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Pyroluria and Orthomolecular Psychiatry

I have previously written about psychomotor patterning – an alleged treatment for developmental delay that was developed in the 1960s. The idea has its roots in the notion of ontogeny recapitulates phylogeny, that as we develop we progress through evolutionary stages. This idea, now largely discredited, was extended to the hypothesis that in children who are developmentally delayed their neurological development could be enhanced if they were made to progress through evolutionary stages. Children were put through hours a day of passive crawling, for example, with the belief that this coax the brain into a normal developmental pathway. The treatment was studied extensively in the 1970s showing that the treatment did not work.

However, those who developed this treatment, Doman and Delecato, did not want to give up on their claim to fame simply because it didn’t work and the underlying concepts were flawed. For the last 40 years they have continued to offer the Doman-Delecato treatment for all forms of mental retardation, surviving on the fringe, all but forgotten by mainstream medicine (except by those with an interest in pathological science).

I was recently asked to look into the claims for a disorder known as pyroluria, and what I found was very similar to the history of psychomotor patterning. There was some legitimate scientific interest in this alleged condition in the 1960s. Studies in the 1970s, however, discredited the hypothesis and it was discarded as a failed hypothesis. The published literature entirely dries up by the mid 1970s. But the originators of the idea did not give up, and continue to promote the idea of pyroluria to this day.

The story is told by Dr. Abram Hoffer himself, the originator of the pyroluria hypothesis. It started with a reasonable idea – since LSD mimics some of the clinical findings of schizophrenia, perhaps we can learn something about the biology of schizophrenia by studying the effects of LSD on the body. He specifically looked at the urine of patients given high doses of LSD before and after treatment. He found an increase in an unknown substance. As Dr. Hoffer recounts:

At first we called it the unknown substance (US), and later the mauve factor because when developed on the paper chromatogram it stained a beautiful mauve. When it was identified we called it, more accurately, kryptopyrrole. We named the disease characterized by large amounts of mauve factor “malvaria,” but Dr. Pfeiffer later gave it the more appropriate term pyrolleuria.

He goes on to recount how he and his team found kyrptopyrrole in the urine of patients who are physically ill, those with depression and other mood disorders, and schizophrenics, but not in healthy controls or recovered schizophrenics. So far this all sounds reasonable. It was later found that kryptopyrrole excretion relates to levels of vitamin B6 and zinc in the body, and therefore schizophrenics can be successfully treated with vitamin supplements.

There is nothing implausible about nutritional or biochemical disorder presenting with psychiatric conditions. In fact, acute intermittent porphyria (also believed by Hoffer to be related to kryptopyrrole) is a known biochemical disorder that presents as acute episodes of psychosis (the movie The Madness of King George relates the story of King George III’s bouts of this disease). Schizophrenia is a debilitating disease and it would certainly be very nice if we could cure it (or even a subset of cases) with a vitamin supplement. That is not, however, how the science turned out. Unfortunately, science does not always conform to what we wish to be true.

Pyroluria (which has various spellings, but this seems to be the most common in current use) did not survive replication. A number of studies in the 1970s failed to confirm the presence of kryptopyrrole in the urine of patients with schizophrenia or prophyria. For example, Gendler et al found no hemopyrrole or kryptopyrrole in the urine of healthy subjects or schizophrenics. Jacobson et al found similar negative results.

The pattern is identical to what I found when I researched psychomotor patterning, a string of negative studies in the 1970s followed by the complete disappearance from the peer-reviewed literature, except in journals dedicated to the now fringe idea. In this case Hoffer decided that he was not the victim of a failed hypothesis, but rather the victim of a conspiracy of mainstream psychiatry that was simply closed to his revolutionary ideas. He founded the journal Orthomolecular Psychiatry, now the Journal of Orthomolecular Medicine – a fringe journal in which he could continue to publish his ideas.

I also looked for research on the related but distinct question of using vitamin B6 to treat schizophrenia. If there were any clinically significant effect it should be easy to demonstrate in clinical trials. I found a few double-blind studies and they show two things: Vitamin B6 has no benefit on psychotic symptoms of schizophrenia, but it may have benefit for motor symptoms – specifically Tardive dyskinesia and Parkinsonism as a side effect of anti-psychotic medication. So B6 does not treat schizophrenia itself, but may reduce the motor side effects of medications used to treat schizophrenia. Perhaps this effect is what has led to anecdotal observations of improvements in schizophrenic patients from B6.

Hoffer, in his telling of the tale, has this revealing passage:

Since schizophrenic patients, most of whom had the factor in their urine, responded better when treated with vitamin B3, I concluded that any psychiatric disease, no matter what they were diagnosed clinically, might also do better with this vitamin. This was confirmed by a large series of open clinical studies. I will not term these studies anecdotal, which has become the politically correct term for denigrating any studies that are not double blind, since all clinical studies depend upon the history or herstory of patients and how they respond, i.e. upon anecdotes. The only difference is that in double blind studies the anecdotes are collected by physicians or others who are blinded by not knowing what treatment is being given. At least this is the theory of this type of procedure. In fact, the vast majority of these studies are so imperfectly blinded that few clinician or nurses have much difficulty deciding whether the patient was on placebo or something more active.

Worshippers of the double blind remind me of the emperor whose nakedness was seen only by a child not yet blinded by tradition. This report by Kraus is an excellent example of the type of anecdotal history which has contributed so much to medicine.

The denigration of double-blind studies and the holding up of anecdotal information as reliable is a sure sign of someone on the fringe, not wishing to listen to the scientific evidence but rather to pick the evidence they want to use because it better suits their theories. We have discussed the weaknesses of anecdotal information many times in the past. Anecdotes are overwhelmed by bias and uncontrolled factors. At best they can be used to generate hypotheses, but not to test them. We need double-blind studies to see if alleged effects are real. There is a kernel of truth in what Hoffer says in that not all studies reported as double-blind are reliable, and imperfect blinding can be a major, and often hidden, weakness of clinical trials. But he misses the point in his criticism.

First I need to point out that the “only difference,” as Hoffer claims, is not that the physicians are blinded – the subjects are also blinded (hence double blind). This is critical to controlling for biasing effects. But also the point here is that while anecdotal reports were positive, well-controlled double blind studies of pyroluria (biochemically and clinically) were negative. You cannot explain this pattern of results with improper blinding. Improper blinding causes false positive results – not false negative results, so Hoffer’s objections make no sense. The better controlled studies were negative, that pattern strongly implies the null hypothesis, in this case that pyroluria does not exist as a legitimate entity and vitamin B6 is not an effective treatment for schizophrenia (although it may help reduce the motor side effects of medication).

The bigger picture here (as with psychomotor patterning) is that it is a fundamentally flawed and failed strategy to essentially take your ball and leave the playground when mainstream science does not support your theory. I guess this also depends on your goals. If your goal is to set up your own clinic and make money treating patients according to your own pet theories, then certainly you can follow the Doman and Delecato pathway. If your goal is to convince the world that your ideas are correct, however, this is the wrong path to take. If your goal is to find the truth and develop treatments that are actually effective and helpful for patients, this is also not the right path to take.

Hoffer has had 40 years to do more and more rigorous research, to produce the data that would convince even a skeptical mainstream scientific community that his ideas are correct. If he truly believes that he is right, then this is the path that would help the most patients by changing the standard of care. Rather, he formed his own fringe journal and fringe community where he can brood about the conspiracy of mainstream psychiatry and rail against the dogma of rigorous scientific research.

Posted in: Neuroscience/Mental Health

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