White Coat Underground

New autism study: science or nonsense?

Bad medical ideas often start with good intentions.  Most doctors are interested in preventing and treating disease, and some diseases are particularly challenging.  Some rise to this challenge, forming clever hypotheses and finding accurate ways to test them, but others aren’t so successful.  Sometimes, hypotheses are too implausible to be worth spending much time on.  Sometimes, the method used to test a hypothesis is simply not valid.

This story begins on the website Age of Autism. AoA is one of the homes of the antivaccination movement and gives a lot of time to those who still believe that vaccinations and other “toxins” cause autism.  The site is full of remarkably paranoid rants.  When Chicago Tribune journalist Trine Tsouderos won an excellence in health care journalism award, AoA accused the CDC and Trib of having “bought” the award. They are boosters of every unproven and implausible “treatment” for autism, such as chelation, hyperbaric oxygen, and chemical castration through lupron injections.  Recently, they provided a platform to Dr. Andrew Wakefield, the physician who’s Lancet paper drawing a link between autism, vaccinations, and gut disorders, was formally withdrawn by the journal’s editors.  Due to accusations of scientific and ethical misconduct, he is likely to lose his license to practice medicine in England.

So it came as no surprise to see one of their writers hyping a study in progress that is testing oral enzymes for the treatment of autism.   In the piece, Theresa Conrick incorrectly implies that the existence of this study is vindication for both the autism-gut hypothesis and for Wakefield’s behavior.


In 1998 Dr. Andrew Wakefield published a paper in the prestigious medical journal the Lancet.  In this study, he claimed that the measles, mumps, rubella (MMR) vaccine caused observable changes to children’s intestines which eventually lead to autism.  The study led directly to falling vaccination rates in the UK, an increase in vaccine-preventable disease, and helped launch the modern antivaccination movement in North American and Europe.  The study, as it turned out, was so fraught with conflicts of interest and poor science that several of the authors dropped their association with it, and it was eventually withdrawn from the journal.  Wakefield himself was lambasted by England’s General Medical Council for his unethical behavior associated with the study, and will likely lose his license to practice medicine. 

Wakefield’s hypothesis about autism and gastrointestinal disease was never terribly plausible to begin with, and despite the retraction of his original study, there persists a belief in many parts of the autism community that the gut is somehow implicated in the development and treatment of autism.  Wakefield still has many zealous adherents and dietary therapies for autism have grown in popularity.  Jenny McCarthy attributes much of her purported success with her child to severe dietary restrictions which she recommends for others.  So far, however, there is no good body of literature supporting any connection between gut disease, diet, and autism.  A new study aims to change that.

According to the hyperbolic language of Age of Autism, you would think that the very existence of this study exculpates Wakefield and vindicates all of the pseudo-experts’ opinions about the causes of autism. But what is behind Age of Autism’s excitement? 

The study is designed to evaluate the affect of “CM-AT”, made by Curemark, LLC, on the symptoms of autism in children.  CM-AT is an enzyme with a proprietary delivery system that is supposed to help digest proteins. 

There are a number of conditions for which orally ingested enzymes can be used.  Lactose deficiency, a common condition in which someone can’t digest the primary sugar in milk, can be treated effectively by taking lactase with dairy meals.  People with pancreatic damage can take pancreatic enzymes to help them digest certain carbohydrates, fats, and proteins.  Assuming that CM-AT actually breaks down proteins in vivo, what hypothesis underlies its use in autism?

According to the brief description at ClinicalTrials.gov:

Treatment is based upon the observation that many children with autism do not digest protein.

I’m unsure what literature supports this assertion.  They do of course give references, but the reference are in large part either irrelevant to the hypothesis or of very poor quality.  For example, one study looked at the co-occurrence of certain medical problems and autism, including GI problems, but the study failed to compare these rates to non-autistic children.  Another looked at parental reports of abnormal stools in autistic kids. Neither of these gives a particularly strong foundation for a study of proteases in autism.  Yet another study extensively quotes the work of Andrew Wakefield, the doctor who was censured in England for his unethical work.  But the most interesting study is one done by Wakefield himself.

In this study, Wakefield reported that he had discovered “new variant of inflammatory bowel disease is present in this group of children with developmental disorders.”  This was a number of years before his famously retracted study in which he blamed the MMR vaccine for autism, the same study for which he was censured.  Before that controversy, a discussion in the journal Histopathology criticized Wakefield’s work, and practically accused him of lying about his methodology:

Sir: The histopathology proforma used for scoring of intestinal biopsies in the paper ‘Enterocolitis in children with developmental disorders’1 by Wakefield et al. receives detailed criticism in the Commentary, ‘Autistic enterocolitis, is it a histopathological entity?’,2 by MacDonald and Domizio. In his response Dr Wakefield states that ‘the proforma was designed by Professor A Dhillon of the Department of Histopathology, who with Dr A Anthony evaluated the sections for the purposes of completion of this proforma’.3

I neither designed the proforma being debated, nor was I a coauthor of the paper in which the proforma was published.

Given Wakefield’s subsequent troubles I find it curious that Curemark chose to cite this study in support of their work.

I spoke to Dr. William E. Gannon Jr. who is directing the study for Curemark.  He has decades of experience running clinical trials.  He reported to me that he is aware of the challenges sometimes associated with research into autism treatments and has worked closely with Curemark and the FDA to make sure this phase III trial is done right.  He has been in continuous contact with study sites to make sure they stay on protocol and avoid inappropriate release of preliminary results.

But it would appear he is being hamstrung by Curemark, who is pumping up CM-AT before the phase III results are available.  Their website currently links to a BusinessWeek article about the product:

“One of the most promising treatments in this category is a drug called CM-AT made by a startup called Curemark. Dr. Joan Fallon, the company’s founder and CEO, observed that many autistics show a strong preference for foods high in carbohydrates and low in protein. A diagnostic test revealed that some autistic children lack enzymes that digest protein. As a result, these children produce fewer of the essential amino acids that are the building blocks for brain development and neuroreception. Fallon believes this deficiency is linked to the most severe symptoms of autism, and she says an early observational study of CM-AT, an orally ingested powder that delivers protein-digesting protease, showed “significant improvements.” Curemark is enrolling patients in phase III clinical trials at 10 to 12 site the largest autism trial to date.” (emphasis mine)

Where did she get these ideas?  What evidence supports this hypothesis?  Who is Dr. Joan Fallon?

First, Fallon is not a doctor; she is a chiropractor.  She is not exactly widely published in the medical literature.  In 2005 she put a piece in Medical Hypotheses (a controversial journal, to say the least) in which she “hypothesizes” that the antibiotic Augmentin may be responsible for autism.  She applied for a patent to use the commonly available laxative lactulose to treat autism.  And she’s promoted the idea that autism is somehow related to the gut.  None of her ideas really hang together.  Is autism caused by a failure of protein digestion?  By an antibiotic?  By toxic ammonia levels?  Whatever the cause, she seems to be looking for a profitable cure.  I’m not sure that she can patent lactulose, but she apparently found a substance she can patent—CM-AT, a proteolytic enzyme in a novel delivery system. 

There are a number of things I find disturbing about this study.  While it appears to be well-run, it fails to conform to an important scientific and ethical standard: plausibility.  According to the Helsinki Declaration protecting human research subjects:

12. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.

Fallon and Curemark have not convinced me that there is any science that would justify their study.  It’s certainly reasonable to take some risks based on sound science, but in this case, all that underlies this study is a handful of very questionable studies.  Citing literature to justify your research is not just some bureaucratic hurdle to leap; it is fundamental to the ethical design of clinical trials. There is no reason to expect that delivering an oral protease to children with autism should improve symptoms of autism.  There is no putative mechanism by which this should work, despite the speculations of the chiropractor CEO of the company that makes the product. 

Given the low plausibility of the hypothesis, even positive results, should they be found, must be interpreted with a high index of suspicion.  The statistics underlying the study of implausible hypotheses tell us that positive results are often due to chance or problems with study design rather than the drug being tested.  This is not an esoteric technical detail.  This is a study being done on child subjects whose parents have been led to believe this treatment may help. There is no reason to believe this is so.  Perhaps some day if there are convincing preliminary studies, the current one would be justified.  At this point, though, it is simply another questionable study built on a foundation of bad science.


  1. #1 Tsu Dho Nimh
    April 6, 2010

    Does she back up her assertions with amino acid levels on blood from these supposedly enzyme-deficient children?

    And if they are, indeed, deficient, wouldn’t straightforward amino acid supplements do the job?

    Except that you can’t patent them, of course.

  2. #2 Harold L Doherty
    April 6, 2010

    I understand that the focus of your comment is to mock the Age of Autism and anyone who dares suggest a possible vaccine autism connection. I have never attributed my 14 year old son’s autistic disorder to vaccines although I am less certain of that since the emergence of what appears to be legitimate concerns with vaccines.

    What is your view of the validity of the epidemiological studies used to allegedly “debunk” any possible thimerosal autism connection? I ask this in light of the changing definitions and increased ascertainment factors. Is it legitimate or valid to use epidemiological studies to say that autism increased in an area, say Denmark, and then turn around and say that increases in autism diagnoses do not reflect real increases in autism because of changed definitions and increase awareness and other ascertainment factors?

    I also ask this in the context of criticisms of the epidemiological studies by persons such as Dr. Julie Gerberding, Dr. Irva Hertz-Pacciotto and Dr. Jon Poling. Dr. Gerberding pointed out thimerosal has continued to be included in vaccines given to pregnant women and that thimerosal crosses the placentas.

    I hope my questions do not sound like a “paranoid rant” and look forward to your expert, informed and considered opinion.

  3. #3 PalMD
    April 6, 2010

    Harold, I’m trying to parse out your comment. First of all, while I do think that AoA is worthy of scorn and mockery, that isn’t the purpose of this post.

    Second, there is no good evidence linking vaccines with autism. The evidence overwhelmingly fails to support the hypothesis that vaccines are causally associated with autism.

  4. #4 MikeMa
    April 6, 2010

    Thimerosal was removed from most vaccines in the late 90’s with no subsequent drop in autism. Thimerosal was never in MMR.
    AoA is easily mocked because they allow no dissent, they refer to logic as if it were a thing to be switched on and off at will. They ignore study after study that disagrees with their theories du jour.

  5. #5 Chuck
    April 6, 2010

    Thimerosal was voluntarily removed from children’s vaccine in 2001. Vaccines manufactured in 2001 had a shelf life until 2003 and could be administered. The diagnostic change for ASD changed in 2000 and the subsequent increase in diagnosis was nothing more then a learning curve by professionals to diagnose a new and broader population.

    The study you referenced has a great many biases built into the results before the study is even finalized.

  6. #6 Shannon
    April 6, 2010

    Latulose is a pretty powerful laxative. it’s used to treat people with liver failure, in order to avoid the toxin dump to the brain associated w/ liver failure.

    It seems very cruel to administer that to autistic children given their sensitivity, particularly if it’s not founded on good reason.

  7. #7 daedalus2u
    April 6, 2010

    I call nonsense. They are elaborate secretin patents.





    Secretin has been shown to not work.

    There was a recent trial on proteolytic digestive enzymes.


    It didn’t show positive results. No reason to suppose this one would either. Why such a large study? To get the $$$ before it is proven to not work.

  8. #8 James Sweet
    April 7, 2010

    It’s been said before, and it is patently obvious after a moment’s consideration, but it bears repeating anyway:

    On average, for every 20 studies into an implausible and ineffective treatment, one of them will come up with a positive result with a >=95% confidence interval.

  9. #9 Azkyroth
    April 7, 2010

    The evidence overwhelmingly fails to support the hypothesis that vaccines are causally associated with autism.

    Evidence which fails to account for two important facts:

    1) a large number of people, like Wakefield, stand to profit from selling and promoting quack therapies and from frivolous lawsuits against vaccine manufacturers.
    2) certain shallow celebrities like Jenny McCarthy have BROKEN children rather than the ones they wanted. Clearly, of course, this turn of events must be SOMEONE’S FAULT!

    When these are taken into account, the underpinning for the antivaccine movement becomes obvious.

  10. #10 Nathan Myers
    April 7, 2010

    On average, for every 20 studies into any set of effective treatments, plausible or otherwise, one will come up with a negative result with a >=95% confidence interval. On top of that, it’s easy to cook a trial to get a negative result if that’s what you’re after (e.g. something unpatentable competing with something proprietary). Most of the precautions in place are meant to prevent false positives, because investors are almost as happy with those.

    As an example of such perfidious trial design, consider how long it took to quantify lead toxicity. For a long time all the supposed controls were saturated with environmental lead. To get meaningful results they finally had to compare to Amazon natives.

    This isn’t to argue in favor of quack treatments, but the religious awe afforded double-blind placebo-controlled trials is misplaced. They’re among the sharpest tools in the drawer, but none too sharp for that.

    I wonder if the positive results often reported for chelation, but not supported by controlled trials, are actually just a consequence of the mineral supplements that chelation patients get. It would be easy to miss differences in such supplementation if you weren’t looking. Mineral supplements are rather safer than chelation, and cheaper.

  11. #11 Azkyroth
    April 8, 2010

    I wonder if the positive results often reported for chelation, but not supported by controlled trials, are actually just a consequence of the mineral supplements that chelation patients get. It would be easy to miss differences in such supplementation if you weren’t looking. Mineral supplements are rather safer than chelation, and cheaper.

    There’s still no plausible mechanism for mineral supplementation changing what is fundamentally just a different neurological configuration, no matter how insistent shallow celebrities are that their children are BROKEN and it must be SOMEONE’S FAULT.

  12. #12 onethird-man
    April 8, 2010

    Nathan, there’s no absolute way to control for everything everywhere at all times, and it is ridiculous to assume malignant intent in every study that doesn’t show what you expect.

    There is no “religious reverence” for placebo controlled double-blind studies any more than there is for the scientific method. Both are extremely useful tools, and good points of base observation. Neither is inviolate or immune to criticism, which is why both are backed up with repeated testing by others in the field, scrutiny by professional organisations or governing bodies, and so-on.

    Many placebo-controlled double-blind studies of medications that are not for extremely serious conditions are also placebo run-up, unknown to the patients. They put everyone on placebo, just to get a good idea of the rate of affliction for completely untreated patients.

    Even then, some people claim, like one woman in a study my wife was part of, to have contracted liver problems requiring expensive liver biopsy testing, all the fault of the study. When she was removed from the study, it was revealed she was on placebo. Her husband called back irate that anyone would give her sugar, which was sure to give her diabetes, and demanded the liver tests anyways.

    So, unless you are advocating keeping lab children, or putting all patients through sterilization procedures and removing all possible conflicting parasites and so-on, I’m afraid no study will ever meet the acceptance criteria you appear to have set up.

  13. #13 Nathan Myers
    April 8, 2010

    one-third: Evidently you are arguing with someone else, who said things I didn’t say. Do you hear voices?

    Azkyroth: Your contempt for others’ suffering comes through loud and clear. In fact, metabolic anomalies are very common in autistic children, and dietary changes that may help to compensate for those anomalies are eminently plausible. Many apparently successful interventions (e.g. that reduce gastrointestinal distress) probably don’t affect the core problem, but minimize a distraction that autistic children are less equipped than others to handle. (Who would this imply is at “FAULT”?)

    A close friend of mine with a profoundly autistic son tried many, many interventions. His criterion for success was if caregivers spontaneously remarked on sustained improvement. The only things he found that helped, of a great many, were vitamin B complex supplements and chelation. Before treatment, his son was non-verbal, so the improvement was dramatic and unmistakeable. (As I noted, I suspect it was not the chelation itself that helped, but the mineral supplements.)

    My daughter was helped by melatonin at bedtime, and by fish oil. They don’t cure anything, yet they improve matters substantially. This is all “anecdotal”, and thus conventionally beneath contempt, but I mention it anyway in case someone reading doesn’t know that inexpensive treatments can help some children in very noticeable ways, despite medical professionals’ pervasive helplessness.

  14. #14 Pat
    April 8, 2010

    Nathan Troll is troll

    “religious reverence” – your words.

    Nice attempt to redirect. Fail.

    “A close friend of mine” starting your next story tells me you are purely anecdotal. Allow me to riposte.

    I have an autistic son. He started nonverbal, and has improved remarkably – and you know what we did? Fed him and kept him healthy and let him know he was loved. And frustrated him. His first sentence to me was because I didn’t get what he was trying to communicate.

    Oddly enough, he continues to progress with the only “therapy” he gets being patience and special assistance with difficult tasks.

    There, anecdotal, and since it doesn’t agree with you, your data must be faulty. I think that’s how you like to work what you oddly enough probably think to yourself is “sciency.”

    Suspect all the crap you like, and yes, anecdotal is beneath contempt when it attempts to sit at the same table with the adults – you know, statistical analysis and controlled studies which you so decry.

  15. #15 nsib
    April 8, 2010

    Hey Nathan,

    First off, here’s a big FUCK YOU for saying that research scientists are corrupt and medical professionals are unfeeling bastards. You certainly have some cojones saying that without a bit of evidence.

    Secondly, concerning your comments about scientific trials, I don’t suppose you know of a better way of doing things? You know, something more reliable or less biased?

    I thought not.

    Finally, your personal experience when it comes to autism is laughable. Considering that autism is often a problem of developmental delay, it’s impossible to tell from one case study whether a particular treatment helped, or whether the improvement was just due to time.

  16. #16 PalMD
    April 8, 2010

    /fetching popcorn

  17. #17 Passerby
    April 8, 2010

    Run a couple of Pubmed search terms, epigenetics and autism and autism and methylation. Looks like this spectrum disorder has mixed epigenetic and genetic inheritance factors associated with aberrations in gene copy number, micro-deletions and duplications, and gene promoter region silencing or up-regulation, along with a mixed bag of enzyme polymorphisms.

    Autistic kiddies have diminished ROS-scavenging / glutathione status.

    The key might just be inadequate methyl donor pools during maternal and very possibly paternal sex cell maturation (histone reprogramming) in the parents. There may also be issues with histone coding.

    *shrug* It’s certainly not vaccines. Where vaccines may play a role is that when given multiply over short periods, the stressed immune system could exert a draining effect on inadequate glutathione status by elevating ROS for weeks to months afterwards. That may push along the emergence of symptoms in affected infants and perhaps affect development of delicate brain centers affecting behavior.

    Redox status is fundamentally important in infants, children and adolescents. Can’t underscore the importance enough and that is why I suggest that lifestyle can and does play a pivotal role in developmental behavioral and metabolic/cellular energetics in key tissues.

    However, the basic disorder aberrations are present long before these kids show symptoms during infancy. It does not arise from vaccine use, period.

    On another blog, when I suggested that lifestyle and environmental factors may affect parental methyl pool andn CNS redox status, a deficit that could play a prominent role in epigenetic alteration of chromosome fidelity and gene expression, an irate anti-vaxer let loose with pure vitriol.

    The proteinemia reported probably relates to altered biochemical pathway function underlying altered sulfur and nitrogen cycling and glutathione pool shortages.

    Example citation, one of dozens in reputable journals.

    How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. NeuroToxicology
    Volume 29, Issue 1, January 2008, Pages 190-201.

    Sulfur cycle polymorphisms can impact quite a few pathways, beyond methylation status, that produce important cofactors and coenzymes seems to be important here.

    Idiot detractors on medical blogs dedicated to anti-wooism who do not necessarily understand the biochemistry and molecular biology behind some of it, do not even bother to run a search to see if what was said might be backed by a growing body of solid citations across a spectrum of subdisciplines.

    It’s not that I necessarily believe the woo masters, its that a lot of pharmacology research targets nuclear receptors that are part and parcel of the biochemistry of diet, sleep hygiene, and physical status related to exercise via immune controls and muscle and nerve cell repair.

    Lifestyle choices.

    Nope. They simply spew their ignorance and call it good.

    I don’t expect much better reception here, after reading the comments.

  18. #18 Pat
    April 8, 2010


    Speculative mechanisms for a disease with an unknown etiology. It might hold some water if we had definite indicators of what autism is.

    Without that, you’re spewing science terms without a filter.

    I can throw around a few – the quantum nature of atoms means at high concentrations such as those in the deoxyribonucleic acid concentration in the nucleus there are fewer regions for ephemeral particles to occupy, so more tightly compacted nuclei (such as those with early-age longer telomeres) have fewer encounters with large-space versus small separation forces such as the Casimir effect. In “older” population reproductive cells (usually the male as the female has most of her oocytes she will have in life by birth) there will be more chance of matching segments incompletely dividing during meiosis and being pushed together by Casimir effect forces and overcoming any repulsion to engage Van der Waals forces and connect the incomplete DNA molecule to itself much like a ribozyme, which is only logical as ribozymes are based on this matching property in the first place for RNA folding.


    There, chew on that and tell me I’m wrong. Oh wait – I have no idea what the cause of Autism is either. I appear to have equally spoken out of my hat.

  19. #19 nsib
    April 8, 2010


    I honestly don’t see the point of your post, or even what you were responding to. Possible epigenetic contributions to autism are certainly an interesting topic, but I don’t see the connection to any of the discussions on this post. Also, while live virus vaccinations do increase oxidative stress to a degree, how would the increased oxidative stress, even in the presence of reduced levels of GSR, lead to worsening of symptoms of autism? The effect would be pretty localized, and last I checked, the arm isn’t really relevant to autism.

    Finally, Neurotoxicology reputation when it comes to autism research has been fairly sketchy, considering that they’re the ones that published Wakefield’s infamous monkey study.

  20. #20 Nathan Myers
    April 9, 2010

    PalMD: What a posse you’ve collected. Have you selected them for a tendency to hallucination (“research scientists are corrupt and medical professionals are unfeeling bastards”? Really?), or did that happen spontaneously? I doubt the general population exhibits the condition to anywhere near this degree.

    Or maybe it’s nothing more than abysmal reading comprehension. Tendency to hallucination would at least be interesting. Poor reading comprehension is just sad.

    Pat, we all “started nonverbal”. Still, to go from nonverbal to verbal in one day seems to me worth investigating, but you are welcome to disagree.

  21. #21 Sharon Astyk
    April 9, 2010

    Note to self – write note about useful and well done post before getting distracted by silly comments. It was a nice post, btw ;-).


  22. #22 madder
    April 9, 2010


    I second the comments by the others, but will pause to commend you for taking on the antivax loons.

    That said, would you mind comparing the “stress” placed on the immune system by a vaccine to that of, say, playing in a sandbox for a few minutes?

  23. #23 Dianne
    April 9, 2010

    That said, would you mind comparing the “stress” placed on the immune system by a vaccine to that of, say, playing in a sandbox for a few minutes?

    Anyone remember the bruhaha a few years ago over asthma and the possibility that over clean childhood environments might be contributing to the development of asthma? I don’t have any idea how good or bad the data actually was, but if we assume, for the sake of argument, that the hypothesis is essentially correct and that the risk of asthma and/or seasonal allergies is increased when the immune system is underexposed to antigens at an early age, where does that leave the whole “stress on the immune system” argument? The data seem to suggest that stress on the immune system is a good thing, indeed the natural and expected thing. Will anti-vaccine advocates then turn around and start arguing that the problem with vaccines is that they don’t stress the immune system enough?

  24. #24 madder
    April 9, 2010


    Will anti-vaccine advocates then turn around and start arguing that the problem with vaccines is that they don’t stress the immune system enough?

    Yes. Yes, they will.

  25. #25 D. C. Sessions
    April 13, 2010

    On average, for every 20 studies into any set of effective treatments, plausible or otherwise, one will come up with a negative result with a >=95% confidence interval.

    Massive educational FAIL there, Nathan.

    False positives come up because comparing two “no effect” interventions doesn’t have any signal to separate from noise. Not so with effective interventions.

    Doubt this? Try it in some other context. For instance, how often does turning on a working illumination system fail to improve the “darkness” condition? Care to do the statistics on that one?

  26. #26 D. C. Sessions
    April 13, 2010

    Will anti-vaccine advocates then turn around and start arguing that the problem with vaccines is that they don’t stress the immune system enough?

    Fashion is cyclical, so I’m betting on it. Back in the 90s (BW: Before Wakefield) the fashion in anvaxxanity was to insist that the diseases we vaccinate against play an essential role in human development. Measles in particular was supposed to be a necessary pediatric milestone.

    So, yes, I think you can count on the “HiB is good for you” meme to come back around. It’s like epidemics: they burn out, and then after a time immunity wanes and a new Pharaohgeneration arises who know not Wakefield, so it goes around again.

  27. #27 Nathan Myers
    April 13, 2010

    DC: I haven’t encountered many broken lightbulbs that seemed to illuminate the room anyway. It’s the norm that promising treatments for female arousal dysfunction fail in trials because placebo noise swamps the effect. That’s just a special case of failed diagnoses poisoning trials. We see it in “depression”, which is a big bag of unrelated conditions, and autism.

    The solution is to avoid fetishizing one standard form of controlled trial, and instead treat trials as an invention that must be adapted to circumstances, like any tool.

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