blocked coronary arteries, 60% of the patients met criteria for significant hostility on standard scales. This is in contrast to a much lower hostility score in healthy Koreans or Americans using the same scale. Both hostility and homocysteine level correlated with earlier return to the hospital with a new coronary event when the Korean patients were followed over time.
All right. So that is just a whole truckload of correlations, without a lot of explanation. And in the papers, there are some interesting suggestions (that the stress hormones deplete the B vitamins, thus raising homocysteine, that homocysteine is directly neurotoxic, causing anger. That homocysteine is associated with higher levels of pro-oxidants and represents an inflammatory state, also neurotoxic.
In the end we have the same prescription to address all the correlations and genetic variations - eat a healthy, nutrient rich diet. Avoid obesity and stress, or engage in stress reduction. Keep your folate cycle humming, and a lot of good things fall into place. Once it is out of whack, a cornucopia of bad juju starts to happen.
Quick and catchy brand new tune by Girls - Honey Bunny (right click to open in new tab)
All right. Homocysteine. If you recall, in protein we eat an amino acid named methionine. Methionine plus various derivatives of the B vitamins, including folic acid vitamin B6 and vitamin B12 helps us make all sorts of stuff from other proteins like DNA, neurotransmitters, etc. Lots of important stuff. Homocysteine is an intermediate in the pathway, that is supposed to be recycled back into methionine (see this diagram) so that the cycle can begin again. Older people and men are likely to have higher homocysteine. Older folks also tend to eat less B vitamins. And folks with hyperinsulinemia are also more likely to have high homocysteine (if you really want your mind blown, check out this anonymous commenter who sounds and awful lot like Dr. K on my latest Psychology Today post linking insulin, homocysteine, selenium, B vitamins, choline, NAC and basically all the pathology of disease in Western Civilization.) Those who are obese are also more likely to have high homocysteine (in some studies but not in others), even with normal serum B6, B12, and folate levels (3).
If you don't have all the B vitamins in the right amounts, or if you are on medications that change the effectiveness of the enzymes in this pathway, or if you are one of 10% of of folks genetically deficient in the MTHFR enzyme, you will end up with extra homocysteine hanging about. And that, my friends, is not good. It's a bit murky, but homocysteine is thought to do all sorts of bad things, like stiffen arteries and increase the proliferation of smooth muscle cells leading to high blood pressure and increased risk of stroke. Homocysteine is also thought to be associated with joint and cartilage stiffness, weak bones, and is probably directly neurotoxic. High homocysteine is associated with increased risk of heart attacks both in baseline healthy folks and in people with previous heart disease, and it is thought to directly damage the blood vessel endothelium and is also probably prothrombic (2). High homocysteine (indicative of an inefficient folate cycle) (the actual level that is high is greater or equal to 11.3 micromol/L, in case you were wondering) means may be low in SAMe. SAMe (as we discussed earlier) is needed in the brain to make many neurotransmitters.
Over the years, high homocysteine has also been associated with anger (1). In fact, each 10 point increase in the Hostility and Hostility Direction Questionnaire is associated with a 2.9 micromol/L increase in homocysteine. Women under psychologic stress have higher levels of homocysteine also. Homocysteine has been investigated a number of times with respect to major depressive disorder, and it was found that only those with the disorder who also have anger attacks (approximately 40%) had significantly higher levels of homocysteine.
Anger on its own is also highly correlated with risk of heart attack. In one study of Koreans getting treatment for blocked coronary arteries, 60% of the patients met criteria for significant hostility on standard scales. This is in contrast to a much lower hostility score in healthy Koreans or Americans using the same scale. Both hostility and homocysteine level correlated with earlier return to the hospital with a new coronary event when the Korean patients were followed over time.
All right. So that is just a whole truckload of correlations, without a lot of explanation. And in the papers, there are some interesting suggestions (that the stress hormones deplete the B vitamins, thus raising homocysteine, that homocysteine is directly neurotoxic, causing anger. That homocysteine is associated with higher levels of pro-oxidants and represents an inflammatory state, also neurotoxic.
In the end we have the same prescription to address all the correlations and genetic variations - eat a healthy, nutrient rich diet. Avoid obesity and stress, or engage in stress reduction. Keep your folate cycle humming, and a lot of good things fall into place. Once it is out of whack, a cornucopia of bad juju starts to happen.
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