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.


  1. As always it's all a self-perpetuating twister of doom, with secondary effects that end up exacerbating themselves through influencing the primary causes. Eep!

    I remember the trials of folate supplementation that didn't reduce heart disease risk even though it reduced homocystine. If you're familiar with that, what's your take on it? Or anybody reading this comment who has an answer for that matter.

  2. Emily is there any indication of the causality between anger and homocysteine? Does excess homocysteine cause anger, or does anger cause excess homocysteine?

  3. Anonymous commenter can't be Dr K -- spelling is too good!

  4. Wow, amazing implications just in the second to last paragraph. "...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." Good stuff!

  5. Stabby - there were several large heart trials with B12, folate successfully lowering homocysteine and no benefit for cardiovascular mortality. However, I believe in the HOPE2 trial there was a reduction in strokes with folate or B12 supplementation. Can't remember which. I think one homocysteine is off there are so many problems that lowering it just using one or two B vitamins is kinda pointless. That's my take.

    JKC - I saw some hand waving in the papers about some sort of "sympathetic nervous system activation" in concert with elevated homocysteine and cause anger, but my second to last paragraph is all the plausible stuff I could find. And the anonymous commenter has some ideas too (though not with respect to the anger).

  6. Just a shot in the dark, I have done no research either way, but perhaps testosterone affects homocysteine levels, therefore the link between is that high testosterone -> anger & high homocysteine? Testosterone is well noted to cause impulsivity anger and aggression by modulating dopamine and serotonin and other factors.

    This may be comparable to testosterone and hemoglobin synthesis, and subsequent athletic performance. We can see links between taking steroids and doing better in all forms of athletics, but I bet we would see a better relationship between tissue oxygenation and athletic performance/endurance. Meaning to say the link between improved athletic performance and testosterone would evaporate if the person was fed a low red meat, low folate, low iron diet for awhile so that they became anemic.IN this case there would be no relationship between performance and testosterone, as the main way testosterone improves endurance is via the cardiovascular dynamics (which are being suppressed with nutrient deficiency).

    Testosterone only facilitates more red blood cells, however ultimately you still need the raw components to make them. Having female ranges of testosterone will prevent male heights of red blood cells, no matter how much iron and folate and b12 consumed.

    The main point I am making is, in this case, in regards to mood, it may not be that there is any relationship between homocysteine and anger but rather this is just a side effect of being male or having a male endocrine profile which then causes anger and hostility for reasons unrelated to the homocysteine level.

  7. One ever so small detail to add: when we talk about measuring levels of homocysteine, we are generally talking about cumulative levels of homocysteine and homocystine (the dimer) and other disulfides. Sorry for the nitpicking..

  8. Woo - one of the papers (and I'm not sure I referenced it) had some detailed information on homocysteine and hormones - it is actually the lack of estrogen that leads to higher homocysteine, not testosterone, as women's homocysteine levels rise after menopause. The authors went so far as to say the *reason* for men being angrier than women was the homocysteine itself, but I felt they were reaching a bit. In any case, many of the heart disease studies were done mostly on men, and the correlation between anger and homocysteine is stronger for men, but also holds for women. (Though I think there were mixed studies to that effect - that's the overall impression I gleaned).

  9. Emily,
    I am fairly certain this might directly apply to me. I realize that you probably couldn't give a straight answer on such a complex phenomena... but if I already knew my fat metabolism seems strange, would it be a big leap to suspect that I might have a homocysteine/folate cycle problem? My diet is already getting some management. Would taking a folate supplement be a vain gesture?

  10. I have B12 deficiency, and I find when I don't get my needle on time I get very irritable. Should I be talking to a doctor about this? What could he do to help if I do? I don't want to come off crazy. People seem to think that this disease is all in my head. I have had to do all my own research. How do I get the hormone test?