HPL molecule artwork free to use and modify.
1. Mauve and mental illness.
When pursuing their investigations into the possible biochemical causes of mental illness, Dr Abram Hoffer working with Dr Humphry Osmond in the early 1950s noticed that a particular chemical tended to show up in greater quantities in the urine of people with more severe psychotic symptoms.
Although the technology of the day precluded an actual identification of this substance, it was characterised by its mauve colour on a paper chromatogram developed with Ehrlich’s reagent which led to it being dubbed the “Mauve factor”. This led to the postulation of a biochemical condition implicated in the development of psychotic symptoms which they termed “Malvaria“, deriving the name from the word “mauve”.
2. Kryptopyrrole and HPL, the confusion.
In 1969 Donald Irvine et al, working with Dr Hoffer, announced that with advances in technology they had succeeded in identifying the Mauve factor as “kryptopyrrole”. This was a pyrrole ring similar to many such produced in the human body each with their own unique variation in composition, some of which are used in the production of heme which is a porphyrin used to carry iron in haemoglobin. From this the term “Pyrroluria”, later reduced to “Pyroluria” was coined to rename Malvaria.
In 1975 Irvine had already announced that with further technical improvements it had been established that ‘kryptopyrrole’ was the wrong identification for the Mauve factor, and that it was instead the similar pyrrole most commonly known today as Hydroxyhemopyrrolin-2-one or HPL. Despite this a number of studies attempting to find kryptopyrrole in the urine of people with psychotic illness using the new techniques were conducted and failed to find it in elevated quantities, leading to the discrediting of the hypothesis.
Irvine restated in 1978 that the Mauve factor was HPL but by then the term “kryptopyrrole” had taken root and is still used to this day interchangeably albeit erroneously with HPL both by detractors and proponents of the hypothesis. A more detailed account of the process of identification can be found here and here. Whether the people using the term ‘kryptopyrrole’ are aware it is erroneous depends on their level of education in this area and this can be confusing.
With the adverse 1973 report by the American Psychiatric Association (see Hoffer’s reply) and the subsequent findings against kryptopyrrole, Orthomolecular Psychiatry under which the Pyroluria diagnosis and treatment fell, was abandoned from consideration by mainstream Medicine. Undeterred, Hoffer and his associates continued with their research.
3. Pyroluria, niacins, and folates.
It had been observed early on by Hoffer et al that large amounts of vitamin B3 (the niacins) reduced both HPL and symptom severity in people with schizophrenia. It was later discovered that B3 along with B9 (the folates) were the primary treatment for a condition with symptoms typical of a form of schizophrenia known as “Histapenia” due to the associated low levels of whole blood histamine (WBH).
It was then discovered later that in general the less WBH present, the higher the amount of methyl groups in the methylation (one carbon) metabolic cycles. This was due to the need for these methyl groups in breaking down histamine, and Histapenia was therefore eventually renamed “Overmethylation” (OM) since the WBH levels were seen to be just a marker for the methyl group levels. The name was due to the theorised cause from too many methyl groups in the methylation cycles leading to excess levels of neurotransmitters such as dopamine and serotonin, causing the psychotic symptoms. This is now seen as mainly due to the epigenetic effect of the high methyl group levels on the DNA.
Conversely a low level of methyl groups correlated with low levels of these neurotransmitters was identified associated with high levels of WBH. This was conversely named “Histadelia” and subsequently “Undermethylation” (UM) as per the previous paragraph. It was found that symptoms were improved by treatment with methionine, a precursor to S-Adenosyl methionine (SAMe) which donates methyl groups to the methylation cycles (“methyl donor”). As per OM, the cause of this improvement is now seen to be the effect of increasing the general epigenetic methylation of the DNA, especially at the histone tails.
The mechanism of action of B3 in this is now seen to be in its role as an indirect cause of the reduction of methyl groups in the cycle, known as a “methyl sink”. That of B9, paradoxically itself a methyl donor, is now thought to be due to its role in reducing methyl groups at the DNA histone tails as per the previous paragraph. It may well be that the people diagnosed with schizophrenia in those days happened to be those whose symptoms coincided with those attributed to OM, and the HPL reduction was a byproduct of their symptom relief. Later on, a distinction was made between the different symptoms associated with methylation issues and high HPL. The association of HPL with oxidative stress will be discussed later.
4. Pyroluria, zinc, and B6.
In the 1970s Hoffer and his team were joined by Dr Carl Pfeiffer and working together it was established that patients with high HPL and symptoms of schizophrenia responded even better to large doses of vitamin B6 (pyridoxine) and zinc. Since the patients had been receiving adequate amounts of dietary B6 and zinc the condition was described as a metabolic or functional deficiency which required massive supplementation though the mechanism was yet unclear.
It was around this time that the theory was first formulated that zinc and B6 were bound to the HPL and excreted, though this was only due to observations in the laboratory with kryptopyrrole and not HPL. The predicted HPL/zinc/B6 complex in urine would remain elusive. Plasma zinc and blood B6, however, are usually low in such cases even though they are still in the normal ranges. Since the body maintains a balance between zinc and copper, low levels of plasma zinc are then associated with high levels of serum copper and these values are used in formulating treatment dosages.
Picture source: www.walshinstitute.org/uploads/1/7/9/9/17997321/biochemical_imbalances_in_mental_health_populations.pdf
The reason for the effect of B6 and zinc deficiencies on mental health may be due to the fact that, apart from the essential roles these play in biochemistry in general, “activated” B6 (pyridoxine) into P5P/PLP (pyridoxal-5-phosphate) using a zinc-dependent enzyme is required to help make neurotransmitters such as serotonin and dopamine. As well, excess copper due to low zinc can lead to excess noradrenaline/norepinephrine, or converting whatever low dopamine already exists.
Much has been made of the link between neurotransmitters and mental illness as the “biochemistry imbalance” requiring medications to address. Up until now general understanding of the mechanism of this seems to have been murky and allowed skepticism of this connection in some quarters.
5. Pyrrole Disorder and oxidative stress.
In the 1980s, with Dr Hoffer having retired, Dr Pfeiffer was joined by Dr William Walsh who had met him on the very day that Dr Pfeiffer had been nominated for a Nobel prize by double Nobel laureate Linus Pauling. Together they made a number of findings about what eventually came to be called Pyrrole Disorder due to the fact that the symptoms that were associated with the elevated HPL were eventually theorised to be caused by oxidative stress (OS).
One reason for this view is that proteins are prone to degradation by OS. HPL may then likely be a residue of oxidative heme degradation. Enzymes are proteins which play vital roles such as in the function of B6 and zinc in creating neurotransmitters among other metabolites. Previously mentioned low-normal levels of B6 and zinc needing massive supplementation may be explained by the need to increase the activity of related enzymes depleted by OS.
The HPL (“pyrrole”) was recast as mostly just a marker of this OS although it had also been shown to have neurotoxic effects of its own in animals and is itself a source of OS. These symptoms were varied but were typically associated with diagnoses of depression, schizophrenia, and other brain, behavioural, and affective disorders.
It has been reported recently that, as a metric of oxidative stress, HPL is found in elevated amounts in people with any kind of illness, stress, toxicity (especially heavy metal), or injury, though the levels are highest in those exhibiting symptoms of the mental or behavioural disorders mentioned previously.
There has been a report presented to the Australian Parliament House of Representatives on a pilot study of the effectiveness of treatment of these disorders, though due to constraints the various conditions which make up this field of Nutrient Therapy were not differentiated in the aggregated results . It is thus impossible to determine precisely what the effectiveness of Pyrrole Disorder treatment alone is, though an idea may be had from the overall results.
6. Ongoing research and treatment.
Today the most comprehensive clinical research on Pyrrole Disorder and the other associated conditions such as UM, OM, and copper overload is conducted by Dr William Walsh and his associates of the Walsh Research Institute in Illinois, USA. Physician training is also conducted in these treatment methods, and physicians all over the world have undertaken this for use in their practices.
Also involved are close associates Drs Albert Mensah and Judith Bowman of Mensah Medical. Many other physicians have received training in methods derived from the primary research though other channels at levels depending on their levels of qualification and how up-to-date and comprehensive the training institutions are. Of these others no assessment can be made by the author, not having had the experience of any of their care.
The author was tested, treated, and given a dramatic increase in well-being and productivity by a Medical Doctor (General Practitioner) who was trained by the Walsh Institute (WRI). This was done through Bio-Balance Health Australia, an Australian partner organisation of the WRI. Australians are lucky to have the highest number per capita of such trained physicians.
It is through this treatment that it may be possible to safely reduce or even cease the use of pharmaceutical medications such as was achieved in the author’s case. Of course, Pyrrole Disorder is seldom found alone but often in combination with the methylation and copper disorders as was also the case with the author. These will be discussed in other articles.
The people who are conducting the valuable clinical research are operating from public charities which are funded to a large extent from the fees charged to the physicians training with them. There are not enough resources to conduct the level of pure research required to extend the understanding of the mechanisms involved, or to conduct the required complex trials which would facilitate the acceptance of this paradigm back into the “mainstream” of Medicine from which it was ‘exiled’ in 1973. Interestingly, it seems that other researchers and academics are coming to the same conclusions perhaps even independently.
It basically comes down to funding which is desperately needed, the kind that can realistically be provided only by government or large businesses. There is ample evidence which points to the potential for successfully passing such trials if they are properly administered with the proper understanding and application of the painstakingly acquired clinical research theory over the years.
Wider pure research into the mechanisms involved will only facilitate this. It can only be hoped by the author that this will eventuate, as the potential cost benefits to Humanity from treatment, welfare, corrective, and social services savings as well as greater work productivity are immense if his own experience is anything to go by. Not to mention the potential reduction in the overall burden of misery.
7. Getting tested, and treated.
The author can only recommend the services of physicians who have had the same training as those whose care he has been under so successfully. This (and its related conditions) is a highly complex issue involving the widely differing biochemistries of individuals due to a combination of genetics and circumstances. There is no “one size fits all” approach to this which is ultimately effective, though there are basic rules.
In order to properly treat these conditions one must have a thorough understanding of Human physiology, nutrition, and biochemistry. In the closed Australian Facebook support group and the international one of which the author is a member there are many people attempting, through lack of funds or access, to treat themselves without the supervision of a physician with these attributes.
This is understandable as proper treatment requires adequate consultation times the remuneration of which are not covered by government funding due to lack of recognition. The same goes for testing, and treatment supplementation. As per the last paragraph of the previous section, there is hope this might change.
In that light here is presented a list of physicians trained by the Walsh Research Institute all over the world, though the majority of them are in the USA. In Australia specifically there is this list of those trained through Bio-Balance Health Australia. Many Medical Doctors and allied practitioners are also trained in this through the Australasian College of Nutritional and Environmental Medicine (ACNEM). It is the wish of the author that those suffering may find the same relief he has, and those wishing to learn more may find what they seek.
The author’s experience as well as a very short summary can be seen in this video: