Gavin,
Here is my take and yu need to consider this possibility: SAMe scares me because it is just 1 step away from homocysteine. Homocysteine causes not only nerve damage but blood vessel damage, which could be a source of headache (and a source of blood pressure issues). I
personally would never take it. I take only the suppkements to generate SAMe naturally because I figure I should not generate it faster than I can clear it. So you clear it via p5p, and molybdenum, and also reduce it by (mfolate and mB12) and also by TMG. These are what I ssupplement. Well, I do not supplement molybdenum per se although it is often in multis I have taken. I was tested high in molybdenum via hair anaylsis. Molybdenum antagonizes copper absorption so care is needed all around.
A long Yasko quote but I think it addresses many issues we've hashed around and it supports the idea for SAMe even more.
''If an individual has the CBS up regulation (C699T), then they will break
down homocysteine more rapidly. This depletes intermediates in the
methionine cycle as well as making more products from homocysteine.
Homocysteine will be converted to cystathionine. This in turn goes to
produce cysteine plus alpha keto glutarate and AMMONIA. What happens next
depends in part on the level of cysteine. When there are higher doses of
cysteine the body will then convert these intermediates to taurine.
(Taurine can be broken down into AMMONIA by bacteria in the gut.) However
if there are lower amounts of cysteine the body will choose to make
glutathione. So, first of all, the amount of cysteine will help to
determine whether we make glutathione or taurine. (J. Nutr. 133:2697-2702,
September 2003). If we have the CBS C699T we will be creating higher
levels of cysteine (due to enhanced breakdown of homocysteine) so we will
almost always be generating taurine rather than glutathione. While the
temptation may be to add glutathione (due to low glutathione levels), this
can create problems. High levels of certain sulfur byproducts can cause
problems in the body. The CBS up regulation is generating so many sulfur
products that added glutathione may be a problem for these individuals. So
a sensitivity to sulfur products and sulfur containing antibiotics may
also be indicative of this mutation. Molybdenum is used to help to convert
the neurotoxic sulfite to sulfate. This reaction will be heavily taxed in
individuals with CBS C69T + + and so you will often see low levels of
molybdenum in spite of constant supplementation. So individuals with a
homozygous CBS C699T will often have no homocysteine, high levels of
taurine (without supplementation) and low levels of glutathione on a urine
amino acid test, as well as low levels of molybdenum on an essential
element urine test.
What may more be of greater importance is that ?when the need is for
energy, and not for cysteine, homocysteine produced is metabolized by
homocysteine desulfhydrase to alpha KG, NH3 and H2S.?(see series of
articles by Stipanuk, MH). Because we are dealing with mitochondrial
issues in most cases we are energy depleted. Methylation cycle mutations
will compound this energy problem as SAMe is used as a methyl donor for
carnitine and COQ 10, both important energy components of mitochondria.
Due to the enhanced conversion of homocysteine we are constantly depleting
intermediates of the methylation cycle. This includes SAMe (needed in this
case for carnitine and COQ10) as well as methionine. Both methionine and
SAMe are also useful for dealing with ammonia, however due to the CBS
C699T we are generating more ammonia and less methionine and SAME. The
more we supplement (which we need to do) the more ammonia we generate, a
true catch 22.
So AMMONIA is generated as a result of transulfuration when cystathionine
is converted to cysteine, from taurine as well as from alpha KG. Under
ideal conditions ammonia will be absorbed in reactions between glutamine,
glutamate and alpha KG. However, (see slides 113 to 116 from MTHFr, Metals
and Methylation ppt) aluminum interferes with glutamate dehydrogenase and
mercury interferes with glutamine synthase. This impairs the pathways that
are normally used for addressing ammonia. In addition, in some individuals
the GAD enzyme may be impaired as a result of viral infection and
methylation status (discussed in the autism book and in the Boston DVDs).
This will create a possible scenario where excess alpha keto glutarate is
being generated by breakdown of homocysteine but it cannot convert
properly to form ie GABA. However this excess alpha KG can combine with
the excess ammonia to form more glutamate. I have previously discussed at
length the relationship between glutamate, excitotoxins and nerve damage.
The ammonia problem can worsen with viral infection. So for an individual
with the homozygous CBS it is a real catch 22. We need the SAMe and
methionine (and Folapro and Intrinsic B12 for that matter) in order to
have methylation so that we can silence the virus and reduce the viral
load. However, every time we add anything that helps the cycle to flow
properly we end up generating more homocysteine, which flows directly to
make more ammonia and sulfur groups, and taurine. We need to address this
part of the cycle in order to get out of the catch 22 we are in. We are
currently evaluating RNAs that may be helpful to support healthy ammonia
levels.
Ammonia will be converted to urea via the urea cycle. This is an expensive
process from the standpoint of BH4 as it uses two molecules of BH4. So the
conversion of elevated levels of ammonia can quickly drain limited stores
of BH4. This can then impact the levels of serotonin and dopamine. I
believe that this is part of the reason why the combination of a CBS C699T
+ + with the A1298C homozygous mutation (which I believe impacts the
reverse reaction through the MTHFR to generate BH4) can have such a
devastating effect.
You are correct that arginine is a starting point in the urea cycle.
However, I do not believe that arginine is the rate limiting factor here.
I think that BH4 is the rate limiting factor in most cases. Arginine can
stimulate the growth of virus. This has been particularly well studied for
herpes virus. So adding additional arginine may lead to increased growth
of herpes virus and may not help the urea cycle if it is not the rate
limiting factor.
Arginine that is not used by the urea cycle can be used to make
creatinine. So if we can decrease the amount of ammonia that is generated.
Then we are using less BH4 and less arginine in the urea cycle. This will
free up BH4 for serotonin and dopamine. It will also free up arginine for
creatinine.
This is all lovely in theory, but what do we actually see in practice?
When we go to a low protein diet, we observe an increase in creatinine and
an increase in metal excretion. This would suggest that we may be on the
right track in addressing this problem. This is another reason to monitor
urines carefully as it may appear as if behaviors are deteriorating and
that a low protein diet is not working, when in fact this is a result of
increased creatinine and metal excretion. I suspect that some of the
behaviors that have been attributed to yeast (silly behavior following
food) may in fact be high ammonia levels generated as a result of CBS up
regulation. This imbalance in ammonia levels will most likely contribute
to gut imbalances and exacerbate yeast issues.
The good news is that the more we understand what is going on the easier
it is to address it. We are in the process of evaluating the benefits of
low protein diets, RNAs and the possible use of BH4 supplementation to
address these mutations. Each day we move a little bit closer to getting
the necessary answers to know how to address these issues.
With love and hope,
Dr. Amy"