Pyroluria, is it real? I'm really skeptical and here is why.

[Dominic Pukallus]

Thanks for all that, very cogent. Speaking of research, I recently found this statement on one of your Australian practitioner's websites, suggesting that recent researchers believe 40 is a more accurate test threshold (in which case at around 20 I don't have it at all, makes my head spin).

"Previously Australian labs reported any result >15 as elevated pyrroles. There has been a lot of research recently into benchmarking Pyrrole results and the new criteria (which I agree with based on clinic experience) is a positive result for Pyroluria is >40."
http://www.truefoodsnutrition.com.au/pyroluria-stress-disorder/

Thanks. I've had a lot of time (and increased capacity) since I got better to research and think about these issues we've been discussing, especially the theme of this thread. I was a big believer in drug-only interventions prior to my amazing improvement, now besides Nutrient Therapy I also see the power of psychotherapeutic, lifestyle, and nutritional treatments. I'd say it's because of the last two that the NT worked so well, and because of this the first one is now really bearing fruit.

I was going to caution on the need for you to seek treatment for this. In one of the articles I linked to in my own article I wrote when I got better there is the finding that as a marker of oxidative stress, HPL will be elevated in anyone who has some physical or even psychological stressor in their life. It's this stress which is now thought to be the cause of the zinc/B6-responsive bag of symptoms which are labeled "Pyrrole Disorder" (PD) and the highest levels are associated with the Mental Health/brain disorders which are the focus of the WRI. My own were above 40 initially.

It's quite possible your moderately high HPL levels are due to whatever else is also associated with the ME/CFS. Treating the PD may provide some relief but I think the best approach is to treat those root issues. It may all well turn out to be related to the lifestyle/nutrition/stress/toxicity/etc issues expressing themselves in ways as individual as the particular circumstances involved. I wish you the best of luck in that quest.

The cut-and-paste jobs are a phenomenon I observe a lot in the Alternative world of anything, due to poor understanding of the scant research which does exist. I find that happens among both proponents and detractors. It's why I wrote my article. https://sites.google.com/view/nutrient-power-group/faq/pyrrole-disorder-aka-pyroluria

 

[pspa123]

I hope it isn't TMI, but I do have tremendous ongoing stress from a severely disabled son, going on 30 years. I think even if I do have PD it's likely either an effect not a cause, or a relatively minor contributing factor, but that said I suppose it still makes sense to try the supplements which is my plan.

 

[pspa123]

I'm not surprised, she's not trained in this and has her own nutritional approach. I suppose all I can say is because people don't understand something it's not real. That's a very familiar story.
D

I meant to respond to this before but wanted to confirm my understanding of Walsh's theories first. Having read more by him, though not everything by any means, he definitely seems grounded in monoamine theories of depression which were in vogue in the 80s and 90s, but which have been exposed in recent years as more big pharma propaganda/metaphor than good science, and which prominent scientist after prominent scientist have disclaimed. There are countless books and articles about this. For example, according to Walsh, one type of depression results from serotonin not staying long enough in the synapses (I read this in conjunction with his theory that folate can be bad for depression because it promotes serotonin reuptake. Well, tianeptine is a serotonin reuptake enhancer that allegedly has a very good track record for depression, and is often cited as a reason the whole serotonin theory is wrong in the first place.). Count me skeptical. First of all, his degree is in engineering, not in anything relevant to brain chemistry and function, if I recall correctly. Second of all, how can ANYONE know what's actually going on in the synapses of a depressed person? We don't have the ability to measure that or look at it to the best of my knowledge. At best, it's a theory, not a fact. A good scientist would not state it as fact. Third, doesn't it seem awfully reductionist and simplistic to attribute a phenomenon as profoundly complex as someone's depression to the behavior of a single neurotransmitter in synapses? Yet that's what he does, see quote below. Frankly it seems ridiculous to me, not unlike those old Paxil commercials which in the rear view mirror seem like parodies when talking about so-called chemical imbalances in the brain. Finally, Walsh claims certain "sub-types" of depression respond very well to SSRIs, but there too researchers have called into serious question whether SSRIs work at all except by means of placebo effect. There is great material on Mad in America on that subject, among other places. Read e.g. David Healy, LaCasse and Leo, Kelly Brogan, Irving Kirsch, Joanna Moncrief.

Here's a good piece, by an alternative medicine guy who I find usually researches things pretty diligently, on the neurotransmitter imbalance myth.

https://chriskresser.com/the-chemical-imbalance-myth/

So all that said, I don't doubt that B6 and zinc are vital for numerous biological functions, or that correcting a deficiency can tremendously benefit people in a variety of ways including mental health. I do wonder, though, based on what I have read so far, about the explanations Walsh offers. They don't seem consistent with so much that I have read, and seem mired in 80s/90s pseudoscience.

Case in point, this from Walsh: "Undermethylated depression arises from low activity at serotonin receptors due to rapid re-absorption after serotonin is released into a synapse. This occurred in 38 percent of the patients studied and is not serotonin deficiency, but an inability to retain the serotonin in the synapse for a necessary amount of time." And he knows this how? Did he examine these people's brains? Obviously not. To the best of my knowledge we don't have the ability to examine neurotransmission at the synaptic level where billions of processes are going on simultaneously, so what he states as fact is at best theoretical speculation from a lab result.

 

[Dominic Pukallus]

I meant to respond to this before but wanted to confirm my understanding of Walsh's theories first. Having read more by him, though not everything by any means, he definitely seems grounded in monoamine theories of depression which were in vogue in the 80s and 90s, but which have been exposed in recent years as more big pharma propaganda/metaphor than good science, and which prominent scientist after prominent scientist have disclaimed. There are countless books and articles about this. For example, according to Walsh, one type of depression results from serotonin not staying long enough in the synapses (I read this in conjunction with his theory that folate can be bad for depression because it promotes serotonin reuptake. Well, tianeptine is a serotonin reuptake enhancer that allegedly has a very good track record for depression, and is often cited as a reason the whole serotonin theory is wrong in the first place.). Count me skeptical. First of all, his degree is in engineering, not in anything relevant to brain chemistry and function, if I recall correctly. Second of all, how can ANYONE know what's actually going on in the synapses of a depressed person? We don't have the ability to measure that or look at it to the best of my knowledge. At best, it's a theory, not a fact. A good scientist would not state it as fact. Third, doesn't it seem awfully reductionist and simplistic to attribute a phenomenon as profoundly complex as someone's depression to the behavior of a single neurotransmitter in synapses? Yet that's what he does, see quote below. Frankly it seems ridiculous to me, not unlike those old Paxil commercials which in the rear view mirror seem like parodies when talking about so-called chemical imbalances in the brain. Finally, Walsh claims certain "sub-types" of depression respond very well to SSRIs, but there too researchers have called into serious question whether SSRIs work at all except by means of placebo effect. There is great material on Mad in America on that subject, among other places. Read e.g. David Healy, LaCasse and Leo, Kelly Brogan, Irving Kirsch, Joanna Moncrief.

Here's a good piece, by an alternative medicine guy who I find usually researches things pretty diligently, on the neurotransmitter imbalance myth.

https://chriskresser.com/the-chemical-imbalance-myth/

So all that said, I don't doubt that B6 and zinc are vital for numerous biological functions, or that correcting a deficiency can tremendously benefit people in a variety of ways including mental health. I do wonder, though, based on what I have read so far, about the explanations Walsh offers. They don't seem consistent with so much that I have read, and seem mired in 80s/90s pseudoscience.

Case in point, this from Walsh: "Undermethylated depression arises from low activity at serotonin receptors due to rapid re-absorption after serotonin is released into a synapse. This occurred in 38 percent of the patients studied and is not serotonin deficiency, but an inability to retain the serotonin in the synapse for a necessary amount of time." And he knows this how? Did he examine these people's brains? Obviously not. To the best of my knowledge we don't have the ability to examine neurotransmission at the synaptic level where billions of processes are going on simultaneously, so what he states as fact is at best theoretical speculation from a lab result.

I'm really glad you've shown an interest in the work of Dr Walsh. Unfortunately, as the saying goes, a little knowledge can be a terrible thing. I really recommend reading the book he wrote on this which outlines the research and clinical outcomes from this which have led to the statements you have problems with. It is a bit dense, but hopefully this should lay some of these issues to rest. I'll keep it short because I really do think you should get it from the horse's mouth but my own observation that the monoamine hypothesis is a myth is in itself a hypothesis due to the fact the people who have relied upon it for medication research and marketing have had only the relative success you speak of. SSRIs have been shown to have greater effect in severe depression more so than in milder cases and these are the ones in which you would expect there to be some biochemical issue. The fact that some people react very badly to these is also accounted for by the different depression profiles relating to methylation. These are explained in the book. You could also watch his videos for a lite version.

Further to methylation, the success of niacins and folates, and deleterious effects of methionine, which Dr Hoffer observed initially in people with schizophrenia as it was diagnosed in the 1950s was not satisfactorily explained ever and constituted a stumbling block in adoption of his treatment methods. Later came refinements which distinguished from further clinical research the two depression/psychosis groups of under/overmethylation (UM/OM) or histadelia/histapenia which are opposite in their treatments and contraindications. The symptoms of UM are those of the negative symptoms of schizophrenia (catatonia, etc) while those of OM are the positive ones (hallucinations, etc). These are consistent with the dopamine effects which are posited for these illnesses which are really just umbrella terms for diverse biochemical conditions according to the Walsh/Pfeiffer/Hoffer paradigm.

It's really the methylation aspect which is key to the understanding of why the monoamine hypothesis may hold true, even if misunderstood as per my comment you quoted. There is a whole new field devoted to nutrigenomics as they pertain to SNPs on the methylation pathway enzymes which concords with this except in the key area of Mental Health/brain disorders which is the focus of the WRI. Depressed or psychotic people with UM diagnoses respond well to SAMe or its precursor methionine whereas similar DSM labeled people with OM diagnoses react very badly, akin to the heretofore unpredicatble SSRI response. SAMe is the major methyl donor to the methylation cycle and as such it was thought that this increased serotonin and dopamine levels, UM having too little and OMs having too much. There was the puzzle of the folate paradox however, as folates are generally methyl donors and they tend to make UMs worse when the opposite effect is observed.

With the advent of epigenetics came the answer: It really seems to be about DNA methylation markers on the reuptake proteins which are dominant in their effect. It really does come down to reuptake over production, as folates are seen to remove methyl markers from individual gene markers and histone tails and therefore promote the expression of these reuptake proteins and lower levels in the synapses. This is, of course, inference from observed clinical effects and current general research. I'm giving you as simple an explanation as I can as this is turning into a book in itself and there's already a much better one out there. This is why histadelia which is diagnosed from high levels of the indirect histamine marker is now known in Walsh terminology as undermethylation, and histapenia (low levels of histamine) is know as overmethylation or even more simply folate deficiency (folates are the main treatment). When dealing with the Lynch/Yasko paradigm the terminology can get tricky but this is resolved when one remembers this is in the separate domain of brain function and neurotransmitters.

I could give a bunch of links supporting this, but in my mind the best thing to do is to read the book. At least, restricting one's research to material available on the WRI sites or Mensah Medical (clinical arm) would give the best available knowledge on this in my view. Of course I have to say neurotransmitters are not everything, for instance Dr Walsh is preparing a book based on his understanding of the possible mechanisms of Bipolar which has resisted treatment so far. His presentation to the American Psychiatric Association recently outlined that it seems to be about oxidative stress (again) impairment of the glia regulating potassium and sodium levels in the extracellular fluid of the brain around the neurons, and the cyclical effect this has on their resting potential due to the resulting cyclical ion channel up-and down regulation. Fascinating stuff. Good luck in your research.

 

[pspa123]

I would settle for one link showing me anyone who has actually examined neurotransmitter activity in human brain synapses, as opposed to theorizing about it based on uncontrolled research. Respectfully, I have seen countless theories propounded on the internet, all backed up articulately by testimonials of the cured and the say-so of the people selling the treatments. Some are utterly implausible (not PD), but it's very hard to prove a negative or convince the choir that it could be wrong. Usually they answer as you just did -- by referring to the words of the charismatic leader (most niche modalities have a key figure such as Walsh, a maverick who defies the establishment and who alone has true insight), although something about that usually strikes me as circular. Actually I started Walsh's book a long time ago in another context (autism) and was put off by it but I don't remember why -- it may have been the biological reductionism, seeing so many complex human conditions solely as some imbalance or other at a biochemical level rather than thinking that the problems also might have something to do with people's actual lives and histories and behaviors and maladaptive thinking in some cases. Sure, PD pays lip service to trauma, but only in the sense that it increases oxidative stress, not in any meaningful sense of its effect on the mind, body and spirit. This is what I find so offensive about monoamine theories aside from the absence of any real scientific evidence -- the notion that we're all just the passive victims of some unseen chemical imbalance. BTW read Blame the Brain by the neuroscientist Dr. Elliot Vallenstein.

Rant over. As nobody else appears to be participating, I will stop and say that I am very appreciative of your responses and glad you have found success on this path. Since there's really no downside, I will give it a try myself, and maybe I'll be pleasantly surprised, but I will be taking a leap of faith against serious skepticism.

PS I hope you will keep your objectivity despite your personal success with Walsh. As the founder of the Science Based Medicine site -- one you probably wouldn't like, but just guessing -- likes to say, the most dangerous words in medicine are "in my experience."

 

[Dominic Pukallus]

I would settle for one link showing me anyone who has actually examined neurotransmitter activity in human brain synapses, as opposed to theorizing about it based on uncontrolled research. Respectfully, I have seen countless theories propounded on the internet, all backed up articulately by testimonials of the cured and the say-so of the people selling the treatments. Some are utterly implausible (not PD), but it's very hard to prove a negative or convince the choir that it could be wrong. Usually they answer as you just did -- by referring to the words of the charismatic leader (most niche modalities have a key figure such as Walsh, a maverick who defies the establishment and who alone has true insight), although something about that usually strikes me as circular. Actually I started Walsh's book a long time ago in another context (autism) and was put off by it but I don't remember why -- it may have been the biological reductionism, seeing so many complex human conditions solely as some imbalance or other at a biochemical level rather than thinking that the problems also might have something to do with people's actual lives and histories and behaviors and maladaptive thinking in some cases. Sure, PD pays lip service to trauma, but only in the sense that it increases oxidative stress, not in any meaningful sense of its effect on the mind, body and spirit. This is what I find so offensive about monoamine theories aside from the absence of any real scientific evidence -- the notion that we're all just the passive victims of some unseen chemical imbalance. BTW read Blame the Brain by the neuroscientist Dr. Elliot Vallenstein.

Rant over. As nobody else appears to be participating, I will stop and say that I am very appreciative of your responses and glad you have found success on this path. Since there's really no downside, I will give it a try myself, and maybe I'll be pleasantly surprised, but I will be taking a leap of faith against serious skepticism.

I was much the same as you in my skepticism but for different reasons, so I wish you luck in your leap of faith. This is only a pilot study and therefore with a very limited form of control, but it may give you an indication of what to expect. Of course, with moderately high levels of HPL as you have any benefit is likely to be of the lesser variety I imagine. www.aph.gov.au/Parliamentary_Business/Committees/House_of_representatives_Committees?url=ee/mentalhealth/subs/attach01.pdf

 

[pspa123]

Thanks, I will take a look at the link to the study later. BTW, for what it's worth I ordered the other Walsh tests because I was curious and the cost was not that great, and I was within the Walsh range but on the low end it for zinc, quite normal for copper, and just slightly above the Walsh range on histamine. So it seems that by his standards anyhow I probably have something worth treating but not off the charts major. I would like to know more about the Australian researchers who want to redraw the PD cutoff at 40, but can't find anything else on it.

Dominic, if I said anything that came across as personal it certainly was not intended that way. Much of my frustration stems from all sorts of failed alternative interventions for my son, and I will save my opinion of Amy Yasko for another day.

 

[pspa123]

Dominic if you're still there, I wanted to mention one other thing that is fueling my skepticism. As mentioned above, I test as slightly undermethylated according to Walsh (though normal according to lab reference ranges). But when I review the Walsh/Mensah symptom/trait lists, while I do have some that fall in the undermethylation category (and who doesn't, from the breadth of the list), my more problematic ones fall in the overmethylation category.

And while some symptoms are overlapping, some seem to be either specific to one category or other, and indeed some are binary in nature -- e.g. seasonal allergies or lack thereof, good or bad reactions to SSRIs, benzos and antihistamines. See http://www.mensahmedical.com/common-symptoms-of-overmethylation/ and http://www.mensahmedical.com/common-symptoms-of-undermethylation/ On most of those, my symptoms would classify me as overmethylated. I just don't know how to reconcile this with the legitimacy of the paradigm.

I wouldn't expect anyone to be a perfect fit, but on the other hand I wouldn't expect someone who is undermethylated to present symptomatically as classically overmethylated.

And talk about an absurdly sweeping generalization: "Most overmethylated persons in the general population tend to be very passionate individuals and often self sacrificing. These individuals may be attracted to professions or hobbies in music and the arts, theater, acting, social services or causes, and philosophy. Often, they may be viewed as underachievers, however, they are best characterized as individuals who march to the beat of their own drum."

Or this: "Many undermethylated persons in the general population tend to be high-achievers and have good mental health. These people tend to be our doctors, lawyers, educators, secretaries, corporate executives, professional athletes and scientists who strive for high career accomplishment. Common to each of these is the perfectionist tendency prompted by undermethylation."

I wish I hadn't read that, and from one of the gurus of this practice area, this is straight off the Mensah Medical site. I'm having a real hard time now taking this seriously. Methylation status determines who becomes a doctor or professional athlete or secretary or actress? For real? It's hard to imagine a more unscientific, ignorant claim.

 

[Dominic Pukallus]

Dominic if you're still there, I wanted to mention one other thing that is fueling my skepticism. As mentioned above, I test as slightly undermethylated according to Walsh (though normal according to lab reference ranges). But when I review the Walsh/Mensah symptom/trait lists, while I do have some that fall in the undermethylation category (and who doesn't, from the breadth of the list), my more problematic ones fall in the overmethylation category.

And while some symptoms are overlapping, some seem to be either specific to one category or other, and indeed some are binary in nature -- e.g. seasonal allergies or lack thereof, good or bad reactions to SSRIs, benzos and antihistamines. See http://www.mensahmedical.com/common-symptoms-of-overmethylation/ and http://www.mensahmedical.com/common-symptoms-of-undermethylation/ On most of those, my symptoms would classify me as overmethylated. I just don't know how to reconcile this with the legitimacy of the paradigm.

I wouldn't expect anyone to be a perfect fit, but on the other hand I wouldn't expect someone who is undermethylated to present symptomatically as classically overmethylated.

And talk about an absurdly sweeping generalization: "Most overmethylated persons in the general population tend to be very passionate individuals and often self sacrificing. These individuals may be attracted to professions or hobbies in music and the arts, theater, acting, social services or causes, and philosophy. Often, they may be viewed as underachievers, however, they are best characterized as individuals who march to the beat of their own drum."

Or this: "Many undermethylated persons in the general population tend to be high-achievers and have good mental health. These people tend to be our doctors, lawyers, educators, secretaries, corporate executives, professional athletes and scientists who strive for high career accomplishment. Common to each of these is the perfectionist tendency prompted by undermethylation."

I wish I hadn't read that, and from one of the gurus of this practice area, this is straight off the Mensah Medical site. I'm having a real hard time now taking this seriously. Methylation status determines who becomes a doctor or professional athlete or secretary or actress? For real? It's hard to imagine a more unscientific, ignorant claim.

I can see that you're still having trouble with the wording of these statements used by the WRI and associates, and their qualifiers. The words "tend to" get used a lot as the decades of clinical observations from which these remarks are derived are indeed broad generalisations and could only ever be such. When you remember the dopamine hypothesis as applied to this, and see UMs as being low in this and OMs as high then these tendencies make sense if you consider the reward pathways and their associated neurotransmitters. This is all I'll say on that, but there is a lot more and scratching below the surface will be very fruitful.

I was wanting to add something more about the dopamine hypothesis in this, and you gave me a pretty good opportunity for which I thank you. In my formal Psychology studies I came across other dopamine-related studies which relate to parkinsonism, as dopamine is also a factor in motor control. People who have impaired dopamine production exhibit similar negative symptoms (catatonic behaviour or affect) associated with severe UM depression and psychosis, while treatment with dopamine or L-dopa (the dopamine precursor) eventually caused them to swing into the same positive symptoms as shown in OM psychosis (hallucinations, etc). This eventually caused treatment to be discontinued in both cases, which isn't covered in the movie.

When you consider SSRIs there is also the surmising that methylation also affects serotonin as well as dopamine. Varying ratios of these two can be imagined to be the cause of a multitude of reactions, which is why OMs prescribed SSRIs have been observed to tend to a suicidal worsening of symptoms. These are pieces of a puzzle which when put together add up to more than just fanciful conjecture in my view, especially when considering the clinical results arising from this. It's always useful to remember that Human neurochemistry is mind-boggingly complex (pun intended), and we're still needing a lot of research in this. I wish it were possible at least to have these results confirmed by other researchers in more appropriate studies, if there were but the wherewithal.

I hope this helps.

 

[ChrisD]

I was diagnosed with Pyroluria a couple of years ago, and afterwards found benefit from supplementing Zinc and B6 in the evenings. I was also told not to have Omega 3 and to actually have more Omega 6 as Omega 3 can trigger Neuropsychiatric symptoms by some mechanism.

After experimenting on and off with Omega3 (3 months on, 3 off again and again) I think it is quite noticeable that my mind is more 'scatty' and 'jumpy' and more susceptible to lower mood etc. for which I have to mitigate for with other supplements. It's becoming quite noticeable now, especially with the stronger fish oils and Krill Oil.

 

[pamojja]

After experimenting on and off with Omega3 (3 months on, 3 off again and again) I think it is quite noticeable that my mind is more 'scatty' and 'jumpy' and more susceptible to lower mood etc. for which I have to mitigate for with other supplements.

You mind is more 'jumpy' while on Omega-3? What are the supplements to mitigate this effect in you?

 

[Lolo]

I tested high for pyroluria some years back. Being treated helped me a lot with anxiety, brain fog and being wired and tired.

 

[garyfritz]

Treated with B6 & zinc, or...?

 

[Lolo]

Treated with B6 & zinc, or...?

Yes B6 and zinc. I think the B6 is activated, can't remember right now.

 

[calexis6666]

B6 and zinc are recommended for diabetics, so I am pretty sure they get deficient due to insulin resistance. B6 is the #1 vitamin to improve sensitivity to insulin (as I have read in many sites for diabetics - haven't really looked up research papers on it).
EDITING to add references:
http://diabetes.diabetesjournals.org/content/38/7/881.abstract
http://www.ncbi.nlm.nih.gov/pubmed/19955400

So, what if I have a Sulfur Intolerance as well as the B deficiency and I cannot handle taking the active B6? I get headaches. How do I correct the Py?

 

[Gondwanaland]

I cannot handle taking the active B6? I get headaches.

In my personal experience this is due to B6 causing an increased need for B2.

 

[calexis6666]

In my personal experience this is due to B6 causing an increased need for B2.

So should I take B2 and B6 together?

 

[calexis6666]

I was diagnosed with Pyroluria a couple of years ago, and afterwards found benefit from supplementing Zinc and B6 in the evenings. I was also told not to have Omega 3 and to actually have more Omega 6 as Omega 3 can trigger Neuropsychiatric symptoms by some mechanism.

After experimenting on and off with Omega3 (3 months on, 3 off again and again) I think it is quite noticeable that my mind is more 'scatty' and 'jumpy' and more susceptible to lower mood etc. for which I have to mitigate for with other supplements. It's becoming quite noticeable now, especially with the stronger fish oils and Krill Oil.

I get terrible headaches after taking B6. I do have Pyroluria as well as CBS. How can I fix the deficiency if I can't take the B6? I may try small amounts...

 

[Gondwanaland]

So should I take B2 and B6 together?

That is what I do, and I only take them at bedtime because B2 makes me very sleepy. I suppose one can take B6 at daytime as long as they take B2 the night before.

 

[calexis6666]

I think I'll try that once I get the ammonia/sulfur out of the body. Thanks!