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FDA Zicam Warning

On June 16th the FDA issued a warning advising consumers not to use Zicam Nasal Gel or Nasal Swabs because of reports that it can damage the sense of smell, a condition called anosmia. This event highlights some problems with current regulations of health products.

There have been 130 cases reported to the FDA of decreased sense of smell following the use of one of these Zicam products – sometimes after a single use, sometimes after repeated use.  All of these cases were reported by patients or their doctors; none were reported by the company, Matrixx Initiatives. According to reports, the FDA has asked Matrixx to turn over 800 consumer complaints regarding to Zicam. There is a 2007 law that requires company to report such complaints to the FDA, although the FDA has not said whether Matrixx violated this law.

Anosmia is a serious medical condition. The senses of smell is one of those things we take for granted until it is gone. People who lack a sense of smell cannot tell if milk has gone sour or if their food is bad. They cannot smell smoke to warn of a fire, nor can they smell a gas leak. The FDA fears that some of the cases of anosmia associated with Zicam use may be permanent.

Correlation does not prove causation, but there is reason to think that the anosmia in some of these cases may have been caused by the zinc in these Zicam products. As the FDA reports, viral upper airway infections can also cause anosmia, but the anosmia that results from zinc is associated with burning and is much more rapid in onset. Apparently some of these cases had features suggestive of zinc-caused anosmia.

Further, it has already been described in the literature that decreased smell (hyposmia) or loss of smell (anosmia) can result from the intranasal use of zinc.

There is some evidence that zinc preparations may reduce the severity or duration of the common cold if used within 24 hours of onset.  This review of the literature concludes:

Clinical trial data support the value of zinc in reducing the duration and severity of symptoms of the common cold when administered within 24 hours of the onset of common cold symptoms. Additional clinical and laboratory evaluations are warranted to further define the role of ionic zinc for the prevention and treatment of the common cold and to elucidate the biochemical mechanisms through which zinc exerts its symptom-relieving effects.

Therefore, intranasal zinc products may have a modest effect in reducing the symptoms of a cold, but come with the risk of permanent damage to the sense of smell. Since the common cold is a self-limited illness that typically lasts about 7 days, this would not seem to be a favorable risk vs benefit ratio.

How, then, did these Zicam products make it onto the market in the first place?

The FDA regulates, among other things, drugs. They require adequate evidence for both safety and effectiveness before a drug can be placed on the market and sold to consumers. They also determine the level of regulation for each drug – can it be sold over the counter, with prescription only, and it is a controlled substance, like a narcotic.

There are two important exceptions to this general rule. The first is an exception that was carved out for homeopathic products in 1938. The FDA states:

The Federal Food, Drug, and Cosmetic Act (the Act) recognizes as official the drugs and standards in the Homeopathic Pharmacopeia of the United States and its supplements (Sections 201 (g)(1) and 501 (b), respectively). Until recently, homeopathic drugs have been marketed on a limited scale by a few manufacturers who have been in business for many years and have predominantly served the needs of a limited number of licensed practitioners. In conjunction with this, homeopathic drug products historically have borne little or no labeling for the consumer.

Homeopathy was much more popular early in the 20th century in the US, and the homeopathic lobby was sufficient to gain legitimacy under the FDA. Specifically, Senator Royal Copeland of New York, a physician trained in homeopathy and a principal author of the FDCA, pushed for the inclusion of homeopathy as approved drugs. Homeopathic remedies are classified as “drugs” by the FDA, which means they fall under FDA oversight, but at the same time they are granted automatic approval as long as they appear in the Homeopathic Pharmacopeia.

What this means is that the Homeopathic Pharmacopoeia Convention of the United State, the non-governmental agency that writes the homeopathic pharmacopoeia, only has to add an agent to their list and it is granted automatic FDA approval.

Homeopathic remedies are typically diluted beyond the point where any active ingredient remains. Therefore, in practice there is no difference between any one homeopathic preparation and any other – or just plain water. (Here is a recent overview I wrote about homeopathy.)

The biggest problem with this regulation is that it amounts to official government recognition of pseudoscience. The FDCA should be amended to remove homeopathy completely.

But there is also a problem with definition. While most homeopathic remedies are diluted to the point that they are indistinguishable from water, that is not a requirement. Lesser dilutions may contain small amounts of active ingredient. If a “homeopathic remedy” contains a biological active amount of a drug as an active ingredient, is it not a regular drug?

This is relevant to Zicam because these products are regulated as homeopathic drugs – which means they were allowed on the market without having to provide any evidence for safety or efficacy.The homeopathic exception allowed the manufacturer to simply bypass the usual requirements, even though Zicam is not really homeopathic but contains biologically active levels of zinc.

But because homeopathic remedies do fall under FDA regulation the FDA has the power to decide that a product poses a safety risk to the public and therefore can demand evidence for safety. In this case the FDA has requested that Matrixx Initiatives “submit a new drug application to demonstrate safety and efficacy.” (I confirmed this over e-mail with the FDA.)

The second exception to the FDA regulation of drugs was created by the Dietary Supplement Health and Education Act of 1994 (DSHEA). This law allows botanical drugs to be sold as supplements, with no requirement to prove safety or efficacy. While with products marketed as homeopathic “drugs” the FDA can step in if they feel there is a safety concern, with supplements under DSHEA the FDA bears a high burden of proof to show that a product is harmful before it can take action.  So far it has only done this for one ingredient – ephedra.

Here, too, we see a significant problem with definition. Why is a botanical drug or herb regulated like food rather than a drug?

A more science-based regulatory system would eliminate homeopathic agents altogether. They are a relic from the past. Further, any substance meant to be consumed or taken internally for its pharmacological activity is a drug and should be regulated like a drug.  This could still leave room for subcategories of drugs, as we have now (for example, over the counter vs prescription only). But regulating herbal drugs as food has only opened the flood-gates for dubious products with even more dubious claims.

Posted in: Herbs & Supplements, Homeopathy, Politics and Regulation

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82 thoughts on “FDA Zicam Warning

  1. John Snyder says:

    The FDA definition of “homeopathic” is the crux of the matter here, and this case may finally bring the fraud of homeopathy out in the open. If there actually is some measurable zinc in this preparation, then it isn’t truly homeopathic, as far as the common usage of the term is concerned. In that case it’s a drug, and therefore was incorrectly labeled and regulated. That is a crime. If there is a homeopathic amount of zinc in Zicam, then zinc is not the culprit here. In that case, it may be one of the “inactive” ingredients (Benzalkonium Chloride, Glycerin, Hydroxyethylcellulose, Purified Water, Sodium Chloride, Sodium Hydroxide), or not a true causal association.

    Another possibility is that there is an undisclosed ingredient that is causing anosmia. Since neither the DSHEA nor the homeopathy exemption from the FDA’s usual regulatory power over drugs is sufficient to ensure that this is not the case, then even this is a distinct possibility.

    It’s time to get rid of the DSHEA for good.

  2. Tim Kreider says:

    Does this product count as “homeopathic” for FDA purposes because “Zicam Cold Remedy Nasal Gel” is in the Homeopathic Pharmacopeia, or because the gel’s ingredients are in the pharmacopeia?

    Who determines that a product counts as “homeopathic” when it has pharmacologic doses of biologically active ingredients?

  3. Tim – that’s the point. Perhaps I did not hit that home strong enough. The FDA was a bit cagey in their communication to me about this, and would not say that any crimes were committed.

    From what I can tell, homeopaths can simply write it down in a supplement to their pharmacopoeia and voila – it’s homeopathic.

    John – you are correct in that there are numerous possibilities here, precisely because the regulations are so bad. The FDA thinks its the zinc because there are already reports in the literature that zinc can cause anosmia, and is associated with burning, which apparently is what was reported to them. So it fits.

    Zicam’s chief ingredients are Zincum Gluconicum 1X and Zincum Aceticum 2X – 1x is a 1:10 dilution, and 2x is a 1:100 dilution – not much, and what is the starting dose?

  4. qetzal says:

    According to this study, Zicam contains 33 millimolar zinc gluconate. 33 mM is a pretty substantial concentration!

    For comparison, typical zinc levels in serum are around 0.015 mM (i.e. 15 micromolar).

  5. Skeptico says:

    In 2002 I emailed the makers of Zicam to ask them why they were claiming their product was homeopathic, although it contained active ingredient. Their reply:

    The HPUS dictates the maximum strength a compound can be for OTC use. In the case of zinc gluconate, it is a 1X dilution. This means that 1 part of zinc gluconate is diluted with 9 parts water. In Zicam we use a 2X dilution. This takes the above dilution and further dilutes it by adding 1 part of it to 9 parts water. This produces a final 1:100 dilution.

    So in other words, they use homeopathic terminology (“2X”), so it’s homeopathic. So it can sneak in without FDA approval.

  6. Joe says:

    The homeopathic pharmacopoeia aside, as I understand it a product is considered homeopathic if it is diluted and properly succussed (shaken, which presumably requires a homeopath or an approved mechanical alternative). Thus, one dilution (1X) should qualify.

    I posed the question “What constitutes a homeopathic remedy?” to a colleague who has thoroughly studied the subject and she responded “How long is a piece of string?”

  7. John Snyder says:

    The “how long is a piece of string” definition seems the most accurate. It looks like we may have come up against the end of homeopathy as we know it in this country. FDA regulation here we come?

  8. Joe says:

    @ qetzal on 17 Jun 2009 at 9:50 am

    My browser, as currently configured, will not open the link you provide because of an unpermitted cookie.

    Unless I have lost my touch, a 1X solution of zinc gluconate (MW 445 g/mol) is a whopping 220 mmolar.

  9. Richard says:

    I don’t think we see eye to eye on this one. While I am very pro-science and pro-SBM, I’m also very pro-health-freedom and pro-personal-freedom of all kinds. For example, while I have nothing but contempt for homeopathy, I don’t believe in regulating it out of existence. I believe that such regulations, far from being a benefit to science, would just make a lot of people angry. I think that education is the answer, not regulation.

  10. John Snyder says:

    A product like Zicam needs to be regulated the same way as any other OTC pharmaceutcal. The fact that a company can claim a product is homeopathic, and then be exempt from safety and efficacy standards, is lunacy.

  11. Prometheus says:

    I would be interested in knowing how Richard defines “health freedom” in the context of Zicam. As I see it, the makers of Zicam are exploiting a loophole in FDA regulations to market a product as a drug without completing the safety and efficacy testing that would be required of a “real” drug.

    How does that enhance “health freedom”?

    The same argument can be made for homeopathy as a whole. Well-designed studies routinely show that homeopathic remedies are no better than placebo – which is what most homeopathic remedies are, being nothing more than water or lactose.

    Does “health freedom” include the freedom to be deceived?

    Homeopathy – in the standard diluted-to-pure-water variety – has the dubious “advantage” of being safer than most real pharmaceuticals – except when it is used in place of real medical treatment. Of course, its effectiveness is also essentially zero.

    However, now we have at least one example of homeopathy’s tacit FDA exemption being exploited to sell a product that causes real injury – all by itself.

    How is this “health freedom”?

    The FDA, through its homeopathy exemption, gives homeopathy a semblance of approval. If the FDA were to require that homeopathic remedies go through the same process that other drugs went through, I think we would all (including the homeopaths) agree that none of them would pass the efficacy tests (although they would probably pass the safety tests).

    I don’t ask the FDA to regulate homeopathy out of existence, I just ask that they subject homeopathic remedies to the safe scrutiny they give other drugs. Level the playing field, as it were. If, as homeopaths argue, their remedies are effective, they would be in a stronger position than ever before. If not…..

    If this seems “unfair”, then how about we level the playing field the other direction – let the pharmaceutical companies introduce new drugs simply by putting them in the PDR? I don’t think anybody would see that as a good idea, yet that is exactly how homeopathy operates.

    I’m still curious how letting one segment of the “health care industry” remain unregulated while another part (the part that does work) is heavily regulated is “health freedom”. If “the people” are to be allowed to freely choose whatever type of health care they get, why do we regulate any of it?

    On the other hand, if a valid role of “the government” is to prevent unscrupulous or overly gullible “practitioners” from deceiving or defrauding (or deceasing) “the public”, why not regulate those practitioners whose “remedies” are demonstrably unsafe or ineffective?

    The “freedom” to choose whatever you want includes the “freedom” to be cheated, deceived, lied to and misled.

    Prometheus

  12. qetzal says:

    @Joe,

    Try this link. Sorry, I didn’t notice the cookie part when I past in the first url.

    I agree that 1 g zinc gluconate + 9 mL H2O should be about 220 mM. If that’s 1X, then 2X would be 22 mM, which is comparable to what the link claims (33 mM). Not sure why there’s a discrepancy, but either way, 22 mM or 33 mM, it’s a pretty substantial concentration.

    @Richard,

    I agree that we shouldn’t make homeopathy illegal or anything. But I do think it should be regulated in a manner more consistent with other products that claim to prevent or treat disease. Education alone is not the answer, IMO.

    Any product that contains sufficient active ingredient to have a pharmacological effect should be held to the same standards as all others in its class. Obviously, there will be some subjectivity about which products would qualify, but in the case of Zicam, I don’t think there’s any ambiguity.

  13. Thanks for this article. I was a bit confused how Zicam was considered a homeopathic remedy since the concentration of zinc gluconate was 33 mmol/l, which doesn’t sound like “diluted to almost zero.” I don’t have firm evidence of my thoughts on the matter, but I think that “homeopathy” has been evolved in a lot of people’s minds into anything “natural.”

    I get frustrated by the inconsistency of FDA regulations, and I know that DSHEA adds to that frustration. If Zicam was regulated like any other OTC compound that makes a medical claim, it would have to prove it’s safety and efficacy. Right now, the safety is suspect, and the efficacy just isn’t there (or at best, suspect too). Personally, I would consider anosmia to be a very serious consequence of using these products, and given that Zicam has almost no possibility of being anything more than a placebo, the risk benefit ratio is way out of acceptability. This drug probably wouldn’t receive FDA clearance.

    The alt-med crowd always jumps on real drugs that have an issue with the FDA, which should prove to them that drugs are closely regulated and the FDA isn’t in the pocket of Big Pharma. I wonder what they’re going to say now? Big Pharma asked the FDA to go after Zicam?

  14. Joe says:

    @qetzal on 17 Jun 2009 at 11:49 am. You are right. My confusion stemmed from Steven Novella on 17 Jun 2009 at 9:22 am. “Zicam’s chief ingredients are Zincum Gluconicum 1X and Zincum Aceticum 2X – ”

    I would not be surprised if different sources provide different statements about the composition.

  15. One more thing. Am I detecting an FDA that is becoming more concerned with scientific evidence? I’m beginning to be optimistic.

  16. “I’m still curious how letting one segment of the “health care industry” remain unregulated while another part (the part that does work) is heavily regulated is “health freedom”. If “the people” are to be allowed to freely choose whatever type of health care they get, why do we regulate any of it?”

    Talk like that is going to bring SD up out of the woodwork to espouse his anarchist libertarian philosophy.

  17. Joe says:

    Michael Simpson on 17 Jun 2009 at 12:51 pm “Am I detecting an FDA that is becoming more concerned with scientific evidence? I’m beginning to be optimistic.”

    I don’t know the origin of your comment; but the FDA has been hobbled by Congress for decades. Congress denied them the power to regulate tobacco, “dietary supplements” and homeopathic claims. The Congress enacted the bill (DSHEA) that required the FDA to take ten years to ban the deadly herb- ephedra. It was Congress that carved out a regulatory exemption for homeopathy.

    The FDA has always been concerned with science, and public health and safety. That’s why thalidomide did not wreak havoc here as it did in Europe. That’s why dangerous products (drugs and “supplements”) are removed from the market.

    Could the FDA do better? Of course; but Congress must take off the handcuffs and give them more money for investigation and enforcement.

  18. TsuDhoNimh says:

    From the Zicam manufacturer’s website:

    The Facts About Zicam Cold Remedy ®

    * Zinc gluconate, the active ingredient in Zicam Cold Remedy, is a drug.
    * Zicam Cold Remedy is not an herbal or nutritional supplement
    * Zicam Cold Remedy products are regulated by the U.S. Food & Drug Administration
    * Zicam Cold Remedy is clinically proven to reduce the severity of symptoms and duration of the common cold by up to 75% faster when treatment begins within the first 24 to 48 hours of symptom onset.

    The National Advertising Division of the Council of Better Business Bureaus to the U.S. Alcohol and Tobacco Tax and Trade Bureau has validated Zicam Cold Remedy’s efficacy claims. OMGWTFBBQ?!?!?!?

    The efficacy was validated by the advertising branch of the Tax and Trade Bureau? Or was it the BBB?

  19. Fred Dagg says:

    Informed consent
    Informed choice
    Let the educated consumer decide based upon the true and correct information.

    This should apply to all Health Care Proceedures, Potions and Pills.

  20. Fred Dagg says:

    If people are intelligent enough to smoke cigarettes,
    intelligent enough to eat the fast food diets avaliable and
    intelligent enough to ride motor-cycles without helmets,
    then they are intelligent enough to read an informed consent form and make a decision.

  21. Fred Dagg,
    Are you sure you’re not really SD?

  22. Fred Dagg says:

    Prometheus

    “Well-designed studies routinely show that homeopathic remedies are no better than placebo”.

    You seem to be contemptuous of the placebo effect.

    Beecher (JAMA 1955;159:1602-1606)encountered a wide variety of placebo response rates, ranging from 15% to 58%. Subsequent studies have encountered placebo response rates from as low as 0% to as high as 100% (Wall PD Pain 1992;51:1-3). Placebo response rates differ considerably according to the circumstances of the study.

    Even recent research into the usefulness of anti-depressants indicate that they are no better than placebos in mild and moderate depression.

    If medicine is to be accountable to science, the role of the placebo must be measured and taken into account. If one ignores the effect of the placebo, it relegates medicine to the status of a medieval guild, the purpose of which is to exploit the suffering of patients for its own gain. (With apologies to Nikolai Bogduk).

  23. Fred, I am very contemptuous of the so-called placebo effect. Please, give me one simple scientific explanation on how it works. Mind over matter? I’m sorry, it’s clear to me that the placebo effect is nothing more than random variation in response rates.

    I’m too lazy to look it up, but I’m guessing that even the most aggressive cancer has some small but measurable remission rate. Someone downing a homeopathic potion, water from Lourdes, or a sugar pill could be “lucky” enough to have that spontaneous remission. The scientific reasoning is probably much more complex, and will be understood in time. And if we figure out what set events lead to a “spontaneous remission” or other “miraculous” cure is when we take the next leap in understanding in the treatment of disease.

    I’m going to pull out that “skeptic” hat (at this point, not made of aluminum foil) and say bluntly, the placebo effect does not exist. A lot of woo-pushing crowd think that providing a placebo effect is a crowning achievement. I say, no, it isn’t.

  24. esalituro says:

    This may be even worse than FDA or Matrixx Initiatives is letting on. In 2006 they settled a class-action lawsuit with 340 individuals who claimed (you guessed it) they “lost their sense of smell” for $12M. The law firm who filed the suit is here: http://www.zicam-cold-eeze-lawyers.com.

    If you look back in the Google News archives, Matrixx has been fighting claims of anosmia since 2004.

  25. Fred Dagg says:

    Hi Michael Simpson

    You are getting confused between spontaneous remission and the placebo effect.

    However, what I was quoting to you on the placebo effect was “science”, so I do not need to prove anything more to you, it has been done. What you are doing now is relying on pseudo-science to validate a spurious argument.

  26. The Blind Watchmaker says:

    Homeopaths seem to be able to change the rules of their nonsense whenever it suits them.

    Here we have a drug, Zicam, with an actual ingredient, present in measurable quantities.

    So much for dilution until just the “memory” or “vibration” is present in the water.

    And what a bout the “rule of similars” and “like cures like”. If this were a homeopathic concoction, it wouldn’t be made of diluted zinc. Wouldn’t it be made of snot taken from someone with a cold and diluted into oblivion?

    The Phoenix Business Journal had an article about this and a quote from a homeopathic “doctor”….

    “Zicam products use a homeopathic remedy called Zincum Gluconicum 2x, which means they require FDA approval.

    Dr. Sam Benjamin, a medical doctor with a homeopathic license, said he can’t figure out why the FDA has taken so long to deal with the issue.

    “I can think of no part of alternative medicine that summons up more worry to conventional physicians than homeopathy,” said Benjamin, who has a medical talk show on KTAR 92.3 FM on Saturdays at 2 p.m. and 1,000 followers on Twitter. “There are so many drugs around that cause problems, why would one event want to expose people to any danger.” ”

    ….I am still trying to figure out what he means. I agree that conventional physicians worry about homeopathy, but I think that he means this in the sense that we are worried about competition. No. We are worried about the public being scammed away from real potential treatments in favor of fancy sounding placebos.

  27. Joe says:

    The Blind Watchmaker on 17 Jun 2009 at 8:10 pm “… a medical doctor with a homeopathic license, said he can’t figure out why the FDA has taken so long to deal with the issue.”

    Doctors with homeopathy licenses can’t “figure out” much.

  28. daedalus2u says:

    Michael, there is a good scientific explanation for the physiological placebo effect.

    http://daedalus2u.blogspot.com/2007/04/placebo-and-nocebo-effects.html

    A problem with nomenclature is that all non-pharmacological interventions that cause apparent improvements in health get lumped in as a “placebo effect”, even when the source of that apparent improvement is measurement error. There is plenty of error, conformation bias, fraud and regression to the mean that is interpreted as apparent improvements in health due to non-pharmacological methods.

    I think there are real physiological effects that can mediate real healing through non-pharmacological means. I don’t think that those physiological effects would work against cancer. Placebos would work best for disorders characterized by low NO, things exacerbated by stress, long term degenerative diseases, hypertension, fibromyalgia, chronic fatigue syndrome, low back pain. The kind of things that acupuncture, Reiki, homeopathy, crystals, and magnets work for; those things all being placebos.

  29. Fred Dagg says:

    In regard to the following citation, I wonder how one can reconcile this statement.

    “The kind of things that acupuncture, Reiki, homeopathy, crystals, and magnets work for; those things all being placebos”.

    Recent research into the usefulness of anti-depressants indicate that they are no better than placebos in mild and moderate depression.

    Kirsch I, Deacon BJ, Huedo-
    Medina TB, Scoboria A, Moore TJ, et
    al. (2008) Initial severity and
    antidepressant benefits: A metaanalysis
    of data submitted to the
    Food and Drug Administration. PLoS
    Med 5(2): e45. doi:10.1371/journal.
    pmed.0050045

    So Michael, you have closed your mind to the prospect that placebos may work. So much for the “scientific method” of discovery?

  30. pmoran says:

    I agree with Fred. We skeptics BADLY need to sort out our thinking about placebo reactions. It is making us look bad.

    This is no place for dogmatism. The supporting science is consistent with a range of possible magnitudes and scopes of placebo “effect”, depending very much upon context, as Fred says. But severe medical imitations apply.

    It is a very plausible phenomenon, given what we know about human suggestibility and distractability. It would have evolutionary benefits.

    Yet a lot that is sometimes attributed to placebo is no “effect” at all. Spontaneous improvements in self-limiting conditions and reporting biases are examples. And by definition there is no intrinsic “effect” of placebo.

    Its presence and its magnitude will depend upon everything ELSE about the medical interaction — all those things that we try to eliminate in our controlled clinical studies. It is thus an extremely difficult phenomenon to isolate and measure and even conceptualize, if that is a word.

  31. Eric Jackson says:

    Just in regards to the Kirsch and Deacon study, it looks like a relatively simplistic approach, probably of that nature to try to get all the trials in. Most of the trials included are six weeks or less, generally regarded as the point in depression treatment where another agent is tried.

    Kirsch’s publication history is rather bizarre to put it bluntly.

    While much of the study is beyond my ability to criticize, one thing did set off some warning sirens in my head. They examined only four antidepressants, and characterized them as all being SSRIs. Two of the four are not SSRIs (venlafaxine and nefazedone). Nefazedone was also taken off the market four years prior to the publication of this study. It’s a relatively minor thing given the content of the publication. But it’s the sort of mistake someone with experience in the area shouldn’t make.

  32. johnny moab says:

    The blind watchmaker was the first to point out what i spotted right away: the zicam products in question are in no way homeopathic because they use zinc as the “active” ingredient. For years now zinc has been touted by zicam and many other non-homeopathic product suppliers as having the ability to ALLIEVIATE the symptoms of the common cold, not produce them. Homeopathy’s founding principal, the “law of similars”, says that the active ingredient must be a diluted and sucussed version of something that causes the offending symptoms in a healthy person.

    Zicam sells other cold remedys that are not labeled homeopathetic and DO contain levels of real medicine and ZINC. So the makers of ziscam are either ignorant of the basis of homeopathy or they are knowingly trading on the “good name” of homeopathy in an attempt to appeal to a certain consumer base, all the while spiking their product with something (zinc) that might work a little on cold symptoms and keep the customers coming back for more. I suspect the latter.

    I checked out the homeopathetic section of my local health food store today, which carries the full range of products from Boiron and Hylands, and found many remedys containing 1x or 2x dilutions.

    So it seems the zicam products in question would qualify as true homeopathic remedys, except that they should be able to CURE the very condition (anosmia) that they have been accused of causing!…Maybe at 2x the potentcy is too low. Zicam should make a 200c dilution which would be much more powerful and see if they can cure these poor souls who claim to have lost their sense of smell…..It’s worth a try Ziscam, what have you got to lose? Your FDA exemption?…….Hey Steve, has anyone considered that maybe some of the smell loss was caused by misuse of the gel swabs, meaning some people are shoving them up their noses a little too far and a little too fast?….Just a thought

  33. David Gorski says:

    I agree with Fred. We skeptics BADLY need to sort out our thinking about placebo reactions. It is making us look bad.

    How so? Personally, I don’t see it, and I don’t see how our thinking about placebo reactions is muddled. The straw man versions told by CAM advocates of our thinking about placebos is muddled, but actual scientific thinking about placebos, although with lots of room for improvement, is not so messed up as to “make us look bad” to anyone other than CAM advocates arguing pseudoscience.

    I’ve heard an argument very similar to yours before in other scientific manufactroversies unrelated to medicine, actually. Can you guess which ones?

  34. Scott says:

    “In regard to the following citation, I wonder how one can reconcile this statement.
    “The kind of things that acupuncture, Reiki, homeopathy, crystals, and magnets work for; those things all being placebos”.
    Recent research into the usefulness of anti-depressants indicate that they are no better than placebos in mild and moderate depression.”

    They’re quite easy to reconcile – in fact, it’s pretty much impossible to come up with any conflict between them. The listed forms of woo have no effect beyond placebo (i.e. they don’t work). Similarly, antidepressants may not work for mild and moderate depression. So what?

  35. tmac57 says:

    What I am getting from this debate on placebos is that “acupuncture, Reiki, homeopathy, crystals, and magnets “, could all be replaced with sugar pills. That should reduce health care costs considerably !

  36. daedalus2u says:

    tmac, not all placebos are created equal, some are more equal than others. I am going to be at the SBM conference at TAM7, and would be happy to participate in a break-out session on the physiology behind the placebo effect (if anyone would be interested I would be happy to prepare something).

  37. Fred Dagg says:

    Scott, your arrogance amazes me with the following quote,

    “Similarly, antidepressants may not work for mild and moderate depression. So what?”

    You are then medicating people unnecessarily and “unscientifically”. The word “unethical” also springs to mind. How do you condone that? How much money is wasted and how many people are walking around on prescribed medication that may have side effects that may damage health etc.

  38. Richard says:

    Thank you for the feedback. I’m not against any and all regulation. I just think people should have the freedom to choose for themselves.

  39. Scott says:

    “You are then medicating people unnecessarily and unscientifically. The word unethical also springs to mind. How do you condone that? How much money is wasted and how many people are walking around on prescribed medication that may have side effects that may damage health etc.”

    Who says I condone giving antidepressants to people with mild to moderate depression? Assuming your citation is an accurate depiction of the state of research in the field, I certainly would NOT condone it.

    The efficacy or lack thereof of a particular drug treatment for a particular condition has absolutely nothing to do with the efficacy of woo, is my point.

    (That’s entirely leaving aside the point that I don’t medicate anybody, not being a doctor.)

  40. Scott says:

    “Thank you for the feedback. I’m not against any and all regulation. I just think people should have the freedom to choose for themselves.”

    “Health freedom” pretty much never has anything to do with people having the freedom to choose what treatments they want. It always seems to be about the freedom of quacks and snake oil peddlers to lie to the public without being called on it.

  41. daedalus2u says:

    Fred, have you ever experienced depression?

    Insufficiently treated depression is one of the leading causes of death, #11 in 2005 with 32,637 completed suicides.

    Depression is a life-threatening disorder that can be difficult to treat, even when people are willing to be treated. Life threatening disorders require effective treatment, and the “risks” of side effects from that treatment must be balanced against the risks of no or under-treatment. Raising crap studies and using bogus arguments to make people less likely to seek treatment is (to me) unconscionable. Suicide kills more people than liver failure.

    That study you cited is crap. The study period was too short, and there seemed to me to be quite apparent bias, in that the authors conclude that:

    ”Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.”

    Huh? The apparent reason for antidepressants working is an artifact due to the placebos not working well enough in the severely depressed patients? Huh? How could they possibly know that? What do they suggest, research on finding better placebos?

    Antidepressants are cheap compared to psychotherapy. Psychotherapy is effective at treating depression. Psychotherapy is a placebo (in that there is no pharmacological or surgical element to it). The combination of psychotherapy and antidepressants works better than either one alone, suggesting that they work via separate mechanisms that can positively interact.

  42. Scott says:

    I *knew* that I was going to regret it if I didn’t have that “assuming your info is accurate” disclaimer in there.

  43. Fred, you quote mined one article out of many. I stand by my statements (based on personal opinion) on placebo effects.

    However, I agree with daedelus (kind of) that there are certain psychological benefits from placebos. It’s when anyone moves the “benefits” of placebos to curing actual diseases (beyond a psychological component) that I jump off the train. When I’m stressed, which leads to headaches and insomnia, I turn to my favorite placebo–comfort food. Kraft Macaroni and Cheese.

  44. daedalus2u says:

    I think there can be actual physiological effects from placebos, but those physiological effects are limited and are mediated through normal physiological control of physiology, not through any mind-body woo-woo or other magical stuff.

    We know that ATP is used as a source of energy for a great many pathways in physiology, and the body’s ability to generate ATP is limited. ATP consumption always equals ATP generation because ATP doesn’t accumulate and ATP that isn’t there can’t be consumed. How does physiology allocate ATP to those myriad pathways? The answer is exquisitely well! We know there are at least hundreds of thousands of individual pathways that consume ATP, and all of these are regulated exquisitely well together. That is each and every single one of those pathways consumes just the right amount of ATP, not too much and not too little. I see the placebo effect as the neurogenic control of physiology, and especially the allocation of ATP between consumption for long term repair pathways and being held available for immediate consumption during a stress response. If you need ATP production capacity to run from a bear, you can’t be using it to repair cell damage. Which is more important? That is something physiology decides on a second-by-second basis. If you want ATP to run from a bear, you have to put that repair off until the stress has been resolved. This is why stress has adverse effects on health and why stress relief is good for just about everything (just about, but not everything). Nitric oxide is the signaling agent that physiology uses to regulate ATP under conditions of stress (and virtually all other conditions too, but this is less well demonstrated, but having multiple mechanisms is unlikely because they all have to work seamlessly under very large dynamic ranges).

    It is easy to reconcile placebo effects improving depression because nitric oxide does have a remarkable effect on depression and I am quite sure low NO is one of the final common pathways of depression. I appreciate my statement is based (somewhat) on an anecdote on myself, but as someone who has been depressed my entire life (at least the last 45+ years that I remember), and someone who has read a great deal about physiology, it is something I know something about.

    I have taken two of the 4 drugs mentioned in that study (Fluoxetine and Nefazodone) as well as others including; imipramine, (tricyclic), phenelyzine (MAO inhibitor), Amoxapine (tetracyclic), and Sertraline (SSRI). All of these “worked”, that is they did improve my mood long term (many months). All of them took some time to “work”, usually a few weeks. The exception being Fluoxetine which produced effects in ~15 minutes (which was quite surprising to me). I spoke to my brother on the phone during that time, and he remarked on my improved mood without knowing I had taken anything for it. All of them stopped working after a time, the exception being Sertraline which I am still on (over 10 years now) but at half the dose I was taking before I increased my NO level. Before I increased my NO level I was using Amoxapine and Nefazodone to “trim” and augment the effects of the Sertraline, the heuristic my doc (MD Harvard, PhD MIT) used was for me to notice side effects, figure out which receptors were being inhibited or potentiated, and then choose another antidepressant with a side-effect profile to have a normalizing effect on those receptors, start at a very low dose and titrate up and down until the optimum result was achieved. That heuristic worked for me because I am pretty sensitive as to how I feel, and can dissociate sufficiently well that I remain objective about it. I appreciate that not everyone can do that.

    Before anyone thinks that all these are all placebo effects, I have high blood pressure and switched from Lisinopril (ACE inhibitor) to Verapamil (Ca channel blocker) and after 2 doses my then wife noticed a severe adverse mood change in me (I did too) and was quite upset with me that I took a third dose “just to be sure” (it was pretty severe, like what I had experienced a decade before when not on antidepressants, as an acute effect brought on by the drug it was pretty easy to dissociate from it in the short term).

    My understanding of how depression is caused/exacerbated by low NO relates to my appreciation that low NO is a major stress signaling pathway, and that under conditions of metabolic stress, NO is lowered to increase aerobic ATP production in mitochondria (by disinhibiting cytochrome c oxidase), and that low NO also signals other stress compensatory pathways. Under near death metabolic stress, physiology induces a state of euphoria. The euphoria of near death metabolic stress is the physiology behind autoerotic asphyxiation. The euphoria of near death metabolic stress is what allows organisms to run themselves to death while being chased by a predator, where to be caught is certain death. Being able to run oneself to death is an excellent survival feature for organisms when the predator tires before the organism dies from exhaustion, allowing it to escape. If organisms could easily invoke this euphoria, they would do so and needlessly risk death such as just claimed the life of David Carradine.

    There has to be an aversive state between the normal “at rest” state and the euphoria of near death metabolic stress. My hypothesis is that aversive state is depression. This hypothesis is consistent with the depression literature which shows reduced brain metabolic activity and blood flow during depression. Reduced metabolic capacity does cause depression (as in vascular depression).

    This hypothesis of depression explains a number of seemingly unrelated observations. First it explains why there is such a thing as depression in the first place, why such a thing (with non-zero chance of suicide) could have evolved as something with a positive survival factor (to prevent invoking the euphoria of the near death metabolic state needlessly). The sensitivity of depression to placebos (placebos raise NO too), the sensitivity of it to multiple drugs via diverse pharmacology; but usually they have the effect of reducing metabolic load (SSRIs), reducing oxidative stress (MAOis), increasing ATP availability (lithium), reducing inflammation (omega-3 fatty acids), improve vascular perfusion, or stress reduction (exercise, meditation). The observations of reduced blood flow, neuroinflammation, and white matter hyperintensities associated with depression all suggest reduced metabolic activity.

  45. pmoran says:

    David “How so? Personally, I don’t see it, and I don’t see how our thinking about placebo reactions is muddled. The straw man versions told by CAM advocates of our thinking about placebos is muddled, but actual scientific thinking about placebos, although with lots of room for improvement, is not so messed up as to “make us look bad” to anyone other than CAM advocates arguing pseudoscience.”

    I am happy to explain.

    We have one group of skeptics using placebo influences to help explain why so many people swear by inactive treatment methods, and another stating categorically that placebo influences don’t exist. That is obvious on this very blog.

    The latter group can be split further. Group 2(a) regards the benefits commonly attributed to placebo as almost totally spurious, and due to spontaneous events and reporting biases. For some even altered perception as to level of symptoms (e.g. “cognitive dissonance”) is not the same thing as REALLY feeling better. This group is able to disregard placebo influence in virtually all settings.

    Group 2(b) is simply working from a more restricted definition of placebo, one which separates the provision of the placebo from all other elements of medical interactions. Usually they will allow the existence of important beneficial non-specific influences of medical interactions when challenged. So they really belong to group 1, for practical purposes, but they sound like group2(a) whenever they talk about placebo.

    I am not just trying to be clever in this and I frankly don’t give a stuff what CAM advocates think. They are mostly away with the fairies, although Weil, Kaptchuk and many others do, I think, understand on some level that CAM is mostly placebo.

    What I do care about is that we are not so incoherent. I also care about what we say to persons who believe they are being helped by pretend medicines. That is one of the cutting edge interfaces of skepticism with AM, a place where we can either make or break.

    I care about us being absolutely right when we comment on the value of these methods to those using them. I care about our views being totally in accord with what the science shows, or in this case, in at least my view, permits.

  46. Fred Dagg says:

    How come, every success a CAM practitioner achieves is “Placebo” or “spontaneous remission”, and those patients who get better after a course of prescribed medication is “Science Based Health care”.
    Considering that I have read that only 20% of “medicine”, is scientifically based, I have trouble reconciling these statements.

  47. daedalus2u says:

    PM, a nice and very clear description of the different conceptualizations of the placebo effect.

    I will be at TAM7 on Wednesday and prepared to talk for hours about what I see as the physiology behind the physiological placebo effect. I will have my laptop which has all the literature references I am using in pdf form.

    I really do think that the physiological placebo effect can be invoked (to some extent) pharmacologically. This is extremely tricky to do, and this terminology isn’t quite precise. What raising basal NO level does is reduce the threshold for invoking the placebo effect. I think that threshold can be reduced essentially to zero, which is almost the same as pharmacologically invoking the placebo effect, but if you needed to run from a bear, your stress physiology could overwhelm that basal NO and invoke a equivalently robust stress response (actually somewhat better because ATP production capacity and reserves would be higher).

  48. pmoran says:

    Daedalus 2. Yours is an interesting and well-developed theory, but I have to say that I still have a totally different concept of placebo influences.

    To my mind they involve a range of psychologically mediated cerebral phenomena, with very limited physiological accompaniments, and no known, or even needed effects upon low-level biochemical processes, and probably no effects upon “healing” of anything in any physical sense.

    I am sure one component is simply the ability to pay less attention to symptoms once having taken action, or having obtained reassurance, regarding them.

    Is there any direct evidence of changes in NO or ATP activity with placebo usage?

  49. tmac57 says:

    Fred-”Considering that I have read that only 20% of “medicine”, is scientifically based…”
    I believe that you have made this statement before. Can you cite a reference for it please?

  50. Fred Dagg says:

    No, I have no reference, but at the same time, when I asked members of this blog,
    “What proprortion of “medicine” was scientifically based?”

    No one answered it.

    Funny that?

  51. tmac57 says:

    Fred- Then I guess that not only is your statement hearsay, it is unattributed hearsay.

  52. daedalus2u says:

    PM, yes there is for NO.

    http://www.ncbi.nlm.nih.gov/pubmed/11245883

    The ATP connection comes from ischemic preconditioning which is a state of reduced ATP demand and also reduced ATP concentration. I talk about this in considerable detail on my blog with a number of links.

    http://daedalus2u.blogspot.com/2007/04/placebo-and-nocebo-effects.html

    One of the things implicating NO is the observation that being given a placebo said to make nausea better actually makes it worse and the same inert material said to make nausea worse actually makes it better. I have links to these papers on my blog. My interpretation is that because the enteric nervous system is mostly nitrergic (uses NO as a neurotransmitter), more NO will cause hyperactivity.

    It is very easy for the body to lower NO levels by generating superoxide. Stress is a state of oxidative stress which is a low NO state. Mostly superoxide is confined to vesicles where it can still pull down the NO level because the vesicles are transparent to NO.

    NO is coupled to ATP via sGC. Low NO does trigger ischemic preconditioning which is a low ATP state. Presumably there is much sharing of pathways between ischemic preconditioning and other stress pathways because they evolved together to do similar things. It doesn’t make any sense to use completely different triggers. Triggering both by low NO or low ATP is how they would evolve.

    Stress response states have to have hysteresis. There has to be a signal to switch physiology back into the non-stress response state. That has to be the opposite of what triggered the stress response in the first place.

  53. Fred Dagg says:

    Well, here is a challenge for everybody, answer my question!!!!

    “What proprortion of “medicine” was scientifically based?”

  54. Mark Crislip says:

    I’ll answer it.

    With Science broadly defined, my practice of Infectious Diseases is 99.73% based on science, and, although I suspect that .27% is not, I can’t think of anything I do that is not science based.

  55. tmac57 says:

    Fred -Steve Novella wrote a blog about this that has already been called to your attention by commenter dt ,but here is the link again:
    http://www.theness.com/neurologicablog/index.php?p=51

    “Thus, published results show an average of 37.02% of interventions are supported by RCT (median = 38%). They show an average of 76% of interventions are supported by some form of compelling evidence (median = 78%).” (he is citing Complementary Therapies in Medicine (2000), 8, 123-126 © 2000 Harcourt Publishers Ltd) See here:
    http://www.veterinarywatch.com/CTiM.htm

    Also dt provided this link:
    http://www.shef.ac.uk/scharr/ir/percent.html

    So I guess that you never bothered reading those items that dt helpfully provided. I guess you have already made up your mind then. No?

  56. David Gorski says:

    tmac57 beat me to it. Steve did an excellent job of explaining.

  57. Fred Dagg says:

    Two different answers, one of you must be wrong?

  58. Psyche78 says:

    Just for clarification, some of the researchers on the STAR*D project recently published findings (http://www.ncbi.nlm.nih.gov/pubmed/19339358) showing that antidepressants ARE far less efficacious in the general population than the Phase III drug trials run by pharmaceutical companies would indicate. The results of that study follows nicely with an article published last year (http://www.peh-med.com/content/3/1/14) by a researcher from Tufts (which did cite the Kirsch study, but also looked at other studies as well) examined how selective reporting of results, the differences between statistical and clinical significance, the use of different study designs, and lack of long-term follow-up, amongst other problems, leads to overestimation of the efficacy of antidepressants.

    And daedalus2u, do you have a citation showing that antidepressants are cheap compared to psychotherapy, especially over the long term? I would be very interested to see such a study.

  59. Fred Dagg says:

    It seems that there is a difference between “evidence based”and “science based”.They are two different things.

  60. pmoran says:

    Daedalus2, that is not the direct evidence I would expect. You are merely interpreting it all in terms of your placebo theory.

    Vagus activity would explain the only clinical study you quote and even if that were NO mediated it provides little support for any general theory of placebo and NO, or the idea that NO is important in any form of objective “healing”.

  61. Joe says:

    @Fred Dagg on 18 Jun 2009 at 10:36 pm “It seems that there is a difference between “evidence based”and “science based”. They are two different things.”

    Very good, are you always so quick?

  62. daedalus2u says:

    Psyche, here is a table of antidepressant drug costs.

    http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/2pager_Antidepress.pdf

    I don’t have figures for psychotherapy, but treatment by a senior clinician is going to be at least $200 per hour. At once a week that is $800 per month. A pretty junior clinician might be $125. That is still $500 per month. There are a number of antidepressants that are 1/10 of that.

  63. Scott says:

    “Two different answers, one of you must be wrong?”

    An entirely invalid conclusion. Note that Mark’s answer was regarding a specific field, tmac57′s was more general. It should be blindingly obvious that it’s completely possible for individual fields to be more or less thoroughly science-based than others.

    That said, I do suspect Mark’s answer to have been one of the 87.36% of statistics made up on the spot, due to the fascinating precision of the figure. I’d be happy to be proven wrong by a cite, however.

    And no, there is no inconsistency between those paragraphs. There can be cause to believe that one answer is likely to be inaccurate without it being the case that it “must be wrong.”

  64. tmac57 says:

    Fred- From now on, whenever you say that ” I have read that only 20% of “medicine”, is scientifically based…”, you can also now say that you have read that about 76% of medicine is scientifically based.
    Just sayin’

  65. Psyche78 says:

    @daedalus2u – considering that you have presented no data on the prescription of rate of newer antidepressants vs. older antidepressants or length of average use of antidepressant (which, to be fair, I do not believe that such a study has been conducted), and you are basing your statement that antidepressants are cheaper than psychotherapy on the assumption that most people pay what I call “rack rate” for therapy for individual psychotherapy (vs. insurance negotiated rates or the lower rates for group psychotherapy or a sliding scale practice) and do not take into account the cost of seeing the doctor (generally a psychiatrist) for prescription and follow-up, I do not believe it is possible to say that antidepressant treatment is cheaper than psychotherapy (especially when you add in the costs of side effects). Furthermore, studies have indicated there is a higher risk of relapse with medication alone – leading to more and longer use of antidepressants.

    Antonuccio, David O., Danton, William G., & DeNelsky, Garland Y. Psychotherapy Versus Medication for Depression: Challenging the Conventional Wisdom With Data Professional Psychology: Research and Practice. December 1995 Vol. 26, No. 6, 574-585.

    Jacobson, Neil S. Cognitive-Behavior Therapy Versus Pharmacotherapy: Now That the Jury’s Returned Its Verdict, It’s Time to Present the Rest of the Evidence. Journal of Consulting and Clinical Psychology February 1996 Vol. 64, No. 1, 74-80.

    Cognitive Therapy Versus Medication in Augmentation and Switch Strategies as Second-Step Treatments: A STAR*D Report
    Michael E. Thase, Edward S. Friedman, Melanie M. Biggs, Stephen R. Wisniewski, Madhukar H. Trivedi, James F. Luther, Maurizio Fava, Andrew A. Nierenberg, Patrick J. McGrath, Diane Warden, George Niederehe, Steven D. Hollon, and A. John Rush
    Am J Psychiatry 2007 164: 739-752.

  66. daedalus2u says:

    Psyche, I am not sure what your point is. I don’t doubt that you can find psychotherapists that are cheaper and/or antidepressants that are more expensive. Both treatments have to be individualized to an individual patient’s needs. There is no “one size fits all”. Withholding treatment is always cheaper, unless you include the costs of the untreated illness. A Band-Aid and a shot of whisky for a compound fracture is cheaper than what would be considered the standard of care.

    Individual psychotherapy is very expensive because it is extremely labor intensive. There is no way around that. The cost has to include that labor and overhead. The average cost per hour has to be the average salary plus benefits and overhead.

    Better and more experienced clinicians are more expensive. They are also more cost effective (in my experience, in general). That cost effectiveness is difficult to measure because there are no instrumental measures of depression and of many other mental health problems, so the severity and the degree of improvement isn’t easily measured or compared between treatment modalities. In my experience, adding an antidepressant to psychotherapy is very cost effective.

    There is a great deal of misinformation put out on antidepressants. Much of it put out by people with an agenda, such as the Scientologists. My understanding of their anti-psychiatry bias is because they don’t want competition or alternatives to their delusional cult.

  67. daedalus2u says:

    PM, I don’t think there is any of what you would consider direct evidence, and I don’t think the technology exists yet to measure it. The levels of NO that are important in this signaling are very low, in the nM/L level with sub-cellular length scales.

    Ischemic preconditioning is something that individual cells do, but also entire tissue compartments. There must be signaling between cells that keep the whole tissue compartment “in sync”, and that signaling can’t be neurogenic because some tissue compartments that exhibit ischemic preconditioning (liver, kidney) are not innervated to individual cells. In the brain, what is called spreading depression isn’t propagated by neuronal signals. We know that ischemic preconditioning is triggered by oxidative stress, which is also low NO. The mediator of oxidative stress, superoxide is an anion, and is confined by lipid membranes. NO is uncharged and freely diffuses through lipid membranes.

    It is better to think of NO as a signaling molecule, like a neurotransmitter (and acting on that type of time scale), rather than as a drug or hormone. The NO is mediating a physiological change via communication rather than by a chemical change. I am not aware of any direct measurement of NO in this context and really can’t think of any way to do it. In spreading depression you can observe changes in the physiological state and changes in activity via fMRI. The vasodilation observed in fMRI BOLD is mediated through neurogenic NO.

    There has started to be some work on NO and wound healing. The problem with what is in the literature is that they are treating it as a drug and not as a signaling molecule. To communicate a signal you need the right amount in the right place at the right time and for the right duration. Getting that by chance through experimentation is quite difficult (and may be individually idiosyncratic).

    There is lots of evidence that physiology works this way, that there are different physiological states. Two extremes are “normal” and the ischemic preconditioned state. Likely those are considerably more complex than we have data to describe. The signals that mediate those changes have to have certain properties. The ATP level has to be the major signaling pathway for signaling and regulating ATP consumption inside a cell. Cell membranes block ATP, so signaling between cells has to be by something else.

    NO fits all the properties that signaling molecule has to have and explains the coupling of physiological states under conditions of hypoxia, ischemia, and “normal” and allows for smooth and regulated transitions between them. Neurogenic NO is used to regulate metabolic activity in the brain; it would be completely surprising if some completely different method were used everywhere else. Because some individual nerve cells do pass between the CNS and outside the CNS (motor neurons), the method(s) have to be compatible. That compatibility is most easily achieved if the method(s) in the multiple tissue compartments are all the same.

    There has to be such a method that physiology uses. That method has to have certain properties and those properties are completely matched by NO (as nearly as I can tell from the literature). That hypothesis does make predictions, and those predictions match what is found in the literature.

    I can’t really think of any experiment that would disprove the hypothesis but that is because experimental techniques are limited. An analogy would be trying to prove that a computer chip didn’t run on electricity using electrical measurement equipment from the 19th century. The technology simply doesn’t allow measurements with the sensitivity, length and time scale necessary to understand in detail what is going on.

  68. Psyche78 says:

    Daedalus2u,

    My point was merely to point out that the statement “Antidepressants are cheap compared to psychotherapy” is a misconception as a blanket statement. Such beliefs have been used to deny parity for psychotherapeutic services and are used to support the idea that “talk therapy” is, for lack of a better word, “woo.” When I see such a statement, I like to clear it up (especially on a blog that purports the present information about science-based medicine). I disagree about being unable to compare psychotherapy cost effectiveness to pharmaceutical cost effectiveness, as there have been well-designed studies (the ongoing STAR*D project, for instance) that have done so, and manualized Cognitive-Behavioral Therapy can be done effectively in 8-10 sessions for mild depression, but, in case you can’t tell, I could go on about this for hours and it’s getting off-topic.

    FWIW, scientologists do not like psychotherapy/psychology any more than they like psychiatry – it’s all about the e-meter and thetans and dianetics for them.

  69. Scott says:

    “PM, I don’t think there is any of what you would consider direct evidence, and I don’t think the technology exists yet to measure it.

    I can’t really think of any experiment that would disprove the hypothesis but that is because experimental techniques are limited.”

    Do you at least recognize the problem inherent in admitting that there isn’t any real evidence for it, but presenting it as established fact anyway? (Even if you don’t intend to, that’s most emphatically the impression you give.)

    “There has to be such a method that physiology uses. That method has to have certain properties and those properties are completely matched by NO (as nearly as I can tell from the literature). That hypothesis does make predictions, and those predictions match what is found in the literature.”

    Not convincing except to argue that there might be grounds to do experiments to test whether there’s anything to it. There is a very important reason why explaining already-known data is not considered any sort of adequate test for a hypothesis. Since effectively EVERY hypothesis seriously proposed is consistent with current data (those that aren’t having already been discarded), only predictions of NEW results can properly test a hypothesis.

    If you could convincingly argue that there are no other hypotheses explaining the same things you claim are explained from NO, then you’d have a bit more of a leg to stand on. But without testable and falsifiable predictions, you’re just not doing science.

  70. daedalus2u says:

    psyche, I freely admit the value of psychotherapy as someone who has been in full-fee therapy with senior clinicians for ~25 years. I have been on meds for a few years less than that, and for the increased effectiveness, the meds were very cheap. I don’t see it as either/or. I agree that there should be mental health parity in health insurance.

  71. daedalus2u says:

    Scott, I said there was no direct evidence, not that there was no real evidence. By direct evidence I mean measurement of NO in the tissue compartment under consideration coincident with the effect being attributed to NO. By that standard there is no direct evidence that SSRIs have an effect on depression. There has been no measurement of serotonin levels in synapses in depression, and no measurement of changes to serotonin levels that correlates with depression (and no physiological mechanism of how changes in serotonin metabolism correlate with changes in depression).

    It is not the case that existing and proposed hypotheses explain all the data. They don’t. There is no hypothesis of depression that explains the metabolic activity of depressed brains, the blood flow in depressed brains, the MRI imaging results of depressed brains, why depression is a side effect of many other diseases and why specific compounds work as antidepressants. The low NO hypothesis of depression does have an explanation for all of these observations and more.

    There is no experimental technique to falsify the hypothesis that serotonin is important in depression. SSRIs improve depression in some individuals, but not in others. That is not “proof” that serotonin is important, and a lack of effect of SSRIs in some individuals is not “proof” that it is unimportant. Is the serotonin hypothesis of depression unscientific? No, because there is evidence, just not direct evidence.

    I appreciate the desire to have new data to verify a new hypothesis. But when a new hypothesis is simpler and explains all the data in the literature and much more data than does any other hypothesis, why does that make it not credible? Particularly when that data is not cherry picked?

    To me, when two hypotheses are compared, the one with the greater explanatory power and the fewer ad hoc rationalizations is preferred. When the difference in explanatory power is large, the timing of the data becomes less important.

    New data is most useful in distinguishing between hypotheses of equivalent explanatory power; when one hypothesis explains 10x or more data than the other hypothesis, my default is to go with the hypothesis with the greater explanatory power. Some people may have a different default. I don’t understand the rationale for a different default in that circumstance.

  72. Scott says:

    “Scott, I said there was no direct evidence, not that there was no real evidence. By direct evidence I mean measurement of NO in the tissue compartment under consideration coincident with the effect being attributed to NO.”

    By real evidence I mean experimental data with the power to falsify the hypothesis.

    “By that standard there is no direct evidence that SSRIs have an effect on depression. There has been no measurement of serotonin levels in synapses in depression, and no measurement of changes to serotonin levels that correlates with depression (and no physiological mechanism of how changes in serotonin metabolism correlate with changes in depression).”

    You’re conflating the two (largely independent) questions of whether they work, and how they work. Quite important to keep those distinct.

    “It is not the case that existing and proposed hypotheses explain all the data. They don’t.”

    OK, so you are making that claim. That gives it a bit more credence.

    “SSRIs improve depression in some individuals, but not in others. That is not “proof” that serotonin is important, and a lack of effect of SSRIs in some individuals is not “proof” that it is unimportant. Is the serotonin hypothesis of depression unscientific? No, because there is evidence, just not direct evidence.”

    It is, however, quite wrong to state that depression IS caused by low serotonin on that basis alone (unless there are other angles of evidence that suggest it). Again, must keep distinct the questions of “does it work” and “how does it work.”

    “I appreciate the desire to have new data to verify a new hypothesis. But when a new hypothesis is simpler and explains all the data in the literature and much more data than does any other hypothesis, why does that make it not credible? Particularly when that data is not cherry picked?”

    If these claims were true (which I am not qualified to address), it would give it modest credibility only. Given that you seem to be the only person advocating it, I must conclude that the people who know more don’t agree with this analysis.

    “my default is to go with the hypothesis with the greater explanatory power. Some people may have a different default. I don’t understand the rationale for a different default in that circumstance.”

    None of the argument you’ve made really justifies presenting it as fact. An interesting hypothesis, perhaps. IF your claims of how much explanatory power it has are correct, it would even be a compelling one. But not established fact by the greatest stretch of the imagination.

  73. daedalus2u says:

    Scott, My statement about direct evidence was to answer a specific question from PM. It was not about “real” evidence; it was about direct evidence which I interpreted as being actual measurement. NO research is extremely challenging because the levels of NO that are physiologically important are so low. There are no techniques to measure them in vivo at the levels that are important. That is true for most things in physiology. Neurotransmitters can’t be measured in vivo on the length and time scales that are important. Does that mean that there is no good evidence for neurotransmitters? No it doesn’t. There is no technique to measure variations in ATP non-destructively in individual cells. Does that mean variations in ATP are not important? No, variations in ATP have to be important because it is only variations in ATP which physiology can use to regulate ATP physiology. I don’t need to measure ATP variations to know that ATP concentrations must vary and those variations must happen in characteristic ways which render cell operation stable.

    There are a great many misinterpretations about ATP which stem from the extreme difficulty of measurements. An important one is the myth of homeostasis. Homeostasis is the mythic principle that keeps things like ATP “in stasis”. There is no such thing, nothing in physiology is static, it is measurement difficulties that have lead people to erroneously believe that things are kept static. No matter how many people believe homeostasis is correct it isn’t. It never was correct and never will be correct. It may have been a useful model 70 years ago when essentially every measurement of physiology showed no changes over time. Now we know that nothing in physiology is static. Some of those changes we can measure, some of them we still can’t. Even though we can’t measure changes we know they are not static.

    http://daedalus2u.blogspot.com/2008/01/myth-of-homeostasis-implications-for.html

    There is a gigantic amount of data that NO is important in brain physiology on multiple scales.

    http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18588525

    Is the data good enough to falsify the hypothesis that NO is important in brain physiology? I am not sure what that even means. If NO is not important in brain physiology then large chunks of the literature are wrong and must be discarded. That would take an extraordinary amount of evidence. Is NO important in depression? NO is important in normal regulation of blood flow, blood flow is perturbed in depression, presumably changes in NO are important in depression. If you go down the list of physiological processes that are perturbed in depression, many of them are regulated through NO signaling and are perturbed in the direction of low NO.

    The experimental techniques needed are extremely challenging. Einstein didn’t have the capability of trains or elevators that traveled at near the speed of light. He used thought experiments to understand how things had to behave under those conditions.

    There are no techniques to measure ATP levels in cells real time. What ever the ATP levels in cells are, they have to obey certain relationships which make them consistent with aspects of physiology that are observable. I try to put a lot of the explanation on my blog. I recognize that the explanations there are brief and incomplete. I am happy to answer questions about NO physiology there.

  74. Fred Dagg says:

    In regard to the treatment of depression, and how it varies from one country to another, have a look at this research.

    http://www.bmj.com/cgi/content/abstract/330/7490/503

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