Neurological Correlates

This blog passes no moral judgments on addiction.

Nicotine is addictive, and addiction is biological, and, being in the biopharma biz, if there’s a pill that works to stop addiction, take two.  This jibes well with President Sneak-a-Smoke bringing tobacco products under the regulatory jurisdiction of the FDA.

No preaching from us. We’d rather complain.

And we do.  Frequent and rambling complaints about the behavior of ex-addicts in our orbit.

Their reply:  “I was an addict so of course my behavior is abominable. I get a pass.”

This is getting old. At some point, once you remove the addiction, the rest of the personality bubbles up in a noxious gaseous release from the roiling toxic living test tube of  neurotransmitters, brain tissue, fatty acids and DNA.

So, here’s my question: How long before the effects of addiction wear off and we’re stuck with the personality?

I say 10 years. The 10 year statute of  limitations for blaming atrocious behavior on prior addiction is has a rational basis in two reports (discussed below) of 10+ year persistence of acquired epigenetic changes due to smoking. After 10 years I’m going to assume any additional atrocious behavior is due to a permanent condition, unlikely to change, and is viewed not as a mitigating factor, but as an aggravating one. No pass no mas.

The studies:  one, epigenetic changes from smoking persist 10+ years in quitters, and two, maternal smoking is correlated with offspring obesity up through about fifth grade — about 10 years — but not longer.

First, the ex-smokers. According to a recent report out of France, smoking causes epigenetic changes lasting years after quitting.   At least one  change results in a drastic reduction of serotonin even in people who had not smoked for an average of 13 years.

Currently smoker and never-smokers have around the same serotonin levels in the systemic circulation.   But,  former smokers have much lower serotonin levels.   No fair, but it gets worse.

Quitters have higher levels of serotonin-break down products — the bits of serotonin left over being cleaved by the enzyme MAOA.

This is counterintuitive: Smoking inhibits MAOA activity.   Shouldn’t smokers have more serotonin than non-smokers if smoking hobbles the enzyme that degrades it?

The answer is that a chemical in cigarette smoke turbocharges cells to crank out more enzyme  –  and this change lasts even after you quit. So, quitters have a double whammy:  More enzyme, and the enzyme is more vicious (without cigarette smoke to disable it). Quitter serotonin doesn’t stand a chance.

In a textbook epigenetic style, cigarette chemicals remove methyl groups from the MAOA gene promoter. (This much was tested in the French paper).   Methyl groups act as a governor on gene activity “gas pedal”  — removed, the gene goes 180 in 25 mph zone. (To oversimplify with a dated metaphor).

I am unclear why, in the absence of cigarette smoke, the demethylation effect persists, but the entire concept of epigenetics is a wild west.  Apparently the endogenous demethylases are activated somewhere along the line.  I had actually suspected tobacco of harboring a tobacco mosaic virus that could jump into human lungs and cause cancer, but there is absolutely no proof of this whatsoever, so don’t anyone go around starting a rumor.  Plus, lactoferrin — a transferrin in the mucosal membranes of the mouth and probably lungs — disables tobacco mosaic virus, so probably it couldn’t be transmissible anyway. (This argues for dunking your farming implements in dilute powdered milk after using them on tomato or tobacco so you don’t spread TMV around; you can than us later for this helpful hint).

So, for 10+ years after you quit smoking, you are serotonin-challenged. Serotonin-disabled.

With what result? Weight gain, for one. Serotonin binds to the 5-HT2c1A receptors in the hypothalamus to reduce appetite. Serotonin down, appetite up.  (Which leads me to wonder if Lorcaserin, a 5-HT2c1A agonist, could get another label indication).

And grumpiness.  The paper at Figure 5 points out that the chemicals in cigarette smoke also regulates GABA receptors — and these are hot spots for moods. Remove them, GABA receptors are in a tizzy, and you get grumpiness.

One technical note: We should be careful to distinguish methyl from menthol. Methyl groups prevent DNA from being transcribed, and thus their removal starts the ball rolling on gene expression ultimately making the MAOA protein. Menthol is a cigarette flavoring that was carved out from the ban on flavored cigarettes. Among African American and Latino cigarette smokers, those smoking menthol flavored cigarettes had a lower quit rate than those smoking non-menthols, and moreover, approximately 70- 80% of African Americans who smoke,  smoke menthol flavored cigarettes, as reported here , and some speculate that the Congressional Black Caucus, in cahoots with Big Tobacco, voted for the menthol carve out to preserve the 28% of tobacco sales.  (Does this conspiracy theory write itself or what?  Pres. Obama must be a fake smoker. He only saying he smokes as a favor to the Congressional Black Caucus that helped him get elected. A true smoker would build a tent beside their office and hold political meetings there like a certain California governor .

There is one more 10-year datapoint: A Japanese study on maternal smoking as an obesity risk in offspring.  Japanese must register their pregnancy to receive healthcare benefits, and so the authors used these data to to determine that maternal smoking while the child is in utero is correlated with childhood obesity — and the obesity effects last about ten years, say, the end of fifth grade. The French study showed epigenetic persistence after 13 years, but this 10-year measurement is in the ballpark.  And anyway, the Japanese study involves young children who may epigenetically bounce back faster than the French ex smokers.

Unfortunately and glaringly negligently, the Japanese miss the epigenetic issue entirely, and hypothesize that child obesity is due to fetal undernourishment when the mother smokes, overcompensated at birth.  Lame.  And, this puts the burden on the parents for behavioral change in child rearing.

A more plausible hypothesis  cigarette smoke chemicals traverse the placenta and strip the fetal MAOA promoter methyl groups. The child has insufficient serotonin to reduce appetite via the 5-HT2C1A receptors in the hypothalamus and therefore is continually hungry and overeats until the end of fifth grade or so.   This should be looked at by the CDC who claims childhood obesity all behavioral and cultural.  I hate to hype child meds, but here, if it is the case that it’s a 10 year epigenetic serotonin thing, then maybe a little serotonin reuptake inhibitor or a 5-ht2c1a receptor agonist might to the trick.

Plus, this makes cigarette adverts to pre-teens particularly nefarious: Having finally overcome the in utero forced epigenetic serotonin depletion, the child now takes up smoking when the tobacco companies advertise cartoon camels. Then, the urge for addiction is even stronger because of the inhibition of the excess MAOA from in utero epigenetic upregulation.

At this point, mothers are blamed.  But, mothers are blamed pretty much no matter what. Although maternal smoking has been blamed for misbehavior in offspring (e.g.,  maternal smoking during pregnancy is associated with offspring conduct disorder)  other studies point to alcohol or general partying lifestyle. In the spirit of equality, the father also does not get off the hook, and paternal epigenetic condition also influences offspring.

And so, the debate is denied by cloture, the legislative history is written and now it is promulgated by fiat: The statute of limitations on blaming atrocious behavior on being a former addict tolls at 10 years from the last serious substance-abusing binge or last entire full pack smoked.

Arbitrary and capricious? Maybe. Unfairly generalizes smoking to all addictions? Yup.

But ease of administrative burden sometimes outweighs the vanishingly small potential for the femptomolar sized injustice that could be made by letting the addicts “in recovery” in my orbit go on and on and on and on for decades.  Stop already.

The implementing regulations require that beyond the limitations period, all  “But I’m a former addict and this is how we act” evidence shall be deemed inadmissible to mitigate accountability for atrocious behavior. Such attempt to introduce evidence of former addiction shall be viewed with extreme asperity and considered –ipse dixit and res ipsa loquiter sed quid in infernos dicet — an aggravating factor.

Citations below the jump:

Launay J-M, Del Pino M, Chironi G, Callebert J, Peoc’h K, et al. (2009) Smoking Induces Long-Lasting Effects through a Monoamine-Oxidase Epigenetic Regulation. PLoS ONE 4(11): e7959. doi:10.1371/journal.pone.0007959 (Link, Trackback)

Sen B, Swaminathan S., “Maternal Prenatal Substance Use and Behavior Problems among Children in the U.S.,” J Ment Health Policy Econ. 10: 189-206 (2007 Dec)

de Boer P, Ramos L, de Vries M, Gochhait S., “Memoirs of an insult: sperm as a possible source of transgenerational epimutations and genetic instability,” Mol Hum Reprod. 2009 Nov 6 epub

Kohta Suzuki, Daisuke Ando, Miri Sato, Taichiro Tanaka, Naoki Kondo and Zentaro Yamagata: “The Association between Maternal Smoking during Pregnancy and Childhood Obesity Persists to the Age of 9–10 Years”. Journal of Epidemiology, 19: 136-142 (2009)

Gandhi KK, Foulds J, Steinberg MB, Lu SE, Williams JM., “Lower quit rates among African American and Latino menthol cigarette smokers at a tobacco treatment clinic,” Int J Clin Pract. 64: 360-367  (2009 Mar)2009 Mar;63(3):360-7 visited 11.29.09