Pyroluria: Hidden Cause of Schizophrenia, Bipolar, Depression, and Anxiety
Symptoms
by Woody McGinnis, M.D.
Orlando 21 May 2004
In the late 1950's a team of Canadian researchers lead by Abram Hoffer encountered an unusal
compound in the urine of schizophrenic patients. The compound produced a lilac-colored
(mauve) spot on paper chromatograms developed with Ehrlich's reagent. The qualitative assay
available at the time revealed the so-called 'Mauve Factor' in about 2/3 of recent-onset
schizophrenics, but not in controls. 100% of the schizophrenic subgroup which recovered on
high-dose niacinamide (vitamin B3) were found to have converted from Mauve-positive to
Mauve-negative. Relapses associated with discontinuation of niacinamide were associated with
reappearance of Mauve.
Through the 1960's Hoffer and others published clinical outcomes on hundreds of schizophrenics
and other high-Mauve diagnostic groups, such as "mentally retarded" and "disturbed" children
and criminals. In the early 1970's an American team lead by Carl Pfeiffer introduced a relatively
simple, quantitative colorimetric assay for urinary Mauve utilizing kryptopyrrole, which is
similar to Mauve, as standard. Pfeiffer demonstrated suppression of urinary Mauve and
commensurate clinical improvement with high-doses of vitamin B6 and zinc, which have
become the treatment of choice.
Originally, Mauve was identified erroneously as kryptopyrrole. 'Kryptopyrrole' is not accurate
terminology for Mauve. Technological advances in the 1970's allowed correct identification of
Mauve as OHHPL (hydroxyhemoppyrrolin-2-one). By synthesis (Irvine), GLC (Graham), and
HPLC/MS (Audhya), biological Mauve is OHHPL. It is a member of the pyrrole family, and
may be correctly referred to as "urinary pyrrole". Interchangeable use of 'Mauve' and 'OHHPL'
seem logical and efficient to this writer.
This compound is detectable in urine, blood and cerebrospinal fluid. It is heat- and lightsensitive, and requires ascorbate preservative if there is any delay in processing. Graham
demonstrated that adjustment to urinary creatinine concentration is not necessary. The Mauve
urine level is a useful predictor of higher vitamin B6 and zinc requirements, and may be used to
help titrate dosage levels in a wide range of behavioral and somatic problems associated with
high excretion. In Europe, especially, many clinicians use Mauve assay in the management of
strictly somatic health problems.
Higher Mauve levels are found in Down syndrome 70%, schizophrenia up to 70%, autism 50%,
ADHD 30%, and alcoholism up to 80%. One mixed group of general medical patients-arthiritis,
chronic fatigue, heart disease, hypertension, irritable bowel and migraine-had mauve elevations
in 43%. One-third of cancer patients--particularly lung cancer--are high-Mauve.
Certain signs and symptoms are more common in high-mauve patients. Pfeiffer reported more
nail spots, stretch marks, pale skin, knee pain, constipation, poor dream recall, morning nause,
light-sound-odor intolerance, migraines and upper abdominal pain. To this list Walsh adds low
stress tolerance, anxiety, pessimism, explosive anger and hyperactivity. Jaffe and Kruesi found
more social withdrawal, emotional lability, loss of appetite and fatiguability. Not all patients with
higher urinary Mauve have all or most of these symptoms.
In 1965, O'Reilly documented association of higher urinary Mauve with stress, and many
publications have confirmed this. An unpublished study by Tapan Audhya in 1992 demonstrated
a significant increase in urinary Mauve in healthy subjects after cold-water stress. Pfeiffer
introduced the practice of giving extra vitamin B6 and zinc-'stress-doses'-to buffer physical or
emotional stress in high-Mauve patients.
Pfeiffer also imprinted the field with the assertion that Mauve complexes with P5P--the active
form of vitamin B6--and zinc, with resultant deficiency of these two nutrients due to increased
urinary excretion. Existing data are insufficient to support or reject this proposed mechanism.
Our current data, pending publication, do establish a strong negative correlation between urinary
Mauve and zinc status, when Mauve is measured either by the colorimetric assay or by
HPLC/MS. A series of 1148 ADHD patients (Walsh) demonstrated a strong negative correlation
(0.974 significance by F test) between Mauve by colorimetric assay and plasma zinc
concentration. Mauve by colorimetric analysis in a mixed group of patients (McLaren-Howard)
demonstrated a strong negative correlation with white-cell zinc (correlation coefficient -0.743).
Also in mixed diagnoses, there was a very strong inverse correlation (coefficient -0.985) between
Mauve by HPLC/MS and red-cell zinc (Audhya). There is sufficient evidence to conclude that
Mauve is a good marker for zinc status.
Riordan and Jackson find that vitamin B6 (pyridoxine) levels are not lower in association with
urinary Mauve. Pfeiffer alluded to lower vitamin B6 function in high-Mauves, as reflected by
lower measured levels of P5P (activated vitamin B6) and EGOT activity. There is no published
data in this area. Suspected functional deficits in activation of vitamin B6 and / or binding by B6dependent enzymes will be discussed later in the context of oxidative stress.
OHHPL has not been studied exhaustively, but preliminary data are very interesting. In 1977,
Irvine demonstrated that OHHPL concentration in urine directly correlated with emotional
withdrawal, motor retardation, blocked affect and severe depression in schizophrenia. He also
demonstrated that intraperitoneal administration of OHHPL resulted in ptosis, locomotor
aberration, and hypothermia in rats. In 1990, Cutler and Graham reported increased backward
locomotion and head-twitching (as with psychotomimetics) in mice after intraperitoneal OHHPL
administration. Graham suggested that the chemical similarity of OHHPL to kainic acid and
pyroglutamate confer excitotoxic properties. This has not been investigated.
That seemingly disparate treatments-niacinamide on one hand, vitamin B6 and zinc on the otherdecrease Mauve and produce concommitant symptomatic improvement is thought-provoking. In
both humans and animals, an ample body of research demonstrates that emotional, nonphysically painful stress increases oxidative stress, measurable as actual oxidized biomolecules.
The behavioral and somatic disorders associated with higher urinary Mauve are also associated
with higher markers for oxidative stress. B6 and Zn and B3 are strongly anti-oxidant, which
strengthens the suggestion that Mauve is associated with oxidative stress.
Lower zinc, as found in higher-Mauve states, certainly is associated with oxidative stress. Zinc is
powerfully anti-oxidant, shielding sulfhydryl groups and protecting lipids from peroxidation.
Zinc induces metallothionein, a very important anti-oxidant protein, and is a constituent of
superoxide dismutase. Levels of vitamin A-a key antioxidant-are maintained by sufficient zinc.
Zinc deficiency results in lower glutathione, vitamin E, glutathione sulfotransferase (GST),
glutathione peroxidase and superoxide dismutase levels. Reactive oxygen species and lipid
peroxides increase in tissue, membranes and mitochondria in zinc deficiency.
Conceivably, poor zinc retention and higher zinc turnover may be a manifestation of oxidative
stress. It is well-demonstrated that oxidants release complexed zinc from zinc-binding proteins,
including metallothionen. Thus, it is suspected that the relationship between oxidative stress and
low zinc are reciprocal.
Vitamin B6 is strongly anti-oxidant. P5P is required for synthesis of glutathione,
metallothionein, CoQ10 and heme, all of which play very important anti-oxidant roles. With
zinc, P5P is required for glutamic acid decarboxylase (GAD), sufficient supplies of which block
excitotoxicity which would otherwise increase oxidative stress. P5P protects vulnerable enzyme
lysinyl groups from oxidation, as specifically in the case of glutathione peroxidase.
Even marginal B6 deficiency lowers glutathione peroxidase and glutathione reductase,
promoting mitochondrial decay and raising measurable lipid peroxide levels. Carbonyl-inhibition
of pyridoxal kinase, which produces P5P, is very strong. It is possible that higher levels of
carbonyls produced by oxidative injury to proteins may exert an inhibiting effect on B6
activation in states of oxidative stress. Besides pyridoxal kinase, the whole family of P5Pdependent enzymes suffer decreased binding in the face of carbonyl inhibition, and certain key
P5P-dependent enzymes such as GAD are impaired by oxidants generally.
Thus, there exist numerous ways by which impaired vitamin B6 function and oxidative stress
reciprocate. Hydroxyl radical and superoxide even attack vitamin B6 vitamers directly. High
doses of B6 may compensate
oxidatively-impaired enzyme and co-enzyme function in high-Mauve subjects.
B3 is strongly anti-oxidant. It is needed for the NADPH which is required for reduction of
glutathione. B3 is a potent free-radical quencher, protecting both lipids and proteins from
oxidation. It blocks nitric-oxide associated neurotoxicity. Normally, the body maintains
relatively high vitamin B3 tissue levels, which can serve a very important anti-oxidant function.
At usual physiologic concentrations, B3 exceeds the anti-oxidant effects of ascorbate in some
studies. Vitamin B3 antagonists increase lipoxidation. Low vitamin B3 decreases metallothionein
and increases apoptosis in brain cells. In experimental mitochondrial toxicity, B3 is
neuroprotective.
Oxidative stress, poor energetics, and excitoxicity are fundamentally inter-related. The three
conditions are both cause and effect one another. This concept helps us understand the possible
relationship of Mauve and oxidative stress, and specifically, a proposed mediating role of low
heme.
Regulatory and erythroid heme appear to exist in separate functional pools. The former is a
constituent or co-factor for many enzymes serving the anti-oxidant defense, prevention of
excitotoxicity, or energy production. These heme-requiring enzymes include: cystanthione
synthase, catalase, heme-hemopexin (translation of metallothionein), pyrrolase, guanylate
cyclase, the cytochromes, and sulfite reductase. Regulatory heme levels must be sufficient to
sustain zinc, vitamin A, and melatonin levels. Cell differentiation, response to growth factors and
resistance to viral infections depends on sufficient heme. Cellular heme levels are lowered by
toxins such as gasoline, benzene, arsenic and cadmium.
Graham demonstrated in animals that intraperitoneal OHHPL lowers microsomal heme levels by
42% within 48 hours of administration. (Cytochrome p450, which contains heme, was lowered
by 50%). If operative in humans at relevant concentrations, heme depression may be a major
toxic mechanism for Mauve, with important implications about zinc and oxidative stress. Ames
demonstrated that equivalent experimental heme suppression in cultured brain cells decreased
intracellular zinc by 50%. Ames further found increases in pro-oxidant iron, decreased
mitochondrial Complex IV (which requires heme), and significantly increased nitric oxide
production after experimental heme suppression of similar magnitude.
It is noted that heme synthesis depends on sufficient vitamin B6 and zinc. In addition, Durko
demonstrated in 1970 that oxidized kryptopyrrole, very similar to OHHPL, binds heme in vitro.
On the preceding bases, a first hypothesis: Mauve may be a significant contributer to oxidative
stress, so may be a good biomarker for oxidative stress.
Preliminary data from Austria (Lauda) demonstrate a modest negative correlation between red
cell glutathione and urinary Mauve by colorimetric assay. A significant inverse correlation exists
between GST and urinary Mauve by colorimetric assay, and pends publication (correlation
coefficient -0.65087, p<0.02). Audhya found very strong inverse correlation (coefficient -0.973)
between OHHPL by HPLC/MS and biotin concentration, also pending publication. It is observed
that biotinidase, which maintains biotin levels, is very sensitive to oxidative stress.
A second hypothesis: Mauve may be a product of oxidation tissue injury. In the case of highMauve schizophrenics, Bibus demonstrated significant depletion of red-cell membrane
arachidonic acid. It is well-established that oxidative attack on arachidonic acid forms
isolevuglandins, which attack protein lysinyl groups to form pyrrolic tissue adducts. These
pyrrolic adducts consistently autoxidize to take the hydroxylactam configuration as in Mauve.
Generation of OHHPL from the pyrrolic adduct would require oxidative scission and
decarboxylation of the pyrrolic side-chains. The latter steps are not without known biochemical
parallel, nor is disassociation and urinary excretion off the monopyrrole, as in hexane poisoing.
The Mauve Factor warrants greater usage by clinicians and more research. There is a need for
controlled therapeutic trials of existing treatments and potential new interventions, particularly
anti-oxidants. Suspected pro-oxidant and excitotoxic properties of OHHPL should be elucidated
in the laboratory. The origin and genetics of Mauve are considered important areas of inquiry.