Food Additives and ADHD: New Evidence of Genetic Factors involving Histamine

Just in time for Halloween, a post about candy, children, and behavior problems.  For many years, parents have noted an association between certain foods and their children's behavior.  "If he eats candy he's out of control."  "If she has anything with red dye in it, she'll be up all night."

These observations have caused many parents to have intimate knowledge of ingredient lists of food items, searching for things like sunset yellow, tartrazine, sodium benzoate, carmoisine, ponceau 4R, allura red, and quinoline yellow.  Avoiding these can be challenging -- find a processed food without sodium benzoate.

Double-blind, placebo-controlled trials have shown that artificial food colors have a significant effect in children with ADHD.  However, many have not been convinced of the association, given a lack of plausible explanations for how this range of food additives could cause behavior changes, including inattention, impulsivity, and overactivity.  Granted, any child will have these characteristics at times, but the Attention Deficit Hyperactivity Disorder (ADHD) diagnosis is reserved for those with such severe symptoms that they interfere with home and school functioning.  And, even in toddlers and 4th-graders without ADHD, food additives have been shown to have and adverse behavioral effect (McCann et al, 2007).

Most of the treatments for ADHD have direct effects on the brain chemical, dopamine.  Indeed, genes influencing the dopamine system (eg, DRD4, DAT1) have been found to be involved.  Yet, there has not been clear evidence of a connection between food additives and dopamine.  There have been some observations that certain food dyes can provoke the release of histamine, causing hives and itching but also inattention, hyperactivity, and dopamine release in prefrontal brain areas.

In the October issue of "the green journal" (American Journal of Psychiatry), McCann's group analyzed six genetic polymorphisms (I explained these here) involving genes affecting dopamine and histamine (Stevenson et al, 2010) in the same group of general population kids (not just those with ADHD) from the 2007 study.  What they found provides one possible explanation for why these additives cause behavior problems.

They found that two polymorphisms in the histamine enzyme gene, HNMT, and one in the dopamine transporter (DAT1) gene, were associated with inattentive and hyperactive symptoms when kids were given juice with the additives in it, compared with juice without the additives.

Meaning that children with these specific polymorphisms (think a genetic code swap, like the difference between "their" and "thier") will have an enhanced effect of histamine on their brain's histamine (H3) receptors and an altered effect of dopamine on the brain.

So, what's it mean?  It means those parents were right, of course.  And, for foods that are targeted for children, the food industry now should pay attention (!) to finding alternatives to these artificial chemical additives.

DBH Gene in Cocaine-Induced Paranoia

So I thought I'd make another post about how more is being learned about our genetic makeup and how that may relate to medication side effects. In this instance, the "medication" is cocaine, which causes a huge release of dopamine. Some folks get really paranoid after using cocaine. This study asked the question "Is reduced breakdown of dopamine associated with paranoia symptoms in cocaine users?"

First some background. The above graphic shows that the neurotransmitter dopamine (or DA) is converted into norepinephrine (or NE, sometimes also called noradrenaline, or NA) by the enzyme dopamine beta-hydroxylase (DBH). You can see that all this enzyme does is add the little -OH (or hydroxy) part to the dopamine molecule to make norepinephrine.

Kalayasiri 2007 showed that a particular mutation (C1021T) in the dopamine beta-hydroxylase (DBH) gene was associated with significantly increased paranoia in a small group of cocaine abusers (see top graph). Cocaine users were blindly provided with different doses of cocaine (bet it was easy to find subjects) and their level of paranoia was rated every few minutes using a Visual Analog Scale (VAS). Users with the TT variant of the gene rated their paranoia level consistently higher than those with the CC or CT gene variant. It has elsewhere been shown that the TT form of the DBH gene is broken, and so is much weaker at converting DA to NE. The resulting higher levels of dopamine in the TT people may be why they get more paranoia.

[Genetics 101 Note: when you see this type of notation, "C1021T", all it means is that at position 1021 along the double-stranded DNA for that particular gene, there is either a C or a T nucleotide at this single point on either DNA strand... if each of your two DNA strands (one from Mom, one from Dad) contain one or the other, then you are homozygous for either one (CC or TT)... if Mom gave you a C and Dad gave you a T, then you are a CT (called heterozygous). Thus there are 3 genetic variants (in this case, CC, CT, or TT) which can exist at this single nucleotide position. These single nucleotide variants, or "polymorphisms", are referred to as SNPs, or Single Nucleotide Polymorphisms. Different SNPs can result in that particular gene's product or function to be enhanced or diminished, resulting in functional variations which may contribute to individual variations in one's response to disease, drugs, or the environment.]

Because this paranoia and related symptoms are uncomfortable to most people, it may serve as a deterrent to using cocaine. In fact, folks with the TT genotype might be at reduced risk of becoming addicted to cocaine because their DBH gene does not work as well. In fact, the alcohol deterrent drug, disulfiram (Antabuse), also happens to block the DBH enzyme (remember, the DBH gene contains the instructions to make the DBH enzyme). This would result in someone with a normally functioning enzyme (from a CC or a CT SNP) to have an enzyme that works like someone with a TT SNP. Antabuse has been shown to be helpful in treating cocaine addiction.

As further evidence of this connection, Schank 2006 used DBH knockout mice to demonstrate hypersensitivity to cocaine in these animals, suggesting that low DBH activity in some cocaine abusers may increase the drug-related dysphoria and aversion, making them less likely to become addicted to the drug.

We hypothesize that the ratio of dopamine (DA) to norepinephrine within noradrenergic vesicles is elevated in TT [homozygous] subjects, so that during cocaine intoxication, DA-mediated neurotransmission is relatively elevated in regions richly innervated by noradrenergic and dopaminergic fibers (e.g., prefrontal cortex). Alternatively, given observations of up-regulated high affinity DA receptor binding sites in DBH knockout mice, TT homozygotes may be hypersensitive to DA, and thereby [may] be more vulnerable to cocaine-induced paranoia.

Pretty cool.