Wednesday, June 3, 2009

Beta blockers: good idea or trap?

For a few months in 2007 I worked very hard at bugging doctors to try to figure out what was going wrong. (A year later I tracked it to a problem with cholinesterase inhibitors, but I didn't know that then.) A neurologist I saw once (and only once) as part of this quest expressed that I was just being overly sensitive and suggested I try beta blockers.

When beta 1 receptors bind to epinephrine they make your heart beat harder and faster. This is what gives you that fluttery messed up feeling when you have to do something like get up and perform in front of a group of people. Beta blockers suppress, or at least attenuate, this effect. They're sometimes used (or abused, depending on your viewpoint) to control physiological symptoms of performance anxiety. This was the basis of his suggestion. Sounds like a good thing, right?

The problem is this: most neurons will adjust their gains and receptor densities to maintain a fairly constant level of input. This is a big part what goes on with things like drug tolerance. In this case, it means that while you're on beta blockers your beta receptors proliferate and ramp their gains to max trying desperately to get the signal level they expect. While the beta blocker levels are stable you feel fine, but when it goes down -- oh man...

I really wish they'd warned me about this when they suggested and/or prescribed the &%^$ things, but I learned this the hard way. I had to stop taking them for a while to do a test. The day after I stopped I felt jumpy, my heart rate was running ~130 just sitting still and ~160-180 if I tried to do anything, and I got really bad cardiac arrhythmia (multiple times per minute -- scary). This was not fun and so, so much worse than what had been happening to me before taking the beta blockers.

I tried to go without them after that, figuring these symptoms would fade and that I'd already paid the worst of the withdrawal symptoms waiting for the stupid test to happen. Months later, when these problems were still much worse than they'd been before and weren't getting any better I gave in and started taking them again. (BTW, the lovely interlude with the generic Ethex Toprol XL described in the last post happened at this point in the story.)

A few months after changing my diet to avoid cholinesterase inhibitors, I started having a different problem: the beta blockers were now too strong. The built up SGA had been keeping the epinephrine level artificially high. Once the level dropped enough, the beta blockers were making my blood pressure go so low I couldn't function.

I was already taking the minimum available dosage. Cutting them in half worked for a few weeks, but they couldn't be subdivided further without destroying the time release. (As described in the last post smooth time release is critical for this stuff.) The only option was go cold turkey and be miserably jumpy, heart racy, and arrhythmic until the beta receptors desensitized back to normal.

I couldn't find any useful info anywhere to help me understand how long that might take. The last experience stopping beta blockers was miserable and ultimately failed, but how much of that was caused by the hypersensitive beta receptors and how much by the high SGA levels?

It wasn't nearly as bad as I'd feared, implying that the SGA levels had been the dominant part of the problem last time. There was a little arryhthmia, but mild, and only for a few days. The jumpiness and heart racing faded slowly over a couple months.

Later, when I got the results back from 23andme, I discovered that I have mutant beta 1 receptors: GG on rs1801252. Only ~4% of the population have this genotype, and it's been associated with "low extroversion." I take that to mean that we suffer the fluttery feeling so bad that we mostly avoid having to be on stage in the first place. This may help explain why the beta blockers were so effective at such low doses.

So, the question is this: should I recommend the use of beta blockers to help counteract the effects of cholinesterase inhibitor sensitivity (CIS) during the detoxification process or not? It helped in the short term, but in the end felt like a trap. Also, I don't know how the mutant receptors play into this. How would this play out in people with CIS but with normal receptors? Sigh, need bigger sample size.

The more troubling thing is that ~millions of people are taking beta blockers for high blood pressure. It seems like everyone I talk to over the age of 60 is either taking them, or their spouses or friends are. Nobody warned them about receptor sensitization and withdrawal effects either. Yikes...

Generic drugs: I'm on to your tricks now

I've been thinking about writing this post for a long time, but was finally kicked into gear by LookyDaddy's recent post referring to the dangers of generic epilepsy drugs.

My first experience with this was about a year ago with Toprol XL. I'd been taking it for months with no problems. Then one refill the pills were clearly different. It turned out that Walgreens was now sourcing generic Toprol XL from a different manufacturer: Ethex instead of Sandoz. They didn't think this was worth mentioning. I only noticed because the size and shape changed.

Right away I started having trouble. During the course of the day I'd go through periods of incredibly low energy and blood pressure -- like, unable to move low -- and periods of jumpy heart racing.

Randy hypothesized that the release rate of the Ethex generic wasn't flat enough. During the low periods it was releasing the drug too fast: beta receptors too blocked, heart going too slow and weak. During the jumpy periods it was releasing too slow: receptors not blocked enough, heart going too fast and hard.

These problems went away within a few hours of getting the name brand. After that, we poked around on the web and found that lots of other people had the same problem with the Ethex generic.

More recently, I started experimenting with bupropion to try to deal with dopamine deficiency. Again they gave me a generic: Teva Budeprion XL. Again there was instability: high dopamine in the morning, sudden crash in the afternoon, ok in the evening after a nap. I thought at first that this was just startup edge effect, but it went on for weeks.

Again, these problems went away right after changing to the name brand. Again, lots of others had similar problems. We learned that two other people we know and care about were also getting screwed up by Teva Budeprion XL and got better when they stopped taking it. Ok, we thought, better put out a warning...

Now, I know this is all anecdotal and there's plenty of people on the net to complain about anything. However, consider this: the time release mechanisms in drugs are considered *inactive ingredients* and are therefore not regulated. They differ between brand name and generic, and even between generics from different manufacturers. The ones that are sophistocated enough to give reasonably flat release profiles are pricey. Generics have low profit margins. Seems like a good target for cost cutting.

Another problem with inactive ingredient substitutions is that they can be a problem for people with sensitivities. The one I have to watch out is potato starch (discussion of use in generics here). Pharmacists don't seem to have access to inactive ingredient information but will supply the phone number of the manufacturer.

I'm sure not all generics are bad, but after getting messed up by the last two in a row I no longer swallow the claim that they're "equivalent." If you're taking a generic, it may perhaps be a good idea to do an experiment:
  • Get one refill, or a partial refill, of the name brand
  • Watch yourself carefully for a few days while still on the generic, then compare how you do with the name brand
  • If you can't notice a difference, go back to the generic with restored peace of mind
  • If you notice a difference for the better, think about how much that quality of life improvement is worth to you compared to the cost differential
I know that for me it's well worth the $15 extra per month to be free of what the Ethex and Teva generics were doing to me.

Monday, June 1, 2009

Comments from Google Site

I have a Google Site at which I am trying to topically arrange info on the cholinesterase inhibitor issue. (Yeah, I know I mention it in almost every blog post -- that's the main thing I'm interested in at the moment.)

Unfortunately it turns out that Google Sites does not support comments from anyone other than owners or collaborators. I found a forum thread that addresses this issue, and it basically says: Blogger is for comments; Sites isn't. Therefore this Blogger post is intended as a place where people can comment on my Sites pages.

Please comment here!

Tuesday, May 26, 2009

"Motivation": Cortex vs. Limbic System

I speculate that dopamine affects how easy or hard it is to initiate activities. This particularly seems to affect activities requiring significant energy, like exercise, and/or decision making, like planning a trip or moving. I introduced this idea a little bit in an earlier blog post.

I found that when I was dopamine deficient, I couldn't initiate exercise myself. I could tag along if someone else initiated it though, and feel better during and after. A woman from my church invited me to go walk with her on Tuesday mornings, and I could do that. My husband and I joined a twice weekly yoga class, and I could go to that.

It seemed silly to me that I couldn't initiate these sorts of things myself. In the past I treated this as a moral failing, and beat myself up about it. That made me feel awful, but I still mostly wouldn't be able to do it. This most recent time I was more accepting about it. I still tried to convince myself to go exercise, but was more gentle about it. Sometimes I would succeed in going and exercising by myself, but mostly I wouldn't. Instead of treating it as a moral failing, I treated it as a science experiment. What was different about the times when I was able to go and exercise?

Once I got the dopamine increased enough I could mostly initiate exercise by myself no problem. It wasn't that I was trying harder, or being more morally upright. It just felt like a road block that had been there was just gone.

When I studied more about dopamine, and what affects it, I realized that dopamine levels seemed to correspond to how easy or hard it was to initiate that sort of activity. When dopamine levels were mostly low, I would only be able to do it as a follower or after some sort of experience that sufficiently increased dopamine. Now that dopamine levels are mostly ok (got the bupropion working right), I can initiate exercise myself most of the time, except after experiences that sufficiently decrease dopamine.

All this made me realize that the concept we call "motivation" really has more facets than I'd realized before. What you think about how much you "should" do something, how much you want to do it, and what you think about where it ranks in your priority and value schemes are one set of factors. How you feel when your think about doing something -- how your biochemistry reacts to the idea -- is another. They're controlled by different parts of your brain (cortex vs. limbic system), and are not always in sync.

I suspect that the latter part is the one that's more tied into physiological state -- how much dopamine, energy, etc. you've got to start with and how those change in reaction to your proposed activity, like exercise. It can agree and reward you with an added burst of dopamine, which makes it real easy and appealing to go off and initiate the activity. It can also disagree and make you feel uneasy about it (not sure if this is it decreasing dopamine, increasing stress chemicals, or both), and make it real hard.

It seems to me that in some cases the meaning of "motivation" is pretty clear:
  • Motivated = cortex decides to do it, limbic system agrees, you do it
  • Unmotivated = cortex decides not to do it
However, what do we say about the case where the cortex decides to do it but the limbic system disagrees? Generally this is where things gets tough and we are prone to beat ourselves up. I bet we end up in this state more often when dopamine is low. I also bet that when dopamine is low and we end up in this state, we're much less likely to be able to force ourselves to initiate the activity anyway. Here's the trap: the way we think about failing to initiate activities like this can further decrease dopamine, making it even harder next time.

I certainly find myself in that state much less often now. For a few months, before using the bupropion to increase dopamine tone, I was in that state almost all the time. I exercise much more often now than I did then. I don't actually decide to exercise any more often -- likely I decide to do it less frequently. The difference is that now it's much easier to follow through on that decision. Does that reflect a difference in "motivation" or not?

Friday, May 15, 2009

Evaluating food risk: "spices" vs. "fava bean flour"

My husband Randy and I recently moved to Pittsburgh. He likes a local chain here called Panera's that looks like a bakery and projects a more-than-usually convincing image of wholesomeness. From the ordering line you can see a glimpse of a convincingly realistic bakery kitchen. This resembles the sort of place where you'd expect the baked goodies to have been baked on-site.

The first time we went there, I wasn't yet ready to take a risk on eating anything there. After all, baked goods are at risk of containing hidden potato starch. I watched him eat a very yummy looking souffle thingy and, truth be told, really wanted to eat one too.

The second time we went there I had decided to take the risk, ask about ingredients, and not feel left out this time. I was reassured that there was a sign behind the counter saying you could ask to see the list of ingredients. I asked for the ingredients for the most conservative souffle thingy they had: the Four Cheese Souffle.

I scanned the list of ingredients quickly looking for nightshade. I didn't see any, but I did see "spices," which can include hidden nightshade (usually paprika or other peppers). I asked if they knew which "spices" it contained, and if I could see the container. They looked at me funny, then looked at each other. I suddenly realized that they must not actually be made on-site. In retrospect, I should have figured that out from the length of the ingredients list, but I wasn't thinking that fast.

I went back to the ingredients binder and looked at the next most conservative item, the Egg & Cheese Breakfast Sandwich. If you go to Panera's Breakfast Sandwiches Menu, you will see that at first glance this contains 3 ingredients, and 12 descriptive words to positively influence you're attitude towards them. However, if you click on "Egg & Cheese" you get the real list, containing 36 ingredients, 29 of which are in the "two slices of freshly baked Ciabatta." The most memorable of these are "fava bean flour" and "distilled monoglycerides."

Admittedly this isn't as bad as an Egg McMuffin which at first glance contains 5 ingredients, but 64 when you dereference the ingredients (35 in "English Muffin", 2 in "Egg", 14 in "Canadian Style Bacon", 13 in "Liquid Margerine"). Now, a lot of those are duplicates, but it would still be a lot if the duplicates were removed. Also, that list includes scarier things, including "high fructose corn syrup", "partially hydrogenated soybean oil" and "artificial flavors" which Panera's happily doesn't.

Despite the carefully crafted image Panera projects, it would be unjust to consider just one of these breakfast sandwiches as "processed" -- they both are. Both are engineered to stimulate your senses in ways that mere unaided nature cannot compete with.

That's what I thought of when reflecting back on the experience. What I thought of while standing around hungrily perusing the ingredient binder is this: which is riskier, "spices" or "fava bean flour"? I vaguely remembered that fava beans have some pretty potent physiological effects, though I couldn't remember what they were. Most importantly, I haven't eaten any since I overcame the cholinesterase inhibitor stuff and started carefully adding foods back in. I didn't even dare to think about the distilled monoglycerides...

In the end, I decided to go for the Egg & Cheese Breakfast Sandwich as the least of three evils (the third being to sit there hungry watching Randy eat his souffle). It was reasonably tasty, and happily I did not notice any nasty side effects of having eaten it.

The next day I made an egg & cheese sandwich at home. The eggs, cheese, and butter were local. (I later got to meet the farmer in Ligonier who raised the eggs.) The bread was organic and baked at Whole Foods. It was yummier, and led to less angst.

Saturday, May 9, 2009

Differential reactivity to emotional inputs and BDNF

Someone on the 23andme forum posted the following paper abstract:

http://www.snpedia.com/index.p­hp?title=Rs6265
1: Am J Med Genet B Neuropsychiatr Genet. 2009 Apr 22. [Epub ahead of print]
BDNF, relative preference, and reward circuitry responses to emotional communication.

Gasic GP, Smoller JW, Perlis RH, Sun M, Lee S, Kim BW, Lee MJ, Holt DJ, Blood AJ, Makris N, Kennedy DK, Hoge RD, Calhoun J, Fava M, Gusella JF, Breiter HC.

Motivation and Emotion Neuroscience Collaboration (MENC), Athinoula A. Martinos Center in Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Brain derived neurotrophic factor (BDNF) regulates neural development and synaptic transmission. We have tested the hypothesis that functional variation in the BDNF gene (Val66Met polymorphism, rs6265) affects brain reward circuitry encoding human judgment and decision-making regarding relative preference. We quantified relative preference among faces with emotional expressions (angry, fearful, sad, neutral, and happy) by a keypress procedure performed offline to measure effort traded for viewing time. Keypress-based relative preferences across the ensemble of faces were mirrored significantly by fMRI signal in the orbitofrontal cortex, amygdala, and hippocampus when passively viewing these faces. For these three brain regions, there was also a statistically significant group difference by BDNF genotype in the fMRI responses to the emotional expressions. In comparison with Val/Met heterozygotes, Val/Val individuals preferentially sought exposure to positive emotions (e.g
., happy faces) and had stronger regional fMRI activation to aversive stimuli (e.g., angry, fearful, and sad faces). BDNF genotype accounted for approximately 30% of the variance in fMRI signal that mirrors keypress responses to these stimuli. This study demonstrates that functional allelic variation in BDNF modulates human brain circuits processing reward/aversion information and relative preference transactions. (c) 2009 Wiley-Liss, Inc.

This is interesting to me. I'll get to why further along in the post, but first I've got some background to fill in:

I've been looking into how the limbic system, which includes the amygdala and hippocampus, is involved in processing and generating emotional communication (facial expression, body language, tone, that sort of thing) and physiological responses to such communication.

It seems to me like for some people, including me, the output of the emotional communication detectors seem to be wired to physiological responses with a much higher gain than they are for other people, like my brother. Put him in a room with an angry person and he'll be aware of it in an abstract sort of way, but physiologically seem unaffected. In the same situation my heart rate will be going crazy and I'll feel a strong urge to run for the exit, even if I know intellectually that the angry person isn't a threat and that I have nothing to do with whatever it is he's mad about. I've put a fair bit of effort into trying to understand this discrepancy.

The limbic system is designed to keep us from getting killed and/or eaten. It responds quickly, but it's not big on context or discernment. It's perfectly capable of causing sympathetic activation, releasing epinephrine (aka adrenaline) and all those other fun stress response chemicals, before the cortex has an opportunity to weigh in on the matter. Anyone who has rounded a corner while hiking and found themselves jumping backwards with their heart racing from what the cortex easily identifies a fraction of a second later as a stick knows this.

Your cortex can then either work to get the limbic system to settle down or make the situation worse depending on how you end up thinking about the event. Even best case though, it takes time for all those nasty stress chemicals to dissipate. So, in the example of me and my brother in the room with an angry person, I don't believe that the difference is due to a difference in how we're thinking about things.

These sorts of differences in reactivity can also be related to a difference in life experience. The limbic system learns and adapts over time based on earlier outcomes -- what circumstances turned out to be dangerous or not. Once you burn your hand on a stove you find yourself acting wary thereafter around stoves even without conscious thought. This is why burning your hand is so much more effective than someone repeatedly telling you to be careful around the stove (limbic vs. cortical processing). However, based on stories my mother told me, the difference between my and my brother's reactions to aversive emotional output in our general vicinity was apparently present from infancy, so I don't think limbic training is enough to explain it.

All this leaves me looking for a genetic basis for this difference. I may have found one potential piece of the explanation in rs1801252, a SNP in the ADRB1 receptor. If I'm interpreting the reference on the SNPedia page right, the fact that I'm homozygous for the atypical version of this (GG) would lead to a more drastic than normal cardiac response to a given level of epinephrine. However, it wouldn't affect the aspects of sympathetic nervous system activation other than those mediated by the beta 1 adrenergic receptors, and I don't get the impression that my brother is experiencing those other effects either. I think he's not ending up with as strong a signal from the emotional state detector system and/or experiencing a lesser limbic reaction to it in the first place.

This brings us back to why this study seems like an interesting potential lead. They're showing a pretty strong difference in limbic response to facial expression based on differences in genotype for BDNF. I've got the version of that SNP that seemed to have the stronger response (CC = Val/Val). I wonder what version of this my brother has? I guess I've gotta get him genotyped to find out...

There's obviously more to it than that. About 68% of the population are also CC on this SNP. If 68% of people have as strong a physiological reaction to emotional output in their vicinity as I do most of them hide it well. Elaine Aron has written a series of books about "highly sensitive people"(HSPs), which I think corresponds fairly well to what I've been talking about. She calls this trait Sensory-Processing Sensitivity (SPS) and estimates 15 to 20% of people to have it. I wonder how well her concept of the SPS trait would correlate with the BDNF genotype and fMRI testing results described in this paper.

I also wonder about how all this relates to autism spectrum disorders. It seems like part of what's going on there is that either the parts of the limbic system detecting the emotional state of others doesn't work well, or the degree to which that information impacts and/or is accessible to the affected individual is muted enough so as to cause them problems. This seems potentially a more extreme degree of the same effect that I've been talking about. Perhaps it's all one spectrum: people like me and other HSPs at one end, people like my brother who match social expectations on this issue in the middle, and people with various degrees of autism spectrum issues at the other end. I could be totally off base here -- I haven't looked into the literature on this issue much at all -- but I think it's an interesting area for study.

Tuesday, April 21, 2009

Dopamine deficiency, Parkinson's, and CIS

I have been reading the 23andme forums quite a bit, on the lookout for things related to the whole cholinesterase inhibitor sensitivity issue. 23andme is working with the Michael J. Fox foundation to make it easy for Parkinson's sufferers to use the service in return for their participation on surveys (see article here). As a result, a lot of people with Parkinson's Disease are active participants. One such participant asked about excess salivation, which I recognized as a symptom of cholinergic excess. So, off I went on a new research tangent...

It turns out that there is a significant overlap between the symptoms of Parkinson's and the symptoms of cholinergic excess. According to the book "Handbook of Parkinson's Disease", decrease in the level of dopamine, as is seen in Parkinson's, can cause the symptoms of cholinergic excess. It says this happens because it's the ratio of acetylcholine activity relative to dopamine activity that's significant.

So, I went out and read about dopamine, and dopamine deficiency. I found all sorts of exciting stuff in that quest -- enough to fill a huge number of future blog posts, so watch out. Click here for a good web page describing the basic neurophysiology of dopamine, and here for a list of the effects of dopamine deficiency. Here are some highlights:
  • High/increasing dopamine levels make you feel good: the "high" caused by many drugs of abuse like cocaine, heroin, and amphetamines work by temporarily greatly increasing dopamine release
  • Low/decreasing dopamine levels make you feel bad: the "low" after such drugs wear off, the plunging feeling when something you did that you expected to be praised for instead results in scorn or abuse, etc. are caused by your dopamine levels decreasing
  • People feel motivated to seek experiences which are expected to increase dopamine, and to avoid experiences which are expected to decrease dopamine.
  • Dopamine is involved in reinforcement training: if you expect a positive outcome of an intended action, you get an increase in dopamine. If you get a positive outcome, you get even more dopamine. If you get a negative outcome, your dopamine drops precipitously.
  • Dopamine is involved in social dominance: successful assertion of social dominance increases dopamine; being the target of someone else's assertion of social dominance decreases dopamine
  • Dopamine is involved in behaviors related to food: eating increases dopamine; chronic overeating decreases dopamine receptors so you have to eat more to get the same "high" (see article on role in obesity here); but, paradoxically, low dopamine decreases motivation for and willingness to expend effort to gt food (in a paper on Regulation of Effort in Food-Seeking Behavior rats are less inclined to press a lever to get food if you suppress their dopamine).
  • Dopamine is involved in sexual behavior: a good description of this role of dopamine is here.
  • Dopamine is related to motivation and perception of one's ability to effect change (empowerment) in general: many of the symptoms of dopamine deficiency relate to lack of motivation and enthusiasm; high dopamine leads to a feeling of "social potency" and the feeling that you can take action that leads to success (and higher dopamine); success at such attempts leads to even more dopamine; failure leads to less dopamine, and makes it harder to try again.
  • Dopamine may be related to subjective experience of temperature: high dopamine makes you feel warmer, low dopamine makes you feel colder. I need to research this more, but I certainly notice this effect correlating with other indicators of dopamine level. I have found some other places that mention this: This page on the effects of heroin lists it, and this paper abstract says increased dopamine increases heat dissipation (skin is hotter, but core gets colder).
Anyway, reading about all this I realized that the state I have been in after getting the cholinesterase inhibitors far enough out of my system looked just like what I'd learned about dopamine deficiency. Sure enough, dopamine reuptake inhibitors, which increase the effect of dopamine by making it spend more time in the synapse, had a huge impact.

I've been feeling a strange inability to initiate action, even for stuff I wanted to do, like make dinner, or start this blog. I could eat plenty if it were put in front of me, but seldom ever felt hungry, and had difficulty making myself prepare food -- particularly anything at all complicated -- even though I know how important it is to eat. (In the old days, I would have just grabbed a snack or microwavable convenience food, but that's incompatible with my efforts to avoid cholinesterase inhibitors, so it's a lot more of a problem now.) I didn't really feel enthusiastic about anything, even stuff I know I would normally be excited about, like the Yuri's Night celebration or seeing old friends I hadn't seen in a long time. Dopamine reuptake inhibitors, specifically bupropion, made all these effects go away within a few hours.

Now, the typical way this would be interpreted in our culture is "oh, that's an antidepressant, so if it helped it means you must have been depressed." I could get into a semantic argument about this, and maybe I should in a future post. (Interestingly, it's also used to relieve smoking addiction -- another condition relating to dopamine and cholinergic receptors.) For now, leave that aside and consider this as a Human System Debugging experiment which confirms that dopamine is likely playing a role here. The fact that the success of that experiment allows me to finally get on with writing this stuff down is a happy side effect. :)

So, putting all that together with the insights from the Parkinson's book leads to an interesting hypothesis: maybe low dopamine increases sensitivity to the effects of cholinesterase inhibitors. If so, then people with conditions which cause low dopamine, such as Parkinson's, or who are deficient in dopamine either by genetic predisposition, current circumstance, or nutritional insufficiency of dopamine precursors may be at greater risk for suffering symptoms of cholinergic excess from ingestion of cholinesterase inhibitors. If they also have a compromised ability to detoxify cholinesterase inhibitors, such as the BCHE, ACHE, and PON1 SNPs described by Dr. Soreq, this could be a bad combination. This is my current favorite hypothesis for conditions which could lead to what I'm calling Cholinesterase Inhibitor Sensitivity (CIS).

Thursday, April 16, 2009

AChE-R and Mass Spectroscopy

Dr. Hermona Soreq and her colleagues have published several papers and a book chapter which talk about various forms of cholinesterase, how they're regulated, and what they do. In particular, they talk about a form called readthrough acetylcholinesterase, or AChE-R, that the body produces in response to acute stress and exposure to cholinesterase inhibitors (CIs).

Apparently AChE-R is not fun stuff. It's pro-inflammatory, may cause neural damage, and may somehow make you more prone to other bad stuff. It hangs around for a long time after the stressful event/CI exposure too.

I want to be able to measure AChE-R, AChE, BChE (butyrylcholinesterase), and PON1 levels. I've got so many ideas for experiments I could run if only I could measure these things. Among other things, I hope it would let me test whether or not strawberries are really cholinesterase inhibitors or not. I really hope not, but a book from 1985 says they are, so I'm avoiding eating them until I can find or perform an independent verification or refutation that finding.

Unfortunately, I don't know how to accomplish measuring these things. I haven't seen anyone other than Dr. Soreq and her collaborators even talk about AChE-R, which is the most interesting one of all. They're mostly in Israel and I'm in the US. Even if they were optimally interested in working with me on this, I doubt samples would make it through customs.

My husband is suggesting we learn how to use a mass spectrometer so we can measure these things ourself. He's doing things like finding online courses and books at amazon and searching eBay for used mass spectrometers.

My idea is to try to find a lab in Pittsburgh (where we'll be for the rest of the year) with appropriate equipment and someone who is willing to help with this. I figure I could barter one-on-one tutoring with lab personnel. I can help them learn how to do various forms of automation to make their jobs easier in return for training and time on their equipment so I can do my cholinesterase inhibitor experiments.

I don't know how to find and set up something like this with an appropriate lab, but this really seems like the best option if I could pull it off. Any leads anyone?

Leaky Gut Syndrome

Another condition that could potentially be related to cholinesterase inhibitor sensitivity is Leaky Gut Syndrome, aka Intestinal Permeability.

The best info I've found on this is in the book Digestive Wellness by Elizabeth Lipski. I stumbled across a web site today that also looks potentially good on this topic, though I haven't read it carefully: http://www.ei-resource.org/illness-information/environmental-illnesses/leaky-gut-syndrome-(lgs)/

The idea is that if you have compromised intestinal permeability, things like cholinesterase inhibitors could enter your system more freely without being broken down properly while within the intestines. Also, solanaceous glycoalkaloids, the cholinesterase inhibitors in nightshade foods, can apparently cause membrane disruption that can lead to and/or exacerbate leaky gut syndrome.

So, you can easily imagine that once this process got started it could form a positive feedback loop and get progressively worse until you stopped eating nightshade, taking NSAIDs, and eating whatever else your gut associated lymphatic tissue had gotten upset about so you could heal.

I've finally started writing up info on avoiding nightshades and other cholinesterase inhibitors at http://sites.google.com/site/annerwright/avoiding-cholinesterase-inhibitors

SNPs for cholinesterase inhibitor sensitivity

I've been trying to understand the potential causes of cholinesterase inhibitor sensitivity. My leading theory at this point relates to single nucleotide polymorphisms (SNPs) affecting the genes for encoding and promotion of acetylcholinesterase (ACHE), butyrylcholinesterase (BCHE), and paraoxonase 1 (PON1).

I've found several papers and a couple of books that relate to these genes and talk about polymorphisms which can result in being more susceptible to cholinesterase inhibitors. I've also signed up for 23andMe which hopefully in 8 more weeks or so will allow me to see which version I have of many of them. If, that is, I can figure out the mapping...

First off, it turns out that there are two ways of reporting the alleles for a given SNP: A=T; C=G. SNPedia uses one way, and 23andMe uses the opposite way. A partial explanation of this is at
http://www.snpedia.com/index.php/Talk:Rs4420638. This isn't complicated, but it does make your head hurt more when trying to compare them.

Secondly, the various sources aren't using a consistent naming scheme. I've tried to start making a table to cross reference the names I've found in the papers to the "rs" codes that 23andMe and SNPedia both use (see http://sites.google.com/site/annerwright/snps). It's a clunky way to do it, and I'm fantasizing about making something with django to do the job better. So, I'm kinda stuck on that project until I either bite the bullet and do it clunky way, or learn enough django to do it the fancy way and possibly enter a bottomless development hole...

Finally, three SNPs into the project I ran into a possible numbering discrepancy. The paper lists the SNP as position -162 on the PON1 gene. SNPedia doesn't list a SNP there, but lists Rs705381 at position -161. Is it the same one?

How many more of these things are going to almost but not quite line up? Aaaahhhh!

It begins

I've decided to start a blog on the general topic of "Human System Debugging."

I call it that because I used to work as a systems engineer for one-off robot systems, and then I got too sick to do that, and nobody could figure out what was wrong. I started applying the techniques of debugging one-off robot systems to figure out what was wrong with myself. The theories I've come up with are rather unconventional in places, but seem to be helping. I hope that that some of the things I'm learning along the way may be of use to others. Hence this blog.

Here are some things I've got so far that may be of interest to someone: