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Folic acid, B12, and cancer risk

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by richvank, Nov 24, 2009.

  1. richvank

    richvank Senior Member

    Overdriving the methylation cycle, elevated sarcosine and prostate cancer

    Hi, all.

    I just learned something that I think I should pass on to you.

    As you know, I have expressed concern in the past about the possibility that high dosages of 5-methyl THF together with high dosages of methyl B12 could overdrive the methylation cycle in people with CFS.

    I have now received plasma amino acids test results from two people who have been on this type of protocol for some time (names withheld because of patient privacy rights), and this is the pattern they have both shown:

    1. MethionineHigh

    2. HomocystineBelow detection limit

    3. Methionine sulfoxide--Detectable to elevated

    3. SarcosineVery high

    4. Serine/Glycine ratio--Low

    5. CystathionineBelow detection limit

    6. TaurineLow-normal

    This is how I interpret this pattern:

    The high methionine level is unusual in CFS, as it is usually low. This suggests that it is being recycled rapidly from homocysteine, unless it is being supplemented.

    The undetectable homocystine, which is the oxidized form of homocysteine, suggests that homocysteine is also very low. This inference can be made because the presence of methionine sulfoxide gives evidence of a state of oxidative stress, which suggests that if homocysteine were present in significant amounts, homocystine would also be detected.

    The combination of inferred low homocysteine and high methionine suggests that the conversion of homocysteine to methionine is rapid, thus inferring that the methylation cycle is running faster than normal.

    The very high sarcosine confirms that the methylation cycle is running faster than normal. The formation of sarcosine from glycine by the enzyme glycine N-methyl transferase serves as sort of a pressure relief valve for the methyation cycle, dissipating methylation capacity by forming sarcosine when the ratio of S-adenosylmethionine to S-adenosylhomocysteine is tending to become too high.

    The low ratio of serine to glycine suggests that the serine hydroxymethyltransferase (SHMT) reaction is running faster than normal, which suggests that tetrahydrofolate is higher than normal, which in turn suggests that the methionine synthase reaction is running faster than normal.

    If the methionine synthase reaction is running faster than normal, the cystathionine beta synthase reaction would not be expected to be able to compete as well as normal for homocysteine, and thus the flow down the transsulfuration pathway would be expected to be lower than normal. Evidence that this true is the undetectable level of cystathionine.

    Additional support for low flow down the transsulfuration pathway comes from the low-normal level of taurine.

    What would be the consequences of overdriving the methylation cycle?

    I think that one would be that the sulfur metabolism, including cysteine, glutathione and taurine would not be able to recover as rapidly as they would if the methylation cycle was not running so fast. This could slow the overall recovery, I think. It would leave the person in a state of oxidative stress longer, and would slow the recovery of the detox system and the immune system, as well as maintaining the symptoms caused by low glutathione for a longer time.

    The other consequence is that sarcosine remains high in an effort to control the SAMe to SAH ratio, which is being pushed higher than normal. Does this matter?
    It looks as though it might, from a paper published last year, abstracted below (the full paper is available from PubMed, by entering the PMID number in their search box, and then clicking on the colored box at the upper right of the abstract page.) Note especially the paragraph that begins with the word "sarcosine":

    Nature. 2009 Feb 12;457(7231):910-4.
    Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.

    Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM.

    The Michigan Center for Translational Pathology, Ann Arbor, USA.

    Comment in:

    * Nature. 2009 Feb 12;457(7231):799-800.

    Multiple, complex molecular events characterize cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical biomarkers for cancer invasion and disease aggressiveness. Although gene and protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized prostate cancer and metastatic disease.

    Sarcosine, an N-methyl derivative of the amino acid glycine, was identified as a differential metabolite that was highly increased during prostate cancer progression to metastasis and can be detected non-invasively in urine. Sarcosine levels were also increased in invasive prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of glycine-N-methyl transferase, the enzyme that generates sarcosine from glycine, attenuated prostate cancer invasion. Addition of exogenous sarcosine or knockdown of the enzyme that leads to sarcosine degradation, sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells.

    Androgen receptor and the ERG gene fusion product coordinately regulate components of the sarcosine pathway. Here, by profiling the metabolomic alterations of prostate cancer progression, we reveal sarcosine as a potentially important metabolic intermediary of cancer cell invasion and aggressivity.

    PMID: 19212411 [PubMed - indexed for MEDLINE]

    I think this is something to be concerned about. In particular, I think it would be wise for any men who have been on this protocol for an extended time to have a digital rectal exam and a PSA test to check for prostate cancer. If prostate cancer is present, I think it would be wise to lower these dosages to allow sarcosine to come down.

    Beyond that, I continue to have doubts about the advisability of use of this high dosage protocol. If sarcosine stimulates prostate cancer, it might stimulate other types of cancer as well. I continue to believe that people should proceed more slowly with treatment, and should monitor the status of their methylation cycle by lab testing during the treatment, aiming to restore it to normal status, rather than to overdriven status.

    Best regards,

  2. aquariusgirl

    aquariusgirl Senior Member

    Taking a step back, might it be a good idea for everyone on this protocol or any protocol supplementing B12 and folic acid and/or the bioactive folates to periodically run blood plasma AAs?

    Also wondering what the symptoms or presentation is of an overdriven methylation cycle?
  3. Freddd

    Freddd Senior Member

    Salt Lake City
    Hi Rich,

    I would like to repost your recent post elsewhere for all interested parties to see as I have in the past. I do believe that it is vital that all these things get airing.

    This is of course of concern to me as it would to anybody. I do have a an annual prostate exam, due next month for the current one. In the past I have had a completely clean bill of health on this, nothing even ambiguous. The dose of mb12 I take has been very carefully arrived at by titration over a nearly 7 year period. The current dose size and frequency is the minimum dose needed to make progress at reversing the nerve damage going to my feet and arms. The dose size is the minimum needed on a daily basis to stop progressive neurological deterioration. It is very sensitive to anything including light exposure of mb12. The day I started it (7.5mg doses), I wasn't able to walk and that was progressing rapidly. If it hadn't cleared up I would have been in a wheelchair wearing diapers. I had been sufferring intermittant incontinance and episodes of drop foot and loss of motor control and sense of position of my leg for 5 years and getting worse. I have had a normal life restored to me. Let's be clear on the stakes that I am playing for

    In the context I am playing in CNS/CFS look like a small subset and an early stage of the problem. It gets much worse from there. I had problems back to 1 year old. I had FMS for 10 years before the CFS kicked in. I had CFS for 5 years before I started devloping signs of SACD. I had signs of SACD for 6 years before footdrop, incontinence and other things happened. I had those for 4 years before I started having visual deterioration.

    As far as other people go, I have outlined a titration path and criteria for determining if more would benefit them. That doesn't mean people read and follow that. My estimate is that perhaps 5% need to go above normal subligual doses. Anybody in a wheelchair or headed for one with urinary and fecal incontinance from these things benefits from these sizable doses.

    There is substantial evidence that some cancers are in fact caused by a deficiency of mb12 and flawed DNA replication. A number (at least half a dozen last I heard) of cancers including colon cancer is being investigated for just such contributing factors, and more are being added to that list.

    There is evidence mounting of the antitumor effects of methylcobalamin which don't necessarily reconcile with other research. Also, the effects of low CSF/CNS levels of cobalamins in CFS/FMS/Alzheimer's look like smoking guns to me. Now it may actually be that best effectiveness for that is actually 5mg (or whatever, that's what a study used) itrathecally twice a year or something like that rather than building a steep diffusion gradiant by upping serum levels is vastly superior.

    Patents exist for the idea of attaching a chemotherapy compound to the cobalt in place of the methyl or other groups to carry it into the heart of each cancer cell and then destructing it.

    Amounts in excess of 5mg sublingual tablet a day have only apparantly benefited me neurologically. Everything else cleared up on that plus 3mg adb12 once a week. The other cofactors though were critically important. Some people have a dramatic clearing of brainfog on 15mg a day of adb12. My optimum appears to be 18mg of adb12 once a week timed for joining the mb12 injection in the diffusion gradiant.

    A problem for presenting any kind of information is that it gets twisted out of shape very quickly. As mb12 has been available for 12 years commercially in the USA and elsewhere if it has some side effects as suggested by this article that might be long enough for these things to start turning up. The beauty of the internet is that it allows a person to extract information being done in millions of individual parallel experiments.

    I have been on the side of moderation and balance, using the minimum that has the necessary beneficial effects. I have partially designed but not yet written software for tracking the changes and effects of all symptoms and problems across a lifetime and dozens of substances including vitamins, drugs and so on, all at the same time, designed to integrate all of the information across potentially millions of people in a distributed processing environment and extracting unique, common and everything in between patterns. I believe that with this that it might be possible to predict who would develop CFS/FMS etc as an adult from childhood history. The patterns are there. My problem is not the design, but that while I was out of the software business and disabled, 100% of the tools have gone through 3 rapid generations of evolution. In 1986 I was writting leading edge articles on leading edge software tools and helping invent object oriented progamming and analysis. Now I'm having to learn how to do displays all over again and am just another beginner in many ways. I have a 20 year hole in my memory. My main project became solving my own problem that was taking my life and mind away while I still had the abilities to do so. I was running out of time as I could hardly read or type any more on the day I decided to take mb12. I had near constant sensory hallucinations of all varieties as my neurology was breaking down. The environment got very noisy you might say.

    The specifics of the biochemistry are very important. I'm going for solving the overall of it with millions of details to be filled in. It's a non statistical basis. Statistics homoginize the pattern details into non existance. Statistical medicine was killing me. I will start searcing for the patterns involving prostate cancer and mb12 and see what I can find.

    We all have to make choices. If a high dose active b12 therapy can give me 30 years of high quality life I would never have had otherwise, bringing me out of a literal hell, and then I get a cancer I might have gotton anyway (what percentage of men die with prostate cancer present?) believe me it is well worth it. I would have spent my last years in a wheelchair in diapers, unable to read and a deteriorating mind, starting a few years ago. All my systems were breaking down. It was highly unlkiely that I would have ever survived to get and maybe die from prostate or any other cancer. Undoubtably mb12 saving lives will mean more people die of other things. That is part of the statistical fallacy. You squeeze out death one place and it pops up somewhere else. In the meantine it has given me 5 years of quality life with possibly decades more to come. Choosing to stay sick to avoid possibly dying of something else possibly decades in the future is a choice we make every day. How many of you avoid charcoal grilled meat or frenchfries or baked breads with crispy crusts or a load of other things known to cause cancer, or heart disease or something. Keep perspective. You pays your money and makes your choices. And 100% of it is fatal. Nobody gets out of this life alive. Driving your car is probably the most dangerous thing most people do and changing a lightbulb in a ceiling fixture may be number two. And taking a walk in sunlight without sunblock. Now there is a known hazard. Keep a perspective.

    And as the time traveler Ferdinan Feghoot said to his son at the cannibal's feast "One man's meat is another man's poi, son"
  4. dannybex

    dannybex Senior Member

    Rich...are you talking about the dosages used in Freddd's protocol, or the Simplified protocol...or both?

    I'm overdue for a prostate exam...doc put if off last year because of other problems, but mainly because my psa was so low. Since then I've read that the psa test may not be so accurate...

    thanks in advance,

  5. richvank

    richvank Senior Member

    Hi, freddd.

    Thanks for the response. Yes, please feel free to repost my message.

    Best regards,

  6. MNC

    MNC Senior Member

    I've been taking Folic Acid and B12 supplements for 8 months. Should I stop them then? I was low in some tests last summer and didn't stop the supplements since then.
  7. Freddd

    Freddd Senior Member

    Salt Lake City
    Hi MNC,

    There would be no reason to think that you should stop folic acid and b12 though you might find it far more effective to take methylb12 and adenosylb12 in the best perfomring brands and Metafolin (methylfolate) as these are many times more effective. The theroretical consequenecs of somebody taking multiple methylators at very high doses over a long period of time don't even begin to apply to you. However, inactive folic acid can cause other problems themselves and the hycbl or cycbl lack genertal effectiveness and are not methylators in their inactive forms and can only become so by taking methy groups from other substances. YOu might want to come over and discuss that at

    First you need to correct the deficiencies and heal all the many symptoms that they cause. Then after healing one might want to look into the balnce of what what is doing, which doesn't mean stopping the very thing that you have a tested deficiency of. That doesn't make sense. For instance in my situation, now 99% healed of everything except of the most severe b12 deficiency damage, I am reviewing the possibly unneeded methylators of my program. I certainly wouldn't stop anything that that is needed to keep me out of a wheelchair or otherwise impair my health. Chances are you will need b12 for life in most cases.
  8. MNC

    MNC Senior Member

    Thank you very much. I am taking daily 1.000 mcg of Methylcobalamine (Now foods brand) and 5 mg of Folic Acid (I don't know what chemical type) and 200 mg of Sam-e (Doctor's Best brand). I am not taking it for methylation therapy or anything. I was just told by the doctor because last summer I had tests showing defficiency along with high liver transaminases, cholesterol, triglycerids, etc. I think I'll stop them anyway, I don't feel any difference and I'm taking it just because I take lots of vitamins and supplements because I eat very poorly.
  9. Freddd

    Freddd Senior Member

    Salt Lake City
    Hi MMC,

    There is only one problem with what you tried taking. It very possibly didn't do anything becaUSe of the brand and type.

    In tests done my 5 hypersensitives, the NOW foods brand methylb12 was 1 - 1.5 stars on the revised ratings. Jarrow and Enzymatic Therapy are both 5 star, much much much more effective. They need to be left for 45-120 minutes to achieve 15-25% absorbtion, as tested against injections. Chewed and swallowed all sublinguals reduce to about 1%, same as oral. Another problem, if the form you actually need is adenosylb12 (Dibencozide) and can't interconvert adequately, the best mb12 in the world wouldn't do much. Adb12 and mb12 do different things. Another problem is folic acid. Abpout 20% can't convert folic acid to an active form. Metafolin, methylfolate , is already active. About 50% can't convert adequate amounts of floic acid. And 100% are linited to a small amount which may be less than you need, about 800mcg.

    At 5mg Metafolin delivers an average of 7 times as much active folate to blood as does 5mg of folic acid. ALso, taking Metafolin with Jarrow or Enzymatic Therapy mb12 may make the active b12s 25-300%, more effective.

    And just so you know what symptoms might be casued by low actove b12s and active folate here is an international list of symptoms, signs and co-correlates of these deficiencies.

    Version 1.0, 07/13/09

    mouth sensitive to hot and cold
    sore burning tongue
    beef-red tongue, possibly smoother than normal
    sore mouth, no infection or apparant reason
    teeth sensitive to hot and cold
    canker sores
    burning bladder (no UTI)
    painful urgency (no UTI)
    burning urethra (no UTI)
    burning muscle pain
    accumulating muscle pains following exertion
    sore muscles
    lack of muscle recovery after exercise
    exercise does not build muscle
    extremely sore neck muscles reversing normal curvature of neck
    exercise deblitates for up to a week, making things much worse
    painfully tight muscles, especially legs and/or arms
    frequent muscle spasms anywhere in body
    muscle pain especially around attachment points to bones
    Eighteen severely tender muscle spots of FMS
    dyspepsia - sick stomach, nausea, regurgitation, vomiting, bloating, not emptying
    altered bowel habits
    abdominal pain
    loss of appetite for meat, fish, eggs, dairy, the only b12 contining foods, nutrient specific anorexia
    intermittent constipation
    intermittant diarrhea
    irritable bowel syndrome
    Crohns disease (direction of causality if any not established)
    Celiac disease (direction of causality if any not established) - gluten sensitivity
    Dairy sensitivity
    sores, ulcers and lesions along entire GI tract or any part
    reduced libido - loss of sexual desire
    loss of orgasmic intensity
    unsatisfying orgasms
    inability to orgasm
    loss and/or change of genital sensations - "gloved" loss of sensation
    burning genital skin sensation
    unable to become aroused
    reduced testosterone

    erectile disfunction
    low sperm count
    poor sperm motility
    Poor sperm quality
    Zero sperm count

    post partum depression
    post partum psychosis
    False positive pap smears, noncancerous cellular changes
    menstrual symptoms
    Frequent miscarriage
    child with neuro tube defects

    rapid heart rate
    heart arythymias
    shortness of breath
    heart palpitations
    weak pulse
    congestive heart failure
    Widespread pain throughout body
    Hypothyroid (direction of causality if any not established)
    High homocysteine
    High urinary MMA

    dizziness - even unable to walk

    SAD - Seasonal Affective Disorder
    mental slowing
    personality changes
    chronic malaise
    poor concentration
    mood swings
    memory loss
    impaired connection to others
    mentally fuzzy, foggy, brainfog
    psychosis, including many of the most florid psychosis seen in literature, megoblastic madness
    strange "smells" that are not present like linen being ironed, burnt odors or tidal flats etc
    strange "sounds" that are not present, rustlings, mummurings, detonations etc
    deja vu experiences
    anxiety or tension
    impaired executive function
    cognitive impairment
    memory impairment
    Hypersensitivity to touch
    Hypersensitivity to odors
    Hypersensitivity to tastes
    Hypersensitivity to clothing texture
    Hypersensitivity to chemicals
    Hypersensitivity to body malfunctions, symtoms
    Hypersensitivity to sounds and noises
    Hypersensitivity to light and visual stimuli
    Hypersensitivity to blood sugar changes
    Hypersensitivity to internal metabolic changes
    Hypersensitivity to temperature changes
    Hypersensitivity to foods
    mild to extremely severe fatigue
    continuous extremely severe fatigue
    easy fatiguability
    severe abnormal fatigue up to and including apparent paralysis leading to death
    spastic paralysis

    sleep disorders
    non restorative sleep
    lack of dreaming
    Night terrors
    Prolonged hypnogogic state transitioning to sleep
    Sleep paralysis
    alteration of touch all over body, normal touch can be unpleasant and painful
    alterations and loss of taste
    alterations and loss of smell
    loss of smell and taste of strawberries specifically
    loss or alteration of smell and taste of potato chips specifically
    roughening and increased raspiness of voice, mb12 can smooth it outin mid word
    blurring of vision - can be sudden onset and sudden return
    dimmed vision - usually not noticed going into it because change can be very slow or present for life
    Visual impairment can be seen; ophthalmological exam may show bilateral visual loss
    optic atrophy
    optic neuritis
    optic neuropathy
    centrocecal scotomata
    intolerance to bright light
    diminished hearing - gradual onset or present for life, sudden return possible
    unclear hearing, garbled
    tinnitus - ringing in ears
    always feeling cold
    intolerance to loud sounds
    intolerance to multiple sounds
    inability to pick pick out one voice amongst many
    Brainstem or cerebellar signs or even reversible (with mb12) coma may occur
    neural tube defect not caused by folate deficiency or child with it
    demyelinated areas on nerves
    subacute combined degeneration
    axonial degeneration of spinal cord
    unsteadiness of gait
    ataxic gait, particularly in dark
    positive Romberg
    positive Lhermittes
    neuropathies, many types
    progressive bilateral neuropathies
    demyelination of nerves - white spots on nerves on MRIs
    loss of detail and sensual aspects of touch all over body
    paresthesias in both feet - burning, tingling,cobwebs, wet, hairs, pain, numbness, etc
    paresthesias in both legs - burning, tingling, cobwebs, wet, hair, pain, numbness, etc
    paresthesias in both hands - burning, tingling, cobwebs, wet, hairs, pain, numbness, etc
    paresthesias in both arms - burning, tingling, cobwebs, wet, hairs, pain, numbness, etc
    Loss of position sense is the most common abnormality (or vibration sense)
    Loss of vibration sense is the most common abnormality (or position sense)
    Loss of sense of joint position
    hands feel gloved with loss of sensitivity
    feet feel socked by loss of sensitivity
    neuropathic bladder
    unable to release bladder, mild to severe
    urinary incontenance - occasionally to frequently
    fecal incontinance - occasionally to frequently
    sudden electric like shocks/pains shooting down arms, body, legs shooting down from neck movement
    standing with eyes closed, a slight nudge or bump causes loss of balance
    most patients have signs of both spinal cord and peripheral nerve involvement
    The effect on reflexes is quite variable
    Motor impairment may range from only mild clumsiness to a spastic paraplegia
    slowed nerve impulses
    decreased reflexes
    difficulty swallowing
    brisk reflexes
    decreased deep tendon reflex
    toes turn up instead of down in reflex to sole stimulation
    Positive bilateral Babinski reflex
    Foot Drop
    impaired white blood cell response
    poor resistance to infections
    easy bruising
    pronounced anemia
    macrocytic anemia
    megablastic anemia
    pernicious anemia
    decreased blood clotting
    low hematocrit
    MCV > 92-94 first warning, MCV > 97-100 alert
    elevated MCH (Mean Corpuscular Hemoglobin)
    elevated LDH
    big fat red cells (when said this way usually with happy or healthy modifying it completely misinterpreting results of MCV
    platelet dysfunction, low count
    white cell changes, low count
    hypersegmented neutrophils
    migraine headache cycles
    inflamed epithelial tissues - mucous membranes, skin, GI, vaginal, lungs, bladder
    inflamed endothelial tissues - lining of veins and arteries, etc
    high CRP without infection
    mucous becomes thick, jellied and sticky
    dermatitis herpetiformis, chronic intensely burning itching rash
    frequent infected follicles
    Seborrheic dermatitis
    skin on face, hands, feet, turns brown or yellow if anemia occurs
    poor hair condition
    thin nails
    transverse ridges on nails, can happen as healing starts
    splits/sores at corners of mouth
    Hyperhidrosis - excessive sweating
    Bariatric surgery
    glutathione, glutathione producing supplements such as NAC/glutamine
    tegretol and some other medications
    Relatives, grandparant, parent, sibling, child, grandchild ever needing b12 shots or supplement
    brain atrophy with ileal tuberculosis preventing b12 absorbtion

    delayed myelination
    failure to thrive
    delayed speech
    frequent or continuous toncilitis
    frequent strep
    frequent pneumonia
    frequent longlasting supposed viral illnesses that linger and linger and linger
    everything goes to the lungs for extended periods
    growing pains
    skin problems
    continuous swolen glands in neck
    low grade fever for years
    Night terrors
    Prolonged hypnogogic state transitioning to sleep
    Sleep paralysis

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