I, too, get emails

Recently, Rebecca posted an email exchange with some jerk who called her dumb. He’s an ass.

But today has been exciting for me, because now I get emails as well!

This morning I got an email (through our handy dandy kick ass comment link over there on your left where you can email me as well!) offering me a chance to try a new, all natural, migraine medicine!

For those of you fledgling skeptics out there who may be confused, this is not how legitimate pharmaceuticals are marketed. You can get free samples from your doctor, or for OTC medications, they come in the mail or with your Sunday paper. I guess with print media slowly dying, the new thing to do is to just email chick blogs and see if anyone wants to try some shit you whipped up in your basement*.

Date: Thu, Jan 7, 2010 at 9:44 PM

Name: Steve Roberts, MD

Subject: Other

Message: Thank you (all) for the interesting and entertaining blog.

The remainder of this message is directed to Elyse.

I am writing simply to offer you a free (of course) trial of my new
‘migraine’ medication.

I would like you to try this because you suffer with migraine – and
especially because you are skeptical – but hopefully still curious.

You can read about the medication on my (still incomplete) site –
perhaps starting here:

If others there would like to sample the product, I am more than
happy to send additional samples – just let me know.
Best wishes, Steve

Fortunately, and unfortunately, for Dr Banjo, I am in the family way these days. I had an offer for him. I was sincerely hoping he’d take me up on it. My reply after the jump:

Hello Dr Roberts!
I’m certainly glad you’ve written. My migraines are persistent little buggers and I’m certainly willing to try anything that’s proven to be safe and effective.

Right now I am 5 months pregnant, so, as you can imagine, the headaches are harder to control due to the fact that so many of the medications out there promise to give me a baby with an extra penis, no eyes, and a heart condition. If it were triplets, I’d roll the dice, but since it’s only one baby, I’m feeling a little helpless.

Before I give you my shipping information, I just have one request.  Could you please send me an affidavit stating that your product is completely safe for me to use during pregnancy? I can only assume that it is since it’s 100% natural. I just worry about the health and well-being of my future offspring and don’t want to blow my vacation budget on things like vestigial penis removal or eye transplants. I’m sure you understand. Vacations are important.

If you cannot provide this, I would be willing to act as a pregnant guinea pig for your research in exchange for a healthy stipend and a promise to help with any costs related to the injury of my fetus. Again, I’m sure this is not a problem since your product is 100% natural. I would also agree to write several articles per week promoting your product on various skeptical websites if your product does work to alleviate my migraines completely.

I look forward to hearing from you, Dr. Roberts!


Elyse Anders

In this economy, a girl’s gotta do what a girl’s gotta do… and I am seriously dying for a Greek Isles cruise. So I was hoping he’d say yes. Instead, I was (once again) informed that I am too snarky for the position.

Actually, I had a substantially longer message written out via your web site – but (only after hitting “send”, mind you) I was told that the message length limit was 1,000 characters (as best I recall.)

You’re too clever for me – by half.

Be well, Steve

Stephen C. Roberts, M.D.

Chief Executive Officer

Protanza Corporation

So,  I remain pregnant and unemployable.

If anyone else out there is looking for me to shill their all-natural crap pills in exchange for shitloads of money, the contact form is to the left. Please use it.

*Dr Steve Roberts likely did not whip this up in his basement. He may have a kitchen or a garden or a bathroom or greenhouse laboratory where he makes his medicine. Please do not assume that I am in any way aware of the manufacturing process of BANJO. I only hope that the process does somehow include a whiskey jug with several Xs on the side.


Elyse MoFo Anders is the bad ass behind forming the Women Thinking, inc and the superhero who launched the Hug Me! I'm Vaccinated campaign as well as podcaster emeritus, writer, slacktivist extraordinaire, cancer survivor and sometimes runs marathons for charity. You probably think she's awesome so you follow her on twitter.

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  1. I’m sorry to say I only have a product that can cause headaches. It’s called “An offer for sex”. Guaranteed to create a headache in any female instantly. So far my product has proven 0ver 99% effective at both causing headaches and preventing pregnancy.

  2. Brilliant response!
    The only thing that ever cured my migraines was being pregnant. It at least has the benefit of being safe during pregnancy.

  3. Dear Elyse,

    Please accept the gift of this revolutionary trepanation kit for help in relieving your migraines.

    Unlike other trepanation kits which use substandard materials which can stain or leave a dingy residue in your hair, this one is made from pure (99.45%) American steel. Each piece has been lovingly crafted to provide a trepanation experience you are sure to remember (maybe).

    Each piece has a leather wrapped handle from cows that died of natural causes and were cured using Native American techniques.

    Also, since our kit is 100% all-natural, it is completely safe for you and your unborn child. The only noted side effects are slight memory loss, head pain, and possible cessation of biological functions.

    We are so sure that you will like this product that we are giving it to you free minus the 69.99 shipping and handling fee. We are sure your testimonial will be a glowing endorsement!

    Also, in case there are actual demons being released from your head, our trepanation kit has also been sanctified at no extra cost!!! It’s a 100 dollar value absolutely free!

    Contact us today!!!

  4. @Anonentity: COTW

    We should have a contest to see how many companies Dr. Steve can start in one year. I mean dId you see his Linkedin page from @Steve? Christ on a cracker!

  5. I suffered from migraines from the time i was 12 until i got married at 28, i have not had a migraine since! I have no explanation of why they stopped then, but am very glad they did.

    when i was young my dad worked for Sandoz (think Hoffman, the dude that invented LSD). they had a couple of meds that were aimed at migraine… i would end up taking like 15 Cafergot PB to try to alleviate the pain, but just ended up passing out from the phenobarbital (PB) in the preparation. Usually when i woke, the migraine would be gone but there never was a guarantee of that. I feel for you Elyse.

  6. @James Fox: I, for one, like the sound of the banjo. Especially when played by Bela Fleck. :-)

    Elyse: I think you should accept a free sample and tell Dr. Steve that when you took it your migraine went away but was strangely replaced by “Dueling Banjos” playing over and over in your head. Make it stop!!

    @anonentity: “Come ‘ere, Wendy. I’m not gonna hurt ya, I’m just gonna bash yer brains in. I’m gonna bash em’, right the fuck in!” Allright, I’m just gonna drill a tiny hole first.

  7. @James Fox: But…but…banjos, harps, and accordions are awesome! If anything can qualify as an instrument from hell, it’s the piccolo.

  8. I looked at his website because migraines is something that nitric oxide is involved in. He has a pretty conventional idea of migraines, an idea which happens to be wrong. Migraines are not caused by too much NO, they are caused by too little NO.

    If his stuff actually does inhibit NFkB, or otherwise interfere with NO physiology, in no way, shape or form is that acceptable for someone pregnant to take. A well known inhibitor of NFkB is thalidomide. At 5 months, it is (probably) too late to get major deformations like extra penises, but not too late to cause problems with neurological disorders or bad epigenetic programming, like for obesity and diabetes.

    Usually, (as pinkbunny mentions) migraines are reduced during pregnancy. This is because migraines are caused by low NO, and pregnancy is a high NO state (I am pretty sure that it is the high NO that causes the nausea, if you have bad nausea, you probably won’t have migraines, but if your migraines cause nausea I don’t have an explanation). It is the bad stuff that happens during pregnancy that correlates with low NO (preeclampsia, gestational diabetes, hypertension, placental insufficiency, etc). Nausea is actually a sign that things are going well.

    I think (but I am a guy so it is easy for me to say) that if you feel nauseous during pregnancy, you should just remember that it probably means everything is going ok and take comfort in that (and not take anything for the pain) (but then I don’t get migraines either).

    High nitric oxide is also what makes people feel like having sex (in part), so having a headache is a sign of low NO and is why it correlates with feeling like not having sex.

  9. The Magic Banjo contains the following “active” ingredients:

    Lemon, Sunflower seed, Verbena, Peppermint, Ginger, Dandelion, Feverfew

    and “inactive” ingredients

    Cellulose, Corn Starch, Citric acid, Stevia, Dextrose, Magnesium stearate, Turmeric

    I’m surprised by the last being “inactive”, as turmeric has been hailed as having health benefits for years. I dimly recall some research in Britain that indicated that its active ingredient curcumin can induce cell death in oesophageal cancer cells and may be a promising anticancer agent. But I suppose the turmeric is just there for colour.

    Personally, I think “Banjo” is a silly name for a substance, much less one that claims to be a panacea for a variety of ills. But then, I live on the anti-inflammatory ketoprofen, which was once marketed as “Orudis”, a name that conjures up fungal infections more than pain relief.

    I used to use Cafergot for migraines, as well, but the headaches stopped in my mid-thirties and only recurred for a month or two after a concussion. One of my doctors told me to find a joint if I didn’t have the med on me; he was right, it worked wonderfully well. Probably not the thing a pregnant lady should indulge in, tho’.

  10. @daedalus2u: Just out of curiosity, is there any human body dysfunction that you don’t claim is caused by a problem with nitric oxide? Your pushing this in every medical context I’ve seen you comment on, here and elsewhere, reminds me a lot of the people who harp on a single questionable cure as a panacea. (Some of them consider themselves skeptics as well.)

    The fact that you don’t even have a handle on the correlation between migraines and nausea makes me wary to accept your views on this topic, especially when it’s yet another variation on the NO theme and involves a lot of “probably”s” and “I think”s.

  11. Oh man, I just went to the Banjo site to see the welcome that Karen posted about, and saw the comment from the person claiming that Banjo has cured her fibromyalgia. This is exactly how the alt-med quack cycle perpetuates itself, not to mention why people believe illnesses like fibro and CFS are imaginary (if they can be “treated” with nonsense like this). Sigh.

  12. @ZenMonkey: Just out of curiosity, is there any human body dysfunction that you don’t claim is caused by a problem with nitric oxide?

    Google rapidly turned up a bunch of research papers on nitric acid and migraine. This is not surprising since NO plays a key role all over the circulatory system including erections. I couldn’t find any evidence, however, that it causes more excellent boobies. Sad, too, but because it was just this close to nominating it for Chemical of the Week.

  13. @davew: This is not surprising since NO plays a key role all over the circulatory system including erections.


    Except that recent research suggests that migraines are not actually vascular headaches, but are a neurological problem.

    Which sort of explains why triptans are effective migraine treatments. Sumatriptan certainly changed my life, especially since my migraines are connected to what I can only describe as crushing depression.

    As far as I can discern, there’s no specific relationship between NO and migraine. The most recent study in 2009 showed that migraineurs with either increased or decreased Nitric Oxide Stress were at greater risk of a migraine, but no causative link has been established.

    Or to put it another way, @daedalus2u, Migraines are not known to be caused by low NO.

  14. Does anyone else feel like he’s now double dog daring you to try his product?

    Sorry, dude, I’m one of those “fake homeopathy skeptics”.

    Can I also say that I love love LOVE when people claim that their product is homeopathy (i.e.; totally and completely fake medicine full of nothing) when really, it’s not even homeopathy. It’s FAKE homeopathy. It’s fake fake-medicine!

  15. Zenmonkey, I only bring up nitric oxide when there is good data in the literature, or a good physiological connection to nitric oxide. I only bring up nitric oxide because that is what I am specializing in. A lot of things are regulated by nitric oxide, many hundreds that are known, probably thousands more that are not known. I don’t bring up other things because I am focused on nitric oxide.

    I do find it curious that when I put limits and qualifications on what I know, you find my statements about what I do know less persuasive. As a skeptic, you can’t use rhetorical arguments or any other arguments not based on facts and logic.

    Migraines are known to be associated with what is know as spreading depression. This is a propagating depression of metabolic activity that can be observed in brains. The person who “discovered” this noticed that when he had a migraine, his visual field went dark at a certain velocity, and that velocity corresponded to the velocity that a spreading depression propagated.

    Spreading depression is an example of ischemic preconditioning, a physiological state that tissue compartments invoke to reduce metabolic demand so that they can survive ischemia. Essentially all tissue compartments do this. It is triggered by oxidative stress, by superoxide, or by a drop in nitric oxide.

    Nitroglycerine reliably causes migraines because it causes a drop in nitric oxide. Many researchers do not appreciate that nitroglycerine causes a drop in nitric oxide, not an increase. Similarly Viagra also reliably triggers migraines. This is because Viagra inhibits the enzyme (phosphodiesterase 5) that cleaves cGMP which is produced in response to NO (acting on sGC). This inhibition cause increased cGMP, which increases the effects of NO in pathways involving cGMP and PDE5 (i.e. erections). There is a compensatory decrease in NO production through feedback inhibition from the higher cGMP levels. Thus Viagra increases the response of NO pathways mediated through cGMP, it decreases the response of NO pathways through all other mechanisms. The triggering of migraine is caused by a drop in NO levels.

    I have a pretty extensive write-up of some of the interactions of NO with the vasculature. I put a section on migraines in there because some people think of migraines has having a vascular component. They don’t really, but over time there can be vascular remodeling due to migraines which is interpreted as vascular damage. It isn’t “damage” per se, it is the normal remodeling of the vasculature under conditions of low NO.

  16. @daedalus2u: Nitroglycerine reliably causes migraines because it causes a drop in nitric oxide.


    Daedulus, I checked the actual medical literature on Migraines and their causes. You’re reading more into the literature than the literature supports. There is no causative link between NO and migraine. The viagra studies do not draw definitive conclusions, nor do the Nitroglycerine studies. Also, several of these studies rely on a now obsolete vascular model.

    So, if you want to rely on facts, the facts do not, at this time, support your conclusion.

  17. Sethmanpio, I disagree. Did you read every reference that I linked to in my write-up on migraines?

    The levels of NO that are important are in the nM/L range. There is no technique to measure these in vivo. The absence of reports that NO is involved in migraine is not evidence of non-involvement of NO.

    The data from the nitroglycerine and Viagra studies does not rely on any model, it is data. I agree that a vascular model is incompatible with the data, a low NO model is not. I am not looking at the conclusions of the Viagra and nitroglycerine studies, but on their data and drawing my own conclusions.

  18. Dr. Steve Bob said, “I am writing simply to offer you a free (of course) trial of my new
    ‘migraine’ medication.”

    Am I the only one wondering why he puts the word ‘migraine’ in quotes? It makes me envision air quotes. ‘Medication’ in quotes seems as if it would be more accurate.

  19. @daedalus2u: I am not looking at the conclusions of the Viagra and nitroglycerine studies, but on their data and drawing my own conclusions.

    Science isn’t about looking at the data and making reasoned conclusions. It’s about accepting the conclusions of other people. What’s wrong with you?!

  20. @daedalus2u: I am not looking at the conclusions of the Viagra and nitroglycerine studies, but on their data and drawing my own conclusions.
    That’s fine. I accept that you have a hypothesis. I also note that this hypothesis is not supported by the literature, and further work should be done before making a declarative statement about what causes the migraine cascade. Your mechanism is, at the moment, pure conjecture.

  21. No sethmanpio, that is not how science works. Accepting other people’s conclusions is not science, being able to support a hypothesis with facts and logic is. Davew was being sarcastic.

  22. The reason banjo-guy puts the tems in quotation marks is because he is violating FDA regulations if he doesn’t (probably he is violating them anyway). He does not have a “medicine”, he has an herbal supplement.

    Medicine is a defined term, either a recognized OTC medicine, an FDA approved medicine, or a new drug medicine (i.e. something for which a new drug application has been filed).

    If something is not one of those, then to call it a medicine or drug is mislabeling. Even calling the ingredients “active” ingredients is mislabeling. Those herbal things are not recognized as “active ingredients” by the FDA.

  23. @davew: Science isn’t about looking at the data and making reasoned conclusions. It’s about accepting the conclusions of other people. What’s wrong with you?!


    Well, for starters, what’s wrong with him is that he made a positive statement about the causes of migraine, but he has no means of testing his hypothesis. Skepticism isn’t about generating your own untestable hypotheses that extend beyond what is known or in fact currently knowable and relaying them as fact.

    The other thing that is wrong with him is that the data simply doesn’t support his conclusions. The fact that you can induce a migraine by creating stress on a system by screwing with the NO levels doesn’t mean much by itself. The question is whether this is happening in patients who are not being so induced, but are still having migraines. That question is completely open, and there is no data to close it.

    Science isn’t about blindly accepting any conclusions, including your own. I’m not saying that daedulus is wrong, I’m saying that his hypothesis is not well supported by the literature, or even by the data.

  24. @daedalus2u: Accepting other people’s conclusions is not science, being able to support a hypothesis with facts and logic is.


    I can support any hypothesis you want with facts and logic. Seriously. Pick any hypothesis you can imagine, I guarantee I can support it.

    That’s not science, it’s psuedoscience.

    Science is when you do your best to destroy a hypothesis with tests, logic or data.

  25. Before reading it, I measured the length of the main web page. After noting its excessive length, I began the rigorous method of measuring it in units of ‘standard quack’ (SQuack). In other words, hitting the Page Down button.

    The mentally disturbed and the ‘quackically over-excited’ create web pages about their new ideas that are well past what you and I would consider long. Perhaps thinking “Bo, oh boy! Do people want to hear what I have to say!” After hitting Page Down for the 5th time on any such page, alarms start going off in my head.

    Banjo measures about 11 SQuacks.

    Also, sethmanapio, scores 1 Scarcasm for not recognizing DaveW’s clear sarcasm.

  26. @maggie: Also, sethmanapio, scores 1 Scarcasm for not recognizing DaveW’s clear sarcasm.


    No, maggie. I recognized that DaveW was being ironic. Dave’s sarcasm is meant to highlight the idea that there is nothing wrong with Daedulus: I.E., he was doing science right. Hence the ironic “What is wrong with you.”

    In my response, I point out that contrary to DaveW’s position, there are in fact a great many things wrong with daedulus’ approach. The emphasized “isn’t” was meant as an agreement with DaveW’s intention (that in fact, science is not about blind acceptance) but to highlight that daedalus is guilty of this blind acceptance himself.

    I realize that I should have put up a “sarcasm aside,” or something to let you know that the content of my post would be a reply to the intended meaning of Dave’s post rather than an actual defense of daedalus, but I generally have a high opinion of the reading comprehension skills of the skepchick community.

  27. Sethmanpio, I have done my best to demolish the hypothesis that migraines are associated with low NO. There isn’t any data in the literature that I have been able to find that is incompatible with it, and I have looked quite hard.

    Show me some data that is incompatible with migraines being caused by low NO and we can discuss it. I have looked very hard for it and as far as I can tell there isn’t any. I appreciate that that doesn’t “prove” that low NO is associated with or causes migraines. But that is true of any hypothesis, they can never be “proven”. Even evolution is not “proven”.

    Just for your information, high nitrosative stress is the presence of both high NO and high superoxide, low nitrosative stress is the presence of high NO and low superoxide, oxidative stress is the presence of low NO and high superoxide. There is no nitrosative stress in the absence of superoxide. Not all researchers appreciate that because sometimes the only superoxide is confined to lipid vesicles and so is not susceptible to being reduced with added superoxide dismutase. NO/NOx chemistry and physiology is quite complex and tricky. There is a lot of misunderstanding in the field, even among senior researchers.

  28. @daedalus2u: I do find it curious that when I put limits and qualifications on what I know, you find my statements about what I do know less persuasive.

    I always find your statements unpersuasive because your tactics in constantly pushing this NO thing are exactly analogous to the quacks who constantly push one kind of CAM or another, adapting it to any and every situation. You reliably bring this up in every medical context I’ve seen you comment on; this is the precise method the med-spammers and snake oil salesmen use.

    I pointed out the limitations of your knowledge because I find it ludicrous for you to speculate about NO and migraines and give advice while you apparently lack an understanding of the basic signs and symptoms of migraines, as evidenced by your comment about nausea. Exactly as I am with the quacks, I find it necessary to point out that some knowledge of engineering does not in this case, or any of the others I’ve personally read from you, qualify you to make any kind of medical suggestions. (Other than “eat leafy green vegetables,” which I will accept is a perfectly good bit of advice for anyone.)

    As I’ve mentioned to you before, I don’t believe you have a clear handle on what skepticism is if you continue to be surprised by people’s objections to what you have to say.

  29. No Zenmonkey, it is you who does not understand skepticism. You are confusing it with cynicism. A skeptic can only argue from facts and logic. If you are using arguments other than facts and logic, you are not using skepticism. The default for a skeptic is “I don’t know”, it is never the cynic’s default of “you must be wrong even though I do not understand what you are saying”.

    The style of argument has no bearing on the underlying reality of the facts and logic in the argument. I do appreciate that pseudoskeptics do rely on things other than facts and logic. That is unfortunate and one of the things I am trying to fight against by example.

    I don’t know the mechanism for the nausea that sometimes accompanies migraine. I freely admit that which I don’t know. I have no need to make stuff up. I have plenty of stuff without making things up. Physiology is really really complicated. It is much more complicated (many orders of magnitude) than most researchers appreciate. It seems “simple” because stuff just happens with no apparent input. It is deceptively simple. Not all people experience nausea with migraines. Why is that? I don’t know. No one knows. That aspect of migraines is not understood sufficiently well for there to be an explanation of why that happens. I am not going to wait for a perfect explanation when there is a good one that provides a useful rational for treatment.

    I really do appreciate that it is impossible to evaluate something you don’t understand. I don’t expect anyone to do so, or to accept what I have to say without understanding it. That is why I am providing links and trying to provide explanations. I appreciate it sounds like cherry picking, and ad hoc stuff, but it isn’t. If you knew the whole literature, you would be able to appreciate that I am not cherry picking, and that there is a lot of stuff that reinforces other things. I am prepared to abandon my ideas if they are shown to be wrong, or if I learn something that is incompatible with them. I haven’t had to go back and modify or correct stuff in my blog because I am pretty conservative in what I have put in there.

    I am not surprised that people are skeptical, I am disapointed that they use non-skeptical arguments to assert their skepticism.

  30. @daedalus2u: Yes, you’ve made this argument before.

    You’ve also assumed before that I started out “cynical” about your claims. (As well as that I am unclear on the difference between cynicism and skepticism. This mistake is understandable as skepticism looks like cynicism to the quacks as well, Deepak Chopra being a perfect example.)

    Guess what: I started out neutral to you — or, rather, at least interested in what you had to say. It’s been your very own comments and emails that have solidified my position on you and your claims.

    So, in that sense, thank you very much for that real-life lesson in critical thinking.

  31. “Skepticism” not based on facts and logic is cynicism, even when it is applied to stuff that is wrong like Deepak Chopra.

    Skepticism is a process which can be applied to factual matters, not interpersonal matters.

    The question “can I trust” person xyz is not something that can be answered factually, and so skepticism is the wrong tool to try and use to answer the question. The only answer skepticism can provide is “I don’t know” because there is no factual basis for trust. One can try to apply the heuristic “trust but verify”, but if one is unable to verify, then a different heuristic should be used.

    If you don’t understand what I am saying, you are correct to not trust it. But deciding you will not trust what I have to say (which you are entitled to do with no data) is different than establishing that I am not trustworthy, and is different than establishing that what I have to say is not correct (which you can only do with facts and logic and which you have not done).

    Some amount of “trust” is necessary for any communication, are the “facts” being conveyed correct or are they not. Since the facts I am conveying are not my facts, they are data from the literature, you don’t have to trust me to accept the validity of those facts, but rather the scientists who reported those facts.

    The normal mechanisms that people use to determine if someone is trustworthy or not, reputation, educational degrees, membership in different groups, publication record, opinions of others, etc. may be useful in establishing an opinion as to trustworthyness, but they are not facts and logic, they cannot be used to establish the truth value of what is being said.

    A stopped clock is correct twice a day. But looking at a stopped clock gives you no information as to what time it is. If you attempt to guess the time by looking at a stopped clock and choosing a time different than what is displayed, you are being a cynic, not a skeptic. In other words, non-facts give you no information on which to base a conclusion. Attempting to use non-facts to figure out something is magical thinking, not skepticism.

    I am not posting here so that people will “trust” me and accept what I say as true. I am posting here so that people will see what I have to say, will become interested in it and find out things about nitric oxide for themselves. I am happy to facilitate that, but it is not something I can impose on anyone. If the way I talk about nitric oxide is so off-putting that you feel you must reject it because of how I am talking about it, that isn’t about me, or about my facts and logic, and isn’t my understanding of skepticism.

  32. @daedalus2u: There isn’t any data in the literature that I have been able to find that is incompatible with it, and I have looked quite hard.


    That isn’t the same as trying to demolish it, Daedulus. The literature is also compatible with the hypothesis that migraines are NOT caused by low NO, because there is nothing in the literature that disproves that hypothesis, either.

    For example, this study shows elevated NO concentrations during migraine attacks in migraine sufferers.

    Dipyridamole induces migraine as well. But you can use dipyridamole to wean someone from inhaled Nitric Oxide, and a dive in Nitric Oxide levels is not a side effect of the drug. So that’s a confounding factor.

    Your hypothesis has some support, but the support is not anywhere near the boundaries of conclusive. The reason that people conduct studies is in order to control for a variety of factors and target one specific factor. Without this kind of research, you can’t make the strong claim that migraines are caused by low NO. You don’t have the supporting research to make the claim you are making.

    You are correct that this is a complex and tricky subject. That’s why I don’t think that it is reasonable to come to a solid conclusion based on no controlled studies without a supporting model. I’m not saying that you are wrong, I’m saying that you don’t have enough evidence to make a positive claim for migraine cause.

  33. Sethmanpio, the first paper does not show an association of elevated NO with migraine. What it shows is elevated nitrite plus nitrate associated with migraine. Nitrite and nitrate are terminal metabolites of NO, the normal concentration of them is a few 10’s of microMolar. The normal concentration of NO is a few nanoMolar. What nitrite plus nitrate indicates is production rate of NO, not NO concentration. This is a common mistake that many researchers make. The concentration of NO is independent of the production rate because it is destroyed as fast as it is produced (i.e. d[NO]/dt = 0, i.e. the concentration stays constant).

    The state of vasodilatation is determined by the NO concentration in the smooth muscle of the endothelium. The endothelium makes NO, and that NO diffuses both into the blood stream, and also in the opposite direction toward the smooth muscle (where it regulates vasodilatation). NO also diffuses past the smooth muscle into the tissues the vessel is transmitting O2 to. It is this NO diffusing into the bulk tissue that inhibits cytochrome c oxidase and regulates O2 consumption by mitochondria. This NO level is highest closest to the vessel, so that the highest O2 level is not all consumed by the closest mitochondria.

    If the vasodilatation of the vessel is “the same”, then we can infer that the NO level regulating the vasodilatation of that vessel is “the same”. If eNOS in the endothelium is producing NO at a higher rate (observed by the higher nitrite plus nitrate levels) but the NO in the smooth muscle is “the same” (observed because there the state of vasodilatation is “the same”), then the gradient of NO from the endothelium to the smooth muscle is larger but more NO is consumed before it makes it to the smooth muscle. This implies that the NO level beyond the smooth muscle is actually lower, that the gradient of NO falls off more rapidly due to the increased consumption. That implies that the NO level in the bulk tissue is lower.

    Nitric oxide synthase makes both NO and superoxide. With sufficient L-arginine, NOS can make mostly NO. If the level of arginine drops, then NOS starts to make superoxide. NO and superoxide react at near diffusion limited kinetics and then make peroxynitrite. Peroxynitrite oxidizes a critical zinc-thiol couple in NOS, making it “uncoupled” and modifying it so that it only produces superoxide.

    Dipyridamole is a PDE5 inhibitor, just like Viagra. It increases the effects of NO through cGMP by inhibiting the PDE5 enzyme that cleaves cGMP. Blood pressure is regulated by NO through cGMP. NO always activates sGC and always makes enough cGMP to cause vasodilatation. That is why sodium nitroprusside can always be used to lower blood pressure because there is never “tolerance” built up to vasodilatation by the NO mechanism. However, there is a reduction in the expression of NOS. It is the reduced expression of NOS and the then lack of any endogenously generated NO from NOS in the lungs which cause the rebound pulmonary hypertension that sometimes follows inhaled NO withdrawal. There is also reduced activation of NOS which can cause rebound hypertension when sodium nitroprusside is stopped. More sodium nitroprusside always causes vasodilatation, so the bottleneck is in the generation of NO.

    Dipyridamole can “rescue” individuals from pulmonary hypertension rebound during cessation of inhaled NO. It does this by turning up the “gain”, the number of cGMP molecules produced per NO molecule. This allows for pulmonary vasodilatation to continue with less NO while NOS expression is resumed.

    All headache caused by dipyridamole is not prompt, a major portion of it occurs ~2 hours later and it is this headache which mimics the headache of migraine and also headaches induced by nitroglycerine.

    My interpretation is that the dipyridamole is causing increased vasodilatation through inhibition of PDE5, and that causes a feedback reduction of NO production by NOS. The vasodilatation was prompt, and had been substantially compensated for when the headache was still going on.

    Dipryidamole can also inhibit NO production by activated neutrophils. The mechanism of this NO reduction is not clear. Where else dipyridamole might be inhibiting NO production is also not clear.

    To me, the strongest implication of low NO in migraine is the association of migraine with spreading depression and ischemic preconditioning. Ischemic preconditioning is known to be produced by low NO in multiple tissue compartments. Ischemic preconditioning is from deep evolutionary time, it has to affect all cells with mitochondria “the same”, it has to affect all the different types of cells in a tissue compartment “the same”, so brain cells (of multiple types) have to also use the same mechanisms for ischemic preconditioning. Ischemic preconditioning is transmitted between cells by a diffusible agent that goes through cell membranes, affects energy status, ATP, and other things. NO is the only compound that fits all the criteria that diffusible agent has to have.

  34. How about this? How about we reach a compromise on this whole NO thing? Let’s all agree that nitrous oxide is the best thing for any condition and get back to talking about how hilarious and snarky I am.

    Whippits for everyone!

  35. @Elyse: Well, I for one was disappointed that there was no actual banjo music at Dr. Steve’s site.

    Thanks Zenmonkey and others – I’ve been seeing Daedelus pitch this NO crap at Skepchick, SBM, and quite a few other blogs, and he never really gets called on it.

    Daedalus2u – I see a lot of verbiage and claims in your various blog comments, but do you actually have peer reviewed published papers to back it up? Are you actually doing real experimentation in an actual professional lab/university/hospital somewhere?

  36. sowellfan, the answer is yes, I have real instrumental data showing spontaneous NO release from the bacteria I am working with coincident with a physiological effect known to be mediated by NO, in vivo, human. The problem is that it is n=1. It is many sigma above background, on multiple occasions.

    And yes, I do have peer reviewed papers on some aspects of this.

    And yes I do have a real lab.

  37. @daedalus2u:

    1. This is a common mistake that many researchers make.

    2. My interpretation is that the dipyridamole is causing increased vasodilatation through inhibition of PDE5, and that causes a feedback reduction of NO production by NOS.

    1. Which then makes it into peer reviewed journals. Repeatedly. Consider the possibility that you are making the rookie mistake, not the senior researchers in the field.

    2. Great! Where’s the test/confirmation of this hypothesis?

    Here’s the problem, Daedulus. You are making several elementary mistakes. First, you’re associating correllation with causation, always a tricky game. Second, you’re making assumptions about what is happening in non-induced migraine based on induced migraine, also a tricky game. Third, you’re assuming that of all the possible things that these drugs could be doing, the single relevant one is lowering NO. Maybe low NO and migraine are side effects of a different problem.

    Show me the peer reviewed paper or even blog post that you wrote prior to 2007 claiming that migraines are not vascular headaches, and I’ll start to believe that you have an elevated understanding of migraine.

    You just simply, absolutely, positively, beyond any doubt, do not have the evidence you need to make the claim you are making. It’s a hypothesis. It’s possibly correct. But you can’t state that you know what causes migraine, because you don’t.

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