Thursday, March 31, 2011

Answering the Critics and Paleo 2.0

It may encourage you to know that I do have critics.  They don't typically show their faces on my blog itself (and I haven't moderated any comments away except some insane unrelated treatise on vaccines and when one single commenter was being a bit too enthusiastic about curcumin to the tune of 10 comments at a time, and all the viagra and birds nest soup spam ("Katherine Woo" and "alan," I'm looking at you)), but they do exist.

An early one had a review of my blog, here - his main critique is that paleolithic human's health is debatable.  Certainly their mental health is, but bones are bones, and metastasis and iron deficiency and whatnot are there for the discovering.  This critique falls into the general one that evolution isn't a good paradigm on which to base a lifelong health prescription.  To which I say - you haven't studied enough anthropology or evolution.  And I still contend that it is a very reasonable assumption that wild-type humans did not struggle with anxiety and depression and other major mental illness to the tune of 26% of the population per year.

Another critique is more generic and one I see on tweets on reddit (where the really cool people tweet rather indifferently) - that I am not proscriptive enough.  "That post was I guess kind of interesting but she didn't really say what to do."  Well, I've trained as a therapist, after all.  Any therapist who tells you exactly what to do is a fool.  If you follow my advice to the letter, you don't give yourself enough credit.  If you do the opposite in defiance, you don't give yourself enough credit. Either way you don't learn a damn thing.  (Little hint to newly minted therapists out there - never ever ever tell someone explicitly not to have an affair.) I'm interested in putting out the information.  It's your life, your body, your mind.  Do whatever you want.

Predictably, the other common critique is that I overreach (that I am perhaps too proscriptive).  An example is this doctor/farmer's tweet -  and that is the critique that I am perhaps most sensitive to.  The wisdom of alternative medicine has been undone by overreaching in the past.  I have no interest in repeating the meme of ridiculous alternative assertion and self-righteous conventional medicine refutation.  I hope I am careful not to overstate my case (as I was careful in the Wheat and Schizophrenia post the good doctor objected to).   Most of what I am interested in has not been properly studied.  But, of course, it ought to be :)

There have been other random and downright bizarre critiques along the way, but, for the most part, the internet reception has been quite positive.  Now that I have moved more mainstream with Psychology Today, I have encountered a bit of anti-psychiatry critique in general, and to be honest I'm not too interested in spending the time refuting it, but I guess I will do my best until it gets too boring.  The major issue I have is when someone assumes I know nothing about mental illness or the natural history of mental illness just because I also have experience with and utilize the medications in treating mental illness.  Yes, I know there are horrific side effects.  Yes, I know there is controversy.  There are even hopeful and Pollyanna ideas that psychosis is more appreciated and accepted in traditional cultures and that our modern ideas and lifestyle have falsely defined and pathologized psychosis.  Well, one of my professors in residency spent a lot of time in remote areas of Africa, and what he found was that the rare-ish person in a hunter gatherer population who is psychotic is either able to keep it together enough to be a bit of a shaman, or he or she is tied to a tree for most of his or her life.

I wish the Pollyanna version was true.  But I live in the real world, as do all of you.

Here is one of my favorite pieces of classical music (right click to open in new tab).  I'm positive I've linked it before, but there are a lot of new readers now, and it is apropos.  La Befana is harsh, and obnoxious, and wonderful, and fast, and celebrates life and humanity.  It is messy and offensive, but everything resolves into beauty at 3:06.  Hold out until 3:06.  In the last part of La Befana is encoded the secret of life and the universe, I promise.  La Befana is science, and surety, and slaughter.  Blood and celebration.  Roman orgies.  Sacrifice, and spring, and life.  Fires at sunset, and a smoky hung-over dawn.

Paleo 2.0 is a go.  (Well, I do take a little exception and think that early human migration patterns suggest that we did, indeed, eat an awful lot of marine animals for many many generations).  But, yeah, for the most part I am a Kurt Harris acolyte - all the more so because he would be uncomfortable with that term.  He is the lean paleo (as in archaic) wordsmith machine.  It's all right to admire.  We need a few touchstones in this post-modern industrial wasteland of human health advice.  What I don't need is some other self-important jerk with a pot belly and bedazzled glasses telling me to eat boneless skinless chicken breast and quinoa.

By all means, make it simple.  What is good for the body is good for the brain.  The neolithic agents of disease are wheat, excess fructose, and excess linoleic acid.  What goes without saying is the nonfood.  Don't eat it.  Oh, and be sensible otherwise.  For the most part, eat when hungry, and don't when you aren't.  Fast every once in a while to enjoy the full human experience of hunger and repletion (not to mention ketosis and autophagy).   Be strong.  Run around the yard and swim in the ocean and sprint up the street and hike up the hill.

What is in store for us?  Inflation?  Peak oil?  Epidemics?  Natural disaster?  Technology and brilliance and flourishing human populations?  Irregardless you will be flexible and physically and mentally healthy, as much as is practical and possible.

Or at least I hope that is so.  For me.  For my children.

No Show at Clinic

So I refurbished another post:

Depression - Caused by Inflammation - Thus Like Other Diseases of Civilization

Such a staid title!  Oh well.  This is serious business.

Tuesday, March 29, 2011

ADHD, Mood Dysregulation, and Micronutrients

What is patently obvious to anyone who has spent more than 10 minutes studying nutrition literature is that any truly effective nutritional intervention will have to be pleiotropic.  That is, muti-faceted.  Adding one isolated mineral or vitamin or spice or whatever on its own is rarely going to hold up to population-wide study, or, as Kurt Harris would say, "no magic foods."  The probable exceptions to this rule in mild conditions are fish oil and magnesium - but that is likely because they are so incredibly vital to health, and so horribly deficient in the SAD.  So I'll grant that a simple magnesium tablet (or hard water) will help cardiac function and anxiety when added to a diet of ho-hos and cheese curls and cola.

Anyway, very recently some psychologists in Christchurch, New Zealand put out this paper (tweeted by Jamie Scott), Effect of Micronutrients on Behavior and Mood in Adults with ADHD: Evidence From an 8-Week Open Label Trial With Natural Extension.  They did something rather sensible - they tested a multimineral/multivitamin.  Here is their perfectly sensible reasoning:  "this approach of using one ingredient at a time may be too simplistic, as interventions of single ingredients may actually upset nutritional balances, creating deficiencies of other nutrients…. therefore, a more effective nutritional intervention to evaluate for mental or physical health may be one containing a broad array of balanced nutrients."  Hallelujah.  I'm not sure how these psychologists keep getting research funding, seeing as how sensible they are, but we have this paper and let's run with it.  Of course, a natural foods nose to tail diet and swimming in the ocean and/or drinking mineral water will give us all the micronutrients we need.  But y'all know that already.

Another cool thing about this paper is that the researchers studied adults with ADHD.  And adults with ADHD tend to be complicated.  See, once you've managed to spend a majority of your life fighting inattention and hyperactivity when everyone else seems to be able to just sit down and do your taxes like you are supposed to, you are liable to be stuck with some ancillary depression or anxiety from the level of stress and frustration that develops from dealing with ADHD.  In fact, 75% of adults with ADHD have an additional psychiatric diagnosis.

In this open-label study, 14 medication-free adults with ADHD and mood issues (episodic symptoms of irritable, low, or elevated mood) were given a supplement called EMPowerplus.  Here's the ingredient list.  This multi is rather expensive (a two month supply at 8 capsules daily is about $75) and was studied previously in bipolar disorder.   In the ADHD study, the participants started of with 5 capsules daily (divided into three doses) and eventually increased to 15 capsules daily (which takes you to > $70 a month for the pills).  My grassfed beef + organ meat and tallow order is just a bit less than $100 a month for the whole family (including shipping), and I get lots of steak included.  Just sayin'.

The results of the trial were impressive.  After 8 weeks, there were significant improvements in all ratings (patient, clinician, and an observer) of mood instability, hyperactivity, quality of life, anger and aggression.  Inattentiveness (the primary ADHD symptom and the basic neurological issue) improved, but remained elevated compared to ratings of people without ADHD.  The study participants were told how to get the supplement, and 7 of the original bought EMPowerplus and kept taking it - after two months their measures continued to improve.  Those who came off the supplement either maintained their initial improvement, or began to regress.  2 participants on EMP+ were also able to quit smoking.  Intriguing!

Perhaps even more interesting is that two of the participants entered the trial with severe Obsessive Compulsive Disorder symptoms, and their OCD symptoms remitted by the end of the trial.  Anyone who treats OCD will understand that OCD is tough tough tough, and in general the gold standard is intensive behavioral therapy plus (typically) the highest available dose of an SSRI that won't take full effect for three months.  The fact that a (I'm hoping, considering the price) pharmaceutical grade multi could ameliorate OCD symptoms, even in a couple of case studies, is amazing.

The discussion in this paper is impressive, and once again far too sensible for standard academia.  Must be that grassfed meat they have available at the supermarket down in New Zealand.  The researchers suggest that neurotransmitter synthesis, second messenger signaling, and the efficiency of brain energetics could all be impacted by our crappy diets (hey, that's the whole thesis of my blog!).  There is evidence that nutrient content of the food supply has diminished over the past 50 years (which is why I subscribe to a summer CSA box from local  farmers who are Joel Salatin acolytes and add organic seashell mineral mush to the fertilizer.)  The researchers were also very fair about the limitations of the trial - it was exceedingly small and open-label with no control.  Basically a wee pilot study, proving nothing, but (hopefully) to be used evidence to apply for much larger (expensive) randomized controlled trials from which we could actually glean some sensible data.

As if that will ever happen.

In the mean time, I will go straight to the fallback of an evolutionary diet plus sensible additions such as dark chocolate.  Just as expensive, perhaps, but a lot tastier.

Sunday, March 27, 2011

Another Refurbished Post and Song

Happy Sunday!  I uploaded/updated another post on Psychology Today.  And here's a song, too, by Nancy Sinatra.

Bang Bang

How Stress Makes You Sick and Sad  (literal titles work well)

Here's one more song, good for a Sunday.  Jeff Buckely Hallelujah.

And one more.  For good luck.  Mad World (the Donnie Darko remix)

Shucks.  Can't really link a Jeff Buckley song without linking his best one ever:  Lover, You Should've Come Over.

Saturday, March 26, 2011

Stress and Your Gut (Or At Least A Mouse's Gut)

Several folks (Julianne and Chris Kresser come to mind) tweeted about this new paper last week, and it really is a doozy.  "Exposure to a social stressor alters the structure of the intestinal microbiota:  Implications for stressor-induced immunomodulation."  The associated editorial is worth a read as well, if you have access.  Also, the journal it comes from, "Brain, Behavior, and Immunity" is very cool.  The entire journal is devoted to subjects of interest to any psychiatrist who looks into the inflammation/brain connection.  And if inflammation itself is truly behind the pathophysiology of psychiatric disorders, then somewhere in the archives or future of this publication will be the holy grail linking inflammation via diet and lifestyle to actual brain pathology.

This paper is a nice start.  First some fun facts.  The external surfaces of the body (that includes the gut, by the way, as we are a funny tube within a tube) are populated with microbes.  So populated, in fact, that 90% of the cells that make up the roving bacteria party + human host are the commensal microbiome.  Yup.  90% of you (by cell number) is them.  Most of these colonizers and symbiotes live in the intestine, especially the large intestine.  In the Matrix world of commensal species, the large intestine is Zion.

Here's the crazy thing - we know very little about these species.  Mostly because the vast majority seem to be absolutely dependent upon us (as we turn out to be symbiotically dependent on them).  They can't be cultured without the host in a lab.  They need a living working gut, where they flourish, but are difficult to study.   That means we didn't have the capability even to catalog the species of gut bacteria until we could practically and relatively cheaply sequence DNA in large amounts, so not until the last 7 years or so.

The beasties live in a "largely stable climax community" in our guts as the result of natural selection for species best adapted to our habits and personal nooks and crannies.  Fortunately, the beastie community is pretty resilient, but factors such as a change in diet and antibiotics will obviously transiently affect the population.  In addition, exposure to stress also changes the population of beasties, the details of which were more clearly elucidated by the work in this paper.

The beasties do all sorts of nice things for us, really.  They make vitamin K, several B vitamins, and eat up carcinogens and other nasties.  Their health and composition are definitely related to the pathology of obesity and of diabetes (at least in mice).  And, not surprisingly, these bacteria impact the immune system.

Germ-free animals raised in sterile environments without commensal microbiota have a different sort of intestinal immune system, with a lower amount of intestinal antibodies and fewer immune cells.  Colonizing these sterile mice will result in normalization of the gut immune system.  Alterations in the intestinal microbiota has been linked to asthma in animals and humans, suggesting that the beasties modulate adaptive and innate immunity.

Y'all might remember that some of those cytokines and immune system chemicals that are produced in the process of inflammation are known to be elevated in the case of depressive disorders.  Chemicals with names like IL-6, TNF alpha, and interferon gamma.  IFNgamma is known to actually cause depression.  Who cares?  Well, translocation of gut bacteria through the gut lining into the comparatively sterile body interior results in a systemic increase in IL-6 and the other cytokines.  We talked about that a little bit in relation to depression and chronic fatigue in posts a few weeks ago.  Psychological stress in humans, such as caring for a sick relative or chronic work stress, also is associated with elevated cytokines IL-6 and TNF alpha.  So the question asked by these researchers (and subsequently answered) is - does psychologic stress change the microbiota population, and is that related to a cytokine change within the body?

The experiment itself was complex and consisted of several different arms, and many mice made the ultimate sacrifice (along with their gazillion commensal microbiota).  In short, some mice were mostly left alone, others were given antibiotics and stress, others just exposed to mean "aggressive mice," others were restrained, and others given antibiotics and restrained...

So what happened to the microbiota and the levels of cytokines in these various experiments?  Well, the mice exposed to stress had definite changes in internal beastie populations.  In general,  exposure to stress (the mean mouse, or restraint) led to "a reduction in microbial diversity and richness."   In addition, exposure to the stressor led to a significant increase in IL-6 levels.  Interestingly, the specific genus of the population of microbiota were significantly related to the generation of IL-6.  TNF-alpha and INFgamma were also increased in stressed mice, but not significantly.

In the antibiotic-treated mice (with a pummeled microbiota), the IL-6 did not increase in response to stress.  Antibiotics reduced the amount of bacteria about 100-fold, so while it didn't eliminate the commensal bacteria by any extent, it made a good dent in the population.

Taken together, these results tell us that stress affects our gut bacteria, which affect our immune system and cytokines.  We know those increases are related to changes in psychological states.

The editorial quote of note:

The strength of implementing a truly integrative systems approach when studying stress physiology has never been clearer than in the work by Michael Bailey and his colleagues in this issue of the journal.  These scientists investigated the impact of stressor exposure on multiple physiologic symptoms, including the intestinal microbiota and the immune system.  These data reveal dynamic interaction between these systems when orchestrating the innate immunological stress response. 

So yes, they control your brain.  To some extent.  Best keep the beasties happy.  Kefir and sauerkraut anyone?

Thursday, March 24, 2011

Dieting Can Make You Lose Your Mind

Refurbished Semi-Starvation post over at Psychology Today, with added squirrel:

Dieting Can Make you Lose Your Mind

As for this blog (which for the forseeable future will have the new cutting edge stuff), I have a big stack of papers to read, and some grouchy ipad posts to write for the weekend!

Monday, March 21, 2011

Low Cholesterol and Suicide at Psychology Today

I've combined three previous posts into a cogent and magnificent piece over on my blog at Psychology Today:

Low Cholesterol and Suicide

- Posted using BlogPress from my iPhone

Sunday, March 20, 2011

ADHD and Omega 3

I did get a chance to read over some interesting papers yesterday. Unfortunately, my home computer stopped working yesterday while I was on twitter. That's probably the universe telling me something. Our interventions seem unable to bring the dead PC back to life. So I'm a little cranky. Also, since it is more difficult to link things on the iPad, it will probably take me a few days to link the papers. In the mean time, you are just going to have to take my word for it. What do you think - is a Macbook is really worth it?

It will not surprise you to know that folks have been looking at the O6:O3 ratio in ADHD - as researchers have been looking at the same thing in depressive disorders and other psychiatric disorders. It may also not surprise you to learn that much of the early research is fairly useless, as ADHD was not defined rigorously and things like medicine, IQ, and education were not always controlled for. However, since 2007, more meaningful work has been done, and several smallish studies have found similar trends to the previous research. The punch line is that folks with ADHD tend to have significantly higher O6:O3 ratios in their bodies than folks without the disorder. Also, kids and young adults with ADHD have lower DHA.

When O3 supplementation has been tried (typically just DHA or EPA and DHA), it has been a bit of a bust (just like the trials with Alzheimer's and several of the trials with depression). Some parents and teacher ratings noted less temper tantrums and better ability to pay attention, but more objective ratings (such as cognitive testing) and independent raters of behavior didn't notice any difference. It is important to keep in mind that O3 supplementation trials have always been more successful in milder and earlier forms of illness - mild cognitive impairment, depressive disorders not complicated with anxiety. Also, to my knowledge decreasing O6 at the same time has never been studied. In addition, while sometimes the placebos are soybean oil or something like that, other times olive oil is used, and there is some evidence that oleic acid might also have beneficial effects on behavior and mood. ADHD strikes young and sticks around. Therefore it is a tough disorder that is in part hard-wired, and in my mind, *just* O3 supplementation is unlikely to be of much benefit.

One more very interesting thing to keep in mind - at least in these studies, overall the diets of the ADHD kids did not differ significantly from the control kids (diets were typically measured with 1-3 day diet logs, so take from that what you will). So the control kids ate just as much O6 and just as little O3 as the ADHD kids. In the study of young adults, the ADHD kids were significantly more likely to take a vitamin pill, and their micronutrient profile on blood testing was actually better or not different than the controls with respect to magnesium levels, iron, folate, zinc, B6, B12, etc. Independent studies of many of those micronutrients showed benefit for ADHD in kids who were deficient in small trials also. Yet despite the similarity in diet, the ADHD kids still had more O6 hanging around in the body, and less O3.

Some other interesting things popped up while reading these papers. In one study, the researchers looked for signs of "essential fatty acid deficiency." People who are too low in PUFAs in general will have dry mouth, thirst, frequent urination, dry and flaky skin, brittle nails, and dandruff. Sure enough, kids with ADHD were more likely to have these symptoms, and the kids with these symptoms had a more out-of-whack O6-O3 ratio and less DHA in the body. Their out-of-whack ratios also responded more robustly to dietary supplementation with DHA than the kids who didn't have symptoms of essential fatty acid deficiency. However, the absolute levels of essential fatty acids in these kids weren't, in the strict sense, deficient, despite the symptoms.

How do we pull all this information together? Well, in my mind, something very important is going on in a subset of kids with ADHD and their needs for PUFAs, and their utilization of them. DHA is vital for neuroplasticity, proper nerve communication, and nerve repair. Once more you will not be surprised that kids and young adults with ADHD have signs of inflammation - higher ferritin, higher IL-1, etc. etc. etc. The inflammatory process may also change PUFA metabolism or utilization, while the PUFA ratio could affect how the inflammatory process is played out. One small study showed that families with an allele of a gene that was super-robust at making a form of the inflammatory cytokine IL-1 had much higher rates of ADHD. It would make sense that certain families are genetically more prone to brain insults caused, perhaps, by lifelong DHA deficiency or O6 excess while the brain is developing. Or it could mean that some of these families have problems with how O6 and O3 are transported or stored or something, so even sufficient amounts in the diet don't add up to enough for them.

We also should keep in mind that the only large dietary study (a dietary pattern study in Australia, and we know that dietary pattern studies may be more problematic than they are worth) showed a higher risk of ADHD in folks who ate a Western diet. Also, boys in the Australian study and in these O6:O3 studies trended towards being more affected by diets or out of whack ratios, and benefited more from supplementation than girls.

Clearly this issue is a rich area for more research. In the meantime, it doesn't hurt to get enough O3 (particularly DHA). If you eat higher fat, enough O6 will naturally come along for the ride, so no eating extra O6 either.

Next week - one or more posts cleaned up and migrated to Psychology Today, updating this post to add references, and who knows what will come down the line so far as papers and new stuff. And probably, a new computer. Sigh.

Friday, March 18, 2011

Human Limitations

I have a tax appointment this morning, two birthday parties this weekend, and an inability to sit for extended periods due to a mishap on the stairs yesterday involving toddlers and mukluk socks.  Everyone is fine except my tailbone.  Excuses, excuses - I likely won't have a true new blog post out this weekend.  Instead, here are some goodies from the archives:

Secrets of the Synapse

Zinc, Depression, and Everything

Acne and Suicide

And because blogging is even more fun when you get paid - if you haven't already (or if you want to re-read), please click over to my two posts at Psychology Today - yesterday I spent some time on the "most read" list (at #5) and was 3rd or 4th in most emailed for much of the day - along with being an "Essential Read" for the site and under the subheading depression.  I have almost 8000 hits for both articles combined. Coupled with PaNu's big entrance, it seems like a great success for paleo!   I also appreciate all the community love in the comments - some newcomers may never have been exposed to these nutrition ideas before and seemed excited, but wanted some tips and had questions about the minutia I wasn't quite prepared for!  Fortunately, you had wonderful ideas and answers over there. 

Welcome to Evolutionary Psychiatry

Your Brain on Omega 3

There is an article or three I would like to blog about - so if I do get a moment, I'll have something new... we shall see!

Sunday, March 13, 2011

Sleep, Behavior, Hyperactivity and Attention in Children

If you ask the experts, they will tell you that approximately 9% of children in the US have the cluster of symptoms defined as ADHD.  5-16% of kids will have what is called "Oppositional Defiant Disorder," where kids deliberately break the rules, are quick to anger, and will often be sensitive and vindictive, among other problems.  Perhaps not surprisingly, these disorders overlap, with something like 50% or more of kids with ODD also having symptoms of ADHD.   It is also stressful and difficult to be surly and argumentative - 35% will also have a mood disorder, such as a depressive disorder.

I've already blogged quite a bit about the best research on the suspected links between diet and ADHD.  Kids diagnosed with ADHD were put on an anti-allergy diet (meat, vegetables, rice, water, pears and, for some, small amounts of wheat, potato, and other fruits), and 60% of them had significant improvement in ADHD and oppositional symptoms, which returned when they were switched back to the "healthy" control diet.  But another important behavioral link to ADHD is sleep quality.  It is known that kids with ADHD are poor sleepers in general compared to kids without ADHD, but what comes first?  Do the brain changes in ADHD screw up sleeping patterns, or do the sleeping pattern problems cause ADHD?  It may actually be a two way street for many, but a compelling recent line of research suggests that lack of sleep may be the causative issue for some kids.

First, some definitions.  There are basically three kinds of "sleep-disordered breathing" in kids:  obstructive sleep apnea (OSA - more common with obesity and allergy where kids get large tonsils and adenoids), upper airway resistance syndrome (UARS - probably also a structural or allergic phenomenon), and primary snoring.  There is also the relatively rare central apnea, where kids stop breathing and drop oxygen levels because the brain seems to forget to tell the lungs to work sometimes in sleep (happens with 10% of people on chronic opiate treatment for pain, too!  Scary.)  The difference between the obstructive and upper airway resistance apneas have to do with differences in how the diaphragm and chest work together to push the air out.  In both cases, the oxygen levels in the blood drop due to not getting enough air.  Do this all night, every night, and your brain gets to be a bit irritated with you.  Brain needs oxygen.  However, even kids who snore without dropping oxygen levels (the primary snorers) have more interrupted sleep and problems similar to those kids with OSA and UARS (1).

What kinds of problems?  Well, hyperactivity, poor attention, if young, lower scores on IQ tests, defiant behavior, poor grades.  Sounding familiar?  Interestingly, studies haven't consistently shown a connection between OSA and defiant behavior and low IQ in adults, though there are issues with inattention in adults (2).  In a study of kids with OSA who have surgery to remove the big floppy tonsils and adenoids that kept them from breathing properly (3), aggressive, inattentive, and hyperactive behavior significantly decreased following the surgery.   That's a pretty telling finding strongly suggesting that poor sleep in kids causes symptoms of ADHD and ODD.

In the German study of 1114 mostly Caucasian kids (1) from a random sample of schoolchildren, 114 ended up being habitual snorers, with most of that number ending up diagnosed with primary snoring, and a smaller number UARS and OSA.  It is interesting to me that number is pretty similar to the 9% overall prevalence of ADHD (though not all snorers had ADHD symptoms, and some never-snorers had ADHD symptoms).  

In the Cinncinati study of overweight older children and adolescents (2), it was noted that childhood obesity rates in 10-16 year olds have tripled in recent decades, to 16%, and minorities are overrepresented in this group.  13-39% of these obese kids will have sleep disordered breathing (SDB).  Among the obese kids without sleep problems, very few made the cut-off in this study for attentional problems, whereas of the kids diagnosed with SDB, 44% of them were defined by parents and 38% defined by teachers as having attentional problems.

To add yet another wrinkle, in a 2008 Yale study, 34 kids age 7-19 with metabolic syndrome and a positive sleep problem questionnaire were recruited to have sleep testing done.  25 of them ended up with sleep-disordered breathing, and those kids had higher sympathetic response (suggesting a raised level of overall stress, which eventually puts one at risk for all those diseases of inflammation, especially depression, anxiety, etc.) and higher leptin levels while insulin resistance was not elevated.  This is some evidence that leptin resistance occurs first, prior to insulin resistance, in the pathology of metabolic syndrome.  Treatment of the sleep-disordered breathing with a CPAP machine (a contraption that you wear at night to help you breathe better) for three months resulted in a near significant decrease in sympathetic activation, and a significant decrease in leptin levels.

Sadly, of a group of obese kids 4-20 years old, 38.7% of the moderately obese had metabolic syndrome , and 49.7% of the severely obese kids did.  Obesity in kids, as well as adults, is associated with hypertension, dyslipidemia, chronic inflammation, increased blood clotting, endothelial dysfunction, and high triglycerides.

The big picture - what is a common solution that would presumably help the inflammatory/allergy and the metabolic syndrome/obesity issues with oppositional behavior and attention in kids all at the same time?  Might it be that same old paleolithic-style diet I keep coming back to, along with regular exercise and dedication to proper sleep habits?   Killing all birds with one skillfully thrown stone, the evolutionary medicine lifestyle.  Again.

Saturday, March 12, 2011

Exciting News

Recently I have been invited to join the regular stable of writers who blog at Psychology Today.  I'm very happy to go forward and represent, to some extent, the paleolithic community with this wider exposure.  I'm also pleased by the intriguing work done by the other bloggers there.  Fortunately, I have complete editorial control over the content of the articles.  I will begin by updating and cross-posting some of my better entries over there, but I may end up putting wholly original material there also.

The blogging over there also pays by the page view.  Seeing as how I just bought a new thyroid textbook, please do me a favor and go have a look!

Welcome to Evolutionary Psychiatry

(Thanks so much to Dr. Kurt Harris for recommending me, and putting me on his blogroll, which is apparently how the editor at PT found my blog.  Didn't mention it at first as I didn't want to spoil his own announcement! However, it does make the opportunity doubly exciting, as the potential to reach the mainstream with PaNu's gift for turn of phrase is just amazing.)

Thursday, March 10, 2011

Hodgepodge of Speculative Neurotransmitter Madness - Magnesium!

Ugh. I have a cold. I had been invincible, contracting H1N1 (most probably) with the only symptoms being a headache, missing norovirus gastroenteritis over Christmas, seeing cold after cold take down others while I had a mere sniffle and a bit of a scratchy throat that resolved in a day. Until the oldest went to pre-school and brought home a doozy, with sniffles keeping her awake, then her sister, who loves to suck her thumb and cannot sleep with a stuffy nose, poor pooky doo - which meant 5 nights in a row of horrible broken sleep, and then I succumbed to the virus myself. Today I caved and bought some sudafed (my name is now on a mysterious government registry of potential methamphetamine makers), and since the strongest substance I normally imbibe is tea, I'm feeling a little racey right now. Racey and less sniffly than this morning. Which is perfect, because Pubmed sent a crazy short paper to my inbox the other day, Dextromethorphan as a potential rapid-acting antidepressant.

Let's keep in mind this 3 page ditty was published in Medical Hypothesis, which we might as well rename "Rampant Speculation That Is Pubmed Searchable." Which is great, really. We can call it the bleeding edge of science. But let's not jump to act on these speculations. Let's learn from them about the brain and how it works.

To be more explicit - DO NOT go out and down a bottle of Nyquil (with dextromethorphan as the cough suppressant ingredient) for its hypothesized antidepressant effects. You may notice that another ingredient of Nyquil is acetaminophen (Tylenol) which we were talking about earlier this month and how unpleasant moderate amounts can be. You've been duly warned.

Back to the paper. It begins with the club drug, horse tranquilizer, and childhood anesthetic agent (kids are apparently less bothered by the hallucinations than adults), ketamine. Ketamine sits on the NMDA receptor and keeps glutamate from doing it's dire deed of letting calcium ions through and wreaking havoc on the poor neurons. There are actually a number of studies (1) showing that IV ketamine infusion can nearly instantly relieve a severe depression. Unfortunately, there is usually a relapse within a few weeks, so it is not the most practical of remedies. But its temporary success has led researchers on the hunt for other pharmaceuticals which will act on the NMDA receptor.

Dextromethorphan is an interesting pharmaceutical primarily used as a cough suppressant. However, it has multiple effects, including NMDA receptor antagonsim (like ketamine), a mu opiate receptor agonist (so it is an opiate), and a serotonin receptor blocker, calcium channel blocker, and muscarinic receptor blocker. Most of the activities of this pharmaceutical can have positive mood effects. Therefore it might have some antidepressant effects, similar to ketamine.

What do we know about antidepressant action at the NMDA receptor? Well, one of my favorite minerals, magnesium, can sit on the receptor and block access to glutamate. Several reports (discussed in my blog post here) connect low magnesium levels to depression, and supplementing magnesium can have rapid antidepressant effects, even in treatment resistant depression. Low levels of magnesium in the spinal fluid have been documented in treatment resistant depression. A randomized controlled trial of magnesium chloride vs. tricyclic antidepressant imipramine showed equal antidepressant efficacy in 23 patients with hypomagnesemia, type II diabetes, and depression (2).

Another antagonist of the NMDA receptor is PCP ("angel dust") which can cause immediate rage and depression - unlike ketamine. (I had the action of PCP backwards at first until Peter kindly corrected me - but the paper was a bit confusing on this point. Nor have I seen PCP usage since 2003 - and then only once, so the pharmacology was rusty. Angel dust is not big around these parts. Probably not that big anywhere considering just how unpleasant it is.)

Back in 2003 I was a resident working the emergency room as the psychiatry consultant, finishing up an evaluation, when a new patient was brought into the ED causing quite a rumpus.   The emergency room resident came up to me almost immediately.  "We have someone else for you."

"Why me?  I bet you $20 she's as high as a kite,"  I said.  (Actually I never would have said that.  Residents are fairly universally destitute and would not risk $20.  Probably I just said, "She's as high as a kite.")  An important distinction, actually, as I can't legally send one to the hospital against her will simply for being high (nor would I want to).  Nor does someone who is high enough to significantly affect judgment technically have the capacity to make important treatment decisions such as "Am I willing to be locked up into a drug treatment program" or not.  Nor does a sit down discussion and motivational interviewing about getting treatment do much good when someone is high.  Therefore, when someone is high, my options as a psychiatrist are essentially nil.  We have to wait until the feet are a bit more on the ground.

Well, the tox screen came back positive for all sorts of things, PCP among them, which I think explained quite the level of rumpus-making - we don't get a whole lot of meth in the Northeast except in certain populations - mostly it is alcohol and opiates and cocaine. A few hours passed by and the person was able to go home with some options for treatment should she choose to pursue them.  

Keep in mind, friends, that PCP and large amounts of ketamine or dextromethorphan cause hallucinations. Which doesn't sound like that much fun to me.

The author if the paper calls for trials of dextromethorphan in the treatment of depression (currently there are none.)

Personally, I'm more intrigued by the magnesium angle. Way more paleo. Cheaper. No hallucinations. No addiction that I'm aware of. And most of those on a standard diet imbibe less than the RDA. Magnesium is one of the few supplements I take regularly, because it is hard to get in appropriate amounts without drinking untreated spring water, and it is so vital.

Further reading:

Magnesium and the Brain

Monday, March 7, 2011

Low Cholesterol and Bipolar Disorder

I would say most cardiologists still believe that for cholesterol, the lower the better. In the diet, in the serum, in the liver, in the arteries. However, it is safe to say that super low cholesterol is not better in the brain. The dry weight of the brain is 60% fat and cholesterol is vital to synaptic function. Low cholesterol seems to be associated with Alzheimer's, suicide, and violent death. The association with depression is spurious. Turns out, however, that people with bipolar disorder also seem to have lower cholesterol - and that it gets lower during mixed manic episodes (a very uncomfortable combination of mania and depression that is particularly hard to treat), and also in manic episodes (1). As the mood swings remit, the cholesterol tends to get higher. And no one really knows why that is or what it means - is it some sort of biomarker of inflammation? Does the low cholesterol itself cause the problem? And yes, bipolar disorder (and depressive disorders) are associated with metabolic syndrome, but especially in bipolar disorder, the link to serum lipid alterations is much stronger to high triglycerides than high LDL or total serum cholesterol. Also interesting - depressed folks with high cholesterol are less likely to respond to antidepressants than folks with low cholesterol.

I've already discussed what low cholesterol can do to the serotonin receptors in Low Cholesterol and Suicide 2. Two different subtypes of serotonin receptor seem to be particularly affected, and as low serotonin is associated with violence and suicide (but not *necessarily* depression), it is intriguing that low cholesterol is associated with the same.

But in chasing down the original paper (2) that sparked this post (in the Journal of Clinical Psychiatry, which has the most user-unfriendly interface and I hate it when I have to find papers there), I came upon a meatier paper on mixed manic episodes, which led to a number of other neurotransmitter and brain stuff and cholesterol papers.  From here on out the neurochemistry is a bit heavy, so strap in.  Here's a nice Graffiti6 song, to make it all wash down easier (right click in new tab).

Big picture - most of the cholesterol we use in the brain is made in the brain.  However, autopsy studies show us that cholesterol levels in the brain correlate to those in the rest of the body, and statins and cholesterol-lowering medicine that cross the blood brain barrier will likely have similar effects in the brain as they do in the liver - at least the work of Golomb seems to suggest this is the case.

So we know from the previous posts that we need cholesterol for proper myelination of nerve fibers (myelin is insulating for electrical conduction and also specially designed so that nerve signals run faster. Demyelination - then you have slow and fritzy conduction, and big problems, as in multiple sclerosis), and we know we need it for proper serotonin signaling. Not only are the 5HT1A and 5HT7 receptors particularly affected (serotonin = 5HT), but cholesterol also stabilizes the serotonin transporters. Cholesterol is a critical component of the "lipid rafts" through which a lot of membrane communication transpires.

In Low Cholesterol and Suicide 2, I also made a brief note that cholesterol may be involved in GABA and NMDA receptor signaling, opioid signaling, and the transport of excitatory amino acids. All those are a rather big deal when it comes down to the totality of how the brain signals information.  So today I wanted to review that in a little more detail.

Glutamate (the excitatory amino acid in question) transport may be entirely altered by cholesterol depletion, at least in mice. It seems to affect the sodium powered transporter directly (3). I talk about glutamate a lot - in fact, last week I called it the excitatory neurotransmitter of doom. Almost every "paleo" intervention (such as ketosis, decreased inflammation, having enough nutrients like magnesium, proper sleep, meditation - which is not paleo, of course, but I feel emulates the necessary "being in the moment" that a hunter-gatherer would face hunting, gathering, collecting, building, etc.) - seems to modulate glutamate in a way that is favorable for neuron plasticity and repair. The SAD and stressful modern life promote glutamate excess, which will tend to cause neurotoxicity and eventually neuron death. Oops.  Having glutamate work for you instead of against you is all about energy and having the right machinery to send glutamate through the transporter at the right place and the right time - so skunking those transporters by depleting them of cholesterol seems like a crazy bad idea.

One of the places glutamate acts is at the NMDA receptor.  Turns out the NMDA receptor itself needs to be rich in cholesterol to do its work. (5)(6) If the NMDA receptor is depleted of cholesterol, there is a potential that it may fire differently, irregardless of the amount of glutamate out there.

And then there is GABA, who is rather like the Glenda the Good Witch compared to glutamate's Wicked Witch of the West. GABA transmission is relaxing. Literally like a nice glass of wine (which affects the GABA receptors). Yoga seems to increase GABA in key areas. Well, cholesterol depletion decreases GABA transmission too (4) (which it seems, in rats at least, that both depletion and major excess of cholesterol will do. So not too high (250% of normal) and not too low (56% of normal in this rat study) Low GABA signaling = anxiety, irritability, and sleep problems (symptoms associated with statin and cholesterol lowering drugs according to Golomb). These symptoms will also be prominent in a mixed manic episode (we did start today with bipolar disorder, after all).
Finally, there is opiate.  Good old opiate.  Opiate receptors (not surprisingly) along with dopamine are involved in the reward system of the brain.  There are several varieties of opiate receptors, but the delta receptor is associated with mood effects (7).  This subject is very complicated and I'd rather conquer it in a few more posts, but the short version is that cholesterol depletion seems to reduce the signaling capability of the delta opiate receptor in neuronal cells.  This could, of course, presumably affect mood.
That's it for now.  And perhaps it is not surprising that cholesterol, in a part of the body absolutely brimming with it, will have explicit effects on nearly every signaling pathway you ever heard of.  Which is why I get a little bit perturbed when you realize that in many statin studies, people with psychiatric illness were excluded.  People with mental illness make up a rather large percentage of the population (NIMH says 26.2% of adults in the US in any given year (8)).  What happens when you take a brain that is already firing a little off, and deplete it of cholesterol?  Gosh, it sure would be nice to know before we recommend statins for large percentages of the population.  Oh, wait, it seems we've already done that...
To be fair, there was a large analysis of statin trials looking for new onset mental illness perhaps caused by statins, not finding it to be the case (9) - though they acknowledge that dietary interventions lowering cholesterol and non-statin drugs did cause issues, suggesting that, yes, indeed, cholesterol is important in the brain, and perhaps the magical anti-inflammatory effect of statins is once again the only thing that saves them from just being plain old harmful to everyone.  And, again, many of those trials excluded people with previous psychiatric illness.  Questions, questions, questions.

Saturday, March 5, 2011

Leaky Gut and Chronic Fatigue Syndrome

Jen linked another Maes leaky gut paper from the comments in the Depression and a Leaky Gut post.  This paper is a case report of a 13 y/o girl with chronic fatigue syndrome.  In January 2005, the girl had a sore throat.  Thereafter she began to have progressive weakness, increasing fatigue, unrestorative sleep, abdominal bloating, headaches, a 22 pound weight loss, and poor concentration to the point where the girl was in a wheelchair and no longer able to study for school.  From the beginning, after nothing too obvious was found by the internal medicine doctor, the patient's parents were urged to take the girl to a psychiatrist.  Instead, the parents took her to a specialist in chronic fatigue syndrome, who checked a number of inflammatory markers, finding many highly positive.  In addition, the girl had high levels of circulating antibodies to the lipopolysaccharide on the outside of some gram negative gut bacteria - suggesting a "leaky gut."

The girl was treated with antibiotics, but steadily worsened, until she was admitted to the hospital to normalize her nutrition.  Then she was sent to neurology where they checked her muscle fibers, finding some abnormalities, but nothing major.  The senior neurologist felt the patient had a symptom of a psychogenic "conversion" disorder, "la belle indifference."  If the girl exhibited this symptom, she would have been oddly unconcerned about her impaired condition.  The term "conversion disorder" is a Freudian one, meaning that anxiety symptoms are being converted into physical symptoms.  Classically, "la belle indifference" is described in cases of hysterical blindness, where someone can't see and doesn't seem too bothered by the fact.

Problem is, people with chronic fatigue often have a depressed affect, so their emotional responses are muted.  They are suffering a great deal, and certainly feel that suffering, but the face and voice might not quite show it.  However, the content of the discussion is telling.  And Maes (a psychiatrist) was angry with the neurologist who diagnosed la belle indifference.  Maes says he detected no sign of unconcern - instead he saw "a young lady who was very ill and suffered from her illness and not being able to go to school and meet with her friends."

Maes continued the work-up and started her on a whole slew of nutritional supplements and the "leaky gut diet."  The corresponding author email bounces, but this paper (after several teases) gives up the following information about the diet:  "consisting of milk allergic, gluten-free and low carb diet." (Thank you, Jen). 

The nutritional supplements had some basis in thought (not surprising, from Maes, who seems to account for everything except for relying on experience from evidence-based medicine - but you can't turn your back on a 13 y/o girl in a wheelchair if you think you can get her to walk out of it.)  First off, the girl's labs showed signs of an increased immune response in some respects, and decreased immune response in others.  They were consistent with lab findings of other people with symptoms of chronic fatigue syndrome, though there are no official lab findings for CFS.  Maes is quite specific, however, in noting each of the innumerable abnormalities she had, and how they link to issues with disparate parts of the gut, nervous, and immune systems. 

He surmises that the activation of immune cytokines and autoimmunity is related to the increased transfer of the bacterial lipopolysaccharide (LPS) across the gut.  He thinks there is a trigger factor, such as exhaustion, emotional stress, or an infection (perhaps the sore throat in this girl's case - she was also found to have a mycoplasma infection, which was treated), that will cause the inflammatory system to fire up.  Some elements of this system seem to help LPS cross over from the gut into the bloodstream.  Then the immune system mounts a response against the LPS - resulting in further inflammation and the acceleration of the symptoms of CFS.  Once again, Maes is exceedingly specific, defining a large cast of immune characters and the responses. 

So, the supplements - L-carnitine, CoQ10, lipoic acid, and taurine (one might recognize these as some of the compounds that are suggested to help mitochondria run more efficiently - and several of them are absent in entirely plant-based diets.)  In order to deleak (sounds better than plug up, I think) the gut, the girl was given L-glutamine, gamma oryzanol, zinc, "etc" along with the gluten-free, casein free, lactose free low carb diet.  

On top of these supplements, the girl was given IVIg infusions (gamma-globulin, to clean up inflammation.  This stuff is prohibitively expensive.  I've seen it used with good effect in the very rare, but completely disabling likely autoimmune condition called "stiff man syndrome."  Ironically that case was referred to me for suspicion of conversion disorder.  It is also used in immune deficiencies and Guillain-Barre and Kawasaki's disease.)   The girl got daily infusions (which I find incredible - these treatments are maybe $3000-$10,000 a pop? Each treatment consists of the pooled IgG antibodies from thousands of blood donors. I don't know for sure, but I've seen those kinds of figures thrown around) for a month, then the more typical dose every two weeks thereafter. 

For the first 6 months of treatment, the girl showed no clinical improvement, though Maes tracked her immune response to LPS, and it was dropping and dropping.    At her visit 10 months into treatment, however, she walked into the consultation room, and said she could read books again, had started swimming lessons, and her sleep was much improved.  LPS response slowly improved, and eventually she was able to return to school, and her abdominal bloating went away.  After about a year, she was pretty much back to herself, and the IVIg treatments were stopped, though her leaky gut diet and supplements were continued.   At two years into treatment, she remained well. 

In the discussion, Maes really lets loose.  The only way in which it could be described as civil is that there was no swearing. 
Although these [CFS] diagnostic criteria are now well-established, many specialists... still miss and dismiss this diagnosis.  They rather conclude that patients with this medical disorder suffer - in accordance with Freud's non-scientific theories - from "conversion symptoms with a strong psychogenic component." ...It is common practice... that those patients... are referred to a psychiatrist to undergo the mainstream treatment for that condition, i.e. psychodynamic therapies.  This means that patients with severe medical disorders are being treated as having a mental illness with "a nonsense treatment" that does not treat anything.

He goes on to rail against a prevailing political wind in Europe, where the National Health Services can evidently dismiss those patients who are considered hypochondriacs, thus avoiding the cost of treating these difficult conditions.

Well.  A recent study did come out showing that graded exercise and cognitive behavioral therapy are helpful for chronic fatigue.  I wonder if the possible reduction in stress response from the light exercise and CBT help the condition.  It is still poorly understood (though Maes seems to feel he has a handle on it).  Nor is there the kind of evidence we need for Maes' enormous intervention to recommend his treatment as standard therapy.  Somehow he was able to get the IVIg and convinced the family to keep going though 6 months of no clinical improvement (though the labs were hopeful).  And, as I said before, Maes couldn't turn his back on a 13 y/o girl confined to a wheelchair when he was certain he could help her.  In general, chronic fatigue has a relapsing and remitting course, but Maes has his biomarkers to show the steady biological improvement.  All the papers on the first page of google I found linking chronic fatigue to leaky gut are by Maes.  There are other studies of LPS and chronic fatigue, most via exposing cell cultures to LPS to stimulate cytokine production.

The mechanisms seem plausible, and the case study is compelling.  We need more data.  And you might not be surprised that I don't see much harm in trying a "leaky gut" diet - why not?  I don't know about all the supplements and any long-term effects.  I do of course advocate a nutrient rich whole foods "paleo" diet with plenty of animal protein and fat goodness - which would replace some of those supplements, though perhaps not in the amounts prescribed (which weren't listed in the paper). So, you see, once again, just by going "paleo," we are seemingly a lot of the way to Maes' elaborate reduction of leaky gut and systemic oxidative stress and inflammation.  Thus our overarching theory still seems good, that many of our modern diseases are a result of the modern diet and lifestyle that our paleolithic bodies simply aren't designed for.  Interesting.

* In full disclosure I am the author of a book, Feeling Better: A 6-Week Mind-Body Program to Ease Your Chronic Symptoms, which is based on some research I have participated in with Dr. Arthur Barsky, my co-author.  He is a world expert on somatization disorders, and due to my affiliation, I am often referred "conversion disorder" cases for consultation.  Sometimes the conversions are very classic - these almost always get better with time and things like physical therapy.  When the patient doesn't get better with a conversion diagnosis and a bit of time, or if the symptoms aren't particularly classic, I tend to suspect some unknown serious medical illness.  Often these unknowns are eventually diagnosed. 

Thursday, March 3, 2011

Brother's Keeper

East of Eden has been on my mind. At the heart of that novel is chapter 34, two pages, 11 paragraphs. The lesson of the entire masterpiece is here.

I believe that there is one story in the world, and only one, that has frightened and inspired us, so that we live in a Pearl White serial of continuing thought and wonder. Humans are caught - in their lives, in their thoughts, in their hungers and ambitions, in their avarice and cruelty, and in their kindness and generosity too - in a net of good and evil. I think this is the only story we have and that it occurs on all levels of feeling and intelligence. Virtue and vice were warp and woof of our first consciousness, and they will be the fabric of our last, and this despite any changes we may impose on field and river and mountain, on economy and manners. There is no other story. A man, after he has brushed off the dust and chips of his life, will have left only the hard, clean questions: Was it good or was it evil? Have I done well - or ill?
Joel Salatin did a recent TED talk linked on an Ancestral Health Blog website found via Brent Pottenger's twitter feed - I tweeted the video to good response last week or so. It's 16 minutes and definitely worth the time - the moral as it were happens at 11 minutes. Joel urges us to live with intention. Not to sleepwalk through life. "If we devote ourselves to sacredness in our vocations, the world will rise to meet us." He talks of a "nobility of personal ministry." He is a religious person, but if you are not religious, the same tenets apply. Happiness is not giddiness and success per se, but rather serenity and intention, if one has a view looking East.

Steinbeck again from Chapter 34:
In uncertainty I am certain that underneath their topmost layers of frailty men want to be good and want to be loved. Indeed, most of their vices are attempted short cuts to love. When a man comes to die, no matter what his talents and influence and genius, if he dies unloved his life must be a failure to him and his dying a cold horror. It seems to me that if you or I must choose between two courses of thought or action, we should remember our dying and try to live so that our death brings no pleasure to the world.
Dr. Eades brushed up against this one story in his last post, The Big Lie, about the folks still clinging to the high glycemic and low glycemic carbohydrates as some sort of last vestige of the diet-heart hypothesis. Some objected in the comments to the reference to Nazis, but how many people have to die a slow disabling death due to these diseases of Western Civilization before the body count is high enough to be evil, and not just incompetence and bad advice? I do not suggest that the evil of a horrific systematic and deliberate extermination is occuring - but when one breaks it down to the first story, perhaps the only story, there is good, and there is evil. Inaction, obtuseness, and neglect from those who choose to be doctors and scientists - pardonable for how long, decades into this latest epidemic of obesity and diabetes and depressive disorders?

We have only one story. All novels, all poetry, are built on the never-ending contest in ourselves of good and evil. And it occurs to me that evil must constantly respawn, while good, while virture, is immortal. Vice has always a new fresh young face, while virtue is venerable as nothing else in the world is.
Most of the time I have more questions and answers. Sometimes the correct path is not clear, or there is no correct path. I would not presume to suggest a specific pattern of virtue to you or anyone, other than to begin with respect for oneself, and one's person. I believe the wise path is to live your days with intention, to do what you love and respect what you do, but of couse in this I do not always succeed.

But if you choose to be a doctor, you choose to be your brother's keeper. The exact line of paternalism vs autonomy is always being redrawn, but one mustn't check one's expertise and brain at the door in service of the party line of the grain or pharmaceutical industry.

Wednesday, March 2, 2011

Problems? I Have a NAC for That

In the comments of the Depression and Leaky Gut post, Tony Mach mentioned an interesting amino acid called N-acetylcysteine (we'll shorten that to NAC) and put up a link to the Wikipedia page "describing its wonders." I'd heard of NAC before, of course, as the punishment/savior for people who show up in the ER having overdosed on that most disgusting of things to overdose on, acetaminophen (Tylenol, or paracetamol). If you decide to down a whole bottle (or far, far less with alcohol - even the upper limits of a normal daily dose can damage your liver when combined with alcohol), you might feel sick immediately, but then perhaps recover and think nothing of it - until a few days later, when the accumulated killing of hepatocytes and rotten liver make you very very ill, and nothing short of a liver transplant will save you. Failing that, you die a rather horrible death. Livers are vital, we have no substitutes, no bypass machines, mechanical livers, or liver-like dialysis machines. Apparently there are 56,000 ER visits a year from tylenol overdoses in the US, and 100 deaths.

Well, if someone shows up with a tylenol OD to the ER, you get a level 4 or more hours post-ingestion, and plot the level and hours post-ingestion on a handy graph. Above the dark line on the graph? Welcome to the world of N-acetylcyteine, a disgusting compound typically administered with fruit juice, but still makes some people vomit. You give a loading dose of 150mg/kg followed by 70 mg/kg for 17 more doses. If you can't keep down the dose, it has to be repeated. During this time is when the psychiatrist is typically called to the ER to figure out whether it is safe to let the person go, or if it was a serious suicide attempt in need of further intervention. It is surprisingly easy to overdose on tylenol accidently, as acetaminophen is in a zillion over the counter medicines, plus perscription painkillers percocet and vicodin, etc. 4000 mg a day is the upper limit of "safe" (without alcohol) - you can get acute liver failure with as little as 7800 mg if you are unlucky.

The treatment is as simple as it is magical - possible fuliminant liver failure on one side, skipping out of the hospital doing just fine on the other. And the treatment has everything to do with the body's master antioxidant, glutathione. Seems that a metabolite of tylenol, NAPQI, kills liver cells like gangbusters. Glutathione can bind to it and render it harmless, but once you run out of glutathione, the leftover NAPQI does its nasty job. That's where N-acetylcysteine (NAC) comes in - it is a ready precursor to glutathione, so your liver can have a bountiful supply to fight off the NAPQI.

Well, have a look at the Wikipedia article. NAC is not only the treatment for mucus build-up in cystic fibrosis, but also acetaminophen overdose, perhaps to reduce the kidney toxicity of contrast dye (though that doesn't seem to be holding up), in interstitial lung disease, and investigationally in reduction of noise-induced hearing loss, lessening the destruction of pancreatic beta cells, curing a hangover, and decreasing symptoms of the flu. But of course I don't care about all that. As a specialist I am required by medical convention to stick to the brain and keep my little nose out of other parts of the body... but NAC has some interesting properties in the noggin as well.

As usual it all goes back to glutamate, the excitatory neurotransmitter of doom. In short, having too much glutamate around is to your neurons rather like whipping your horse to go and go and go until you kill it. Horses and brains need time at pasture, chilling out and eating appropriate foods, and sometimes a nice rubdown and brushing. Well, NAC seems to be able to get into some tricky areas of the brain and do some amazing management of glutamate. Over the past few years, a number of intriguing studies have come out using NAC alone or as adjunct treatment for some difficult psychiatric conditions. Some of these were decent multicenter randomized controlled trials. The real deal.

These tricky conditions? Trichotillomania (compulsive hair-pulling, which is both common and exceptionally difficult to treat - several decades of research has come up with nothing as effective as the NAC trial!). Schizophrenia. Bipolar Depression (another very difficult and disabling condition that doesn't respond particularly well to therapy or medicine). And there is an ongoing study on OCD. The studies vary between 2000-4800mg daily of the capsules (I'm assuming these are better tolerated than the emergency room drink), and in most of the studies, there were more adverse events and side effects in the placebo arm than in the treatment arm. Many of the studies were as long as 6 months, which is a lifetime for randomized controlled clinical trials, and all of the studies had positive effects. That is pretty astounding, considering how pharmaceutical companies have no doubt spent millions and millions chasing down bipolar depression, for example, without much to show for it (there's quetiapine, fluoxetine, and olanzapine+fluoxetine with modest effects). Another cute little study used NAC to reduce cocaine cravings - again, something for which there is really no effective FDA-approved medical treatment.

Why would a precursor for the master antioxidant have anything to do with glutamate in the brain? The mechanism is sort of hysterically complicated, so I'll quote the trichotillomania paper for fun:

[NAC] is a hepatoprotective antioxidant that is converted to cysteine, a substrate for the glutamate-cysteine antiporter. This antiporter allows for the uptake of cysteine, which causes the reverse transport of glutamate into the extracellular space, which stimulates inhibitory metabotropic glutamate receptors and, thereby, reduces synaptic release of glutamate. The restoration of the extracellular glutamate concentration in the nucleus accumbens seems to block reinstitution of compulsive behaviors.

Translating the sciencespeak: NAC helps excess (and toxic) glutamate stop being at the wrong place at the wrong time. It helps us put that brain out to pasture for some rest and recovery.

What are the downsides of NAC? I can think of two problems that might be biggies - first off, NAC is a mucolytic that thins mucus by cutting disulfide bonds. I suspect that might raise risks - one wouldn't want too little mucus. Mucus is important. Paul Jaminet mentions this issue and links a study here. Also, cutting disulfide bridges within the body is what that inflammatory baddie homocysteine is supposed to do, leading to crispy collagen and inelastic elastin in the arteries (which would possibly first show up as high blood pressure).

Of course, no hunter gatherer was chugging 2 grams of NAC daily. It's not evolutionary psychiatry. But it does seem to have the potential to replicate, perhaps with some downsides, the natural brain glutamate situation of a lower-stress life with plenty of appropriate minerals and micronutrients. Hey, maybe even absence of tons of carbs on top of an inflammatory rodent diet. Or some ketosis. We live a modern life - some brains are already tracking in the wrong direction. It would certainly be worth studying NAC further so we have more information, and, in my view, in intractable or otherwise untreatable conditions that significantly impair functioning, giving it a try.