Tuesday, 29 December 2015

Matjaz's cocktail - grade 2 Oligodendroglioma

Hello all!

Ok, so here is my cocktail and a little backstory:

because of mild headaches at back of the head/in the neck that started in February 2015 I was sent to MRI (neurologist was suspecting some kind of vertebrae deformation) in May 2015. It unexpectedly showed tumor in right temporal lobe (premotor cortex, some of it in insula) - while I was waiting to get the MRI the headaches went away, so it was kinda incindental discovery.

Underwent awake surgery with 100% resection with small safety margin of healthy tissue around the tumor. Tumor volume around 8,5 cm^3, pathology showed "grade 2 oligodendroglioma, IDH mutated, cells do not express GFAP , Neu N, internexin a and p53. The expression of ATRX is retained. Absence of overexpression of cMet . The Ki67 proliferation index is estimated at 1%. 1p/19q codeletion and no EGFR overexpression"

Surgery and following MRIs:

1st December 2015 - Complete Resection which is also confirmed with MRI ~30 hours after surgery
March 2016 - Clear MRI, small area of scar tissue
September 2016 - No change

My cocktail (for long term maintenance) at the moment is:

5x 600mg Mushroom Science Coriolus Super Strength
1x 4,5mg LDN
1x 5000 IU Vitamin D3
2x 850mg Metformin

4x 500mg Nutrivene Longvida Curcumin
2x 1000mg Super Omega 3

1x 200 mcg Selenium
1x 10mg Melatonin
17 mg/kg/day DCA (discontinued for 6 months or so because of  neurotoxicity - on Visual Evoked Potentials exam there was significantly lower nerve conductivity as should be, probably because of ~9 months DCA administration).

The post is updated regularly after every MRI (every 6 months for now). Also I am verry happy to receive any suggestions or answer any questions!

Best regards,


  1. Hi Matjaz,

    My understanding is that with a supratotal resection of a grade 2 oligodendroglioma, you have a significant chance of not having to worry about this for a very long time (if ever). For example, Dr. Berger from UCSF said "We did a study on low-grade gliomas and found that if post-operative imaging shows that we were successful in completely removing the tumor, we can now achieve nearly a 100 percent ten-year survival." [1]

    Of course, being prudent shouldn't hurt. But I would be extra careful about unnecessary sideeffects (as with THC/CBD).

    Did the pathology say anything about 1p/19q codeletion?

    [1] https://www.ucsfhealth.org/doctors_and_clinics/features/berger_mitchel/

  2. Hello marian,

    first of all thank you got your input and sorry for the late reply.
    It didn't say anything about 1p/19q, I will ask my doctor in a week on my control MRI.
    I am trying a lot of non-toxic supplements, that aren't likely to contribute to tumor resistance or hypermutation in future.
    If you mean dizziness, sleepiness as unnecessary sideeffects for THC/CBD I didn't have any when I was trying with THC/CBD oil as suppository

  3. Just got official results from my March 2017 (15 months post-op) MRI. Everything stable. There was a small area (few mm big) of hyperintense FLAIR on 9 months post-op MRI, which wasn't there before - but since it didn't change, it was concluded that it is most likely a post operative gliosis (scar tissue).

    1. Stable is good! I hope that is indeed just scar tissue.

    2. Didn't see the reply until now. Yes, I hope so too - it was concluded that it is scar tissue by 2 seperate radiologists (not just according to stable size, but some other stuff (can't remember the words :)) & I assumed if it was glioma regrowth the increase in size would be somewhat linear in that 6 month time window rather than absent.

      Anyway, I have another question if anyone has opinion on it. About 9 months or so ago I stopped taking DCA after ~ 6 months of use. Reason were hand tremors and VEP (visual evoked potential) exam, which showed abnormally lower amplitude of signal in my visual pathway (I guess goes under peripheral neuropathy). After stopping DCA everything came back to normal.

      Since I still have about 200 grams of DCA left in the freezer and it expires in 6 months, I was wondering if I would give it a go one more time.

      I read a few studies and I really can't decide. On one hand there are studies which show inhibited IDH1 mutated glioma cell proliferation; some show no effect in lower grade tumors; again others say you might even make it worse, depending on schedule and dosage. There is also the fact that I take metformin, which is known to cause increase in lactate and DCA was/is used to lower it.

      Maybe someone has a suggestion or an opinion on this matter? THANK YOU!

    3. My views on DCA for IDH-mutant lower grade gliomas has wavered over the years, but the most recent evidence suggests it might not be particularly useful for these tumors.

      As one piece of evidence, lactate dehydrogenase A (LDHA) is profoundly downregulated (through promoter hypermethylation) in IDH mutant tumors compared to non-mutant. This is the enzyme that converts pyruvate to lactate and leads to the buildup of lactate in tumors such as glioblastoma.

      In line with this, there was no elevation of lactate detected in experimental IDH1-mutant tumors in mice.

      Hyperpolarized 13C MR imaging detects no lactate production in mutant IDH1 gliomas: Implications for diagnosis and response monitoring

      Another recent study analyzed mRNA expression of various genes in low grade IDH-mutant gliomas versus GBM and found that IDH-mutant tumors follow rather different metabolic pathways, converting lactate to pyruvate and using the pyruvate to support the citric acid cycle, unlike GBM which shows a typical Warburg effect.

      "In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma"

      All of this evidence is suggesting that DCA, which channels pyruvate into the mitochondria and the citric acid cycle and prevents its conversion into lactate is probably much less useful for IDH-mutant gliomas than it might be for GBM. There was one study showing DCA did inhibit IDH1-mutant neurosphere proliferation in vitro, but the concentration of DCA used in that study (10 millimolar) is at least 10 times higher than achievable levels in blood plasma.

      While I do support the use of metformin, I believe the benefits are mainly indirect (effects in circulating glucose/insulin, perhaps immune effects) rather than direct effects on tumor cells in the brain. The primary site of action of metformin is likely the liver.

      With the current evidence, I wouldn't put DCA on a cocktail list for lower grade IDH1-mutant gliomas, especially with your history of side-effects on DCA. I would of course change my views based on any future evidence to the contrary.

    4. Thank you for the answer Stephen. I did see the above studies (or rather studies' discussions) and it is even more confusing :)

      For example the "In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma" concludes that DCA is viable option for IDH wild type glioma and certainly not for IDH mutated.

      Then there are studies which showed decreased PDH in IDH1 mutated cells - for example


      And if I understand correctly these studies suggest DCA is viable option for IDH mutated, since PDH is downregulated?

    5. The study above, done at UCSF, used normal human astrocytes engineered to be IDH1-mutant, and gene expression was compared to normal human astrocytes without IDH1 mutation. Studies like this can't always replicate what happens in spontaneous human IDH1-mutant tumors though.

      For example, in the engineered cell lines: "Both
      PDK1 and PDK3 showed significant, high magnitude increases in
      transcript expression in IDHmut cells compared to IDHwt."

      But in actual human tumors: "The lower grade glioma results with
      regard to PDK expression were less consistent with the cells
      findings. PDK1 and PDK3 expression levels were down..."

      The human tumor data tells us that LDHA (which converts pyruvate to lactate) tends to be actively suppressed in IDH1-mutant gliomas, and is at even lower expression levels than normal human brain. The other pathways for pyruvate is to get converted to acetyl-coenzyme A by PDH complex, or to oxaloacetate by pyruvate carboxylase. Both of these pathways feed the citric acid cycle in the mitochondria.

      The bulk of the evidence is telling us that unlike GBM cells which want tend to convert pyruvate to lactate, IDH-mutant gliomas do the opposite, converting lactate to pyruvate, which along with glucose-derived pyruvate gets fed into the early stages of the citric acid cycle in the mitochondria.

      Personally I think "In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate
      anaplerosis in IDH1-mutated glioma" gives the best insights into the unique metabolism in IDH1-mutant cells, and is based on expression profiles of actual human tumors, not engineered cell lines.

    6. The "In silico..." paper shows that members of the PDH complex PDHB and PDHX are significantly higher in IDHmut low grade gliomas compared to IDH wild type low grade gliomas. Also, average expression of PDK1 and PDK3 is lower in IDH1-mut low grade gliomas versus wild-type. (PDKs are the actual molecular target of DCA).

    7. I did some more research on IDH1 mutated gliomas. As it was mentioned in this "in silico" paper: "our data predict that inhibitors of glycolysis, such as HK2/3 and PKM2 may be the most promising for IDH1WT glioma, whereas inhibitors of the TCA cycle and the glutamatolysis pathway such as metformin, chloroquine and eEGCG may possess a therapeutic index in IDH1MUT glioma."

      I looked into EGCG and there are quiet a few studies on EGCG inhibition of GDH / intracellular α-KG level.

      Glutamate dehydrogenase (GDH) regulates bioenergetics and redox homeostasis in human glioma.

      Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1

      Anyone looked into it before? I think we didn't mention EGCG for IDH1mut specifically in the past

    8. I have seen the studies leading to the suggestions of EGCG, metformin, and chloroquine for IDHmut glioma. These studies were all in vitro studies using unrealistic drug concentrations (as usual).

      1) In the Seltzer, Riggins et al. study from 2010, EGCG very modestly reduced proliferation of D54 (GBM) cells with an inducible IDH1 mutation, at 25 micromolar. A more impressive effect was observed at 50 micromolar. Both of these concentrations are unrealistic, especially in the central nervous system. After a single oral dose of 800 mg EGCG about 1 micromolar can be found in the plasma, but only a small fraction of this likely penetrates the central nervous system, as no EGCG was detected in the cerebrospinal fluid after consumption of green tea containing 206 micromoles (94 mg) of EGCG.

      http://cancerres.aacrjournals.org/content/canres/suppl/2010/11/01/0008-5472.CAN-10-1666.DC1/sfi_g6.pdf (Supplementary Figure 6 from Riggins Study)

      Do flavan-3-ols from green tea reach the human brain?

      In fact, the same group (Riggins et al.) from Johns Hopkins abandoned this approach and decided to focus on hypomethylating agents (5-azacytidine) for IDHmut gliomas instead. Greg Riggins himself told me "Yes I do think IDH1 mutations create a alteration in glutamate metabolism and we investigated this from one important aspect 4 years ago. The difficulty has been translating the therapeutic targets in this pathway into a useful therapy. The compounds we tried did not work in vivo, despite the in vitro predictions."

      Chloroquine may be a glutamate dehydrogenase inhibitor in vitro, but again unrealistically high concentrations are required for enzyme inhibition in the lab conditions: the chloroquine IC50 for GLUD1 is 50 micromolar and 140 micromolar for GLUD2. Compare that with steady-state plasma levels around 1 micromolar after 4 months on the standard dosing in humans. It's true that chloroquine is lipophilic and could accumulate in brain tissue to a higher concentration than found in blood, though it's important to remember it's not total tissue concentration of a drug that is active, but in general the unbound fraction (the "free drug hypothesis")

      Likewise for metformin. Yes metformin impairs IDHmut cell proliferation to a marginal degree at 100 micromolar and profoundly at 1 millimolar but these concentrations are 10x and 100x higher than maximum concentrations of metformin in plasma with standard diabetic doses (ie 10 micromolar, and metformin concentrations in rat frontal cortex are also in that same range after oral dosing).

      I would be much more impressed with EGCG, chloroquine, and metformin as glutamate dehydrogenase or IDH-mutant specific inhibitors if these effects were observable at the clinically achievable concentrations, or if these observations translated to in vivo work. However, all of these agents have multiple mechanisms of action and my comments aren't meant as an argument against their use.

  4. Hi Matjaz,

    Your cocktail looks similar to mine, minus a few supps that I've taken that are more related to chemo.

    A couple questions though.

    1) Have you done any testing with Metformin to see its affect on blood glucose and if so what did you find? I've done some trials with keto diet using a glucose/ketone meter and using metformin was not able to see it cause any notable change in glucose, whereas specific foods for me really triggered swings and forced me to do a very limited choice of foods. One caveat though is I bought metformin from India. It was in very professional looking packaging, but the pills themselves seemed a bit on the crumbly side compared to normal so maybe they were fakes.

    2) Did you doc prescribe LDN or how are you getting it?

    In terms of suggestions I'd say in general it seems like cancers are often adaptable, but that adaptation carries a cost. Therefore possibly cycling every ?month? or 2 a regimen may be beneficial? Likewise our normal systems will also adapt and regulate to a steady input and so may up or down regulate to offset some supplements. Not much chance of backing this up in detail with studies, but seems like something worth considering.

    Overall though, good news on continuing stable MRI's!


    1. Hello Bryan!

      I did monitor my blood glucose for a few weeks after I started taking metformin. I take it 2x per day, once in the morning and once in the evening after a meal. I didn't really check if blood glucose drops after metformin, I just watched if it stays in normal range (which it did). I think Steve (who sometimes visits this blog and is an MD) said that metformin doesn't impact blood glucose in individuals who don't have diabetes. As Stephen also mentioned, metformin effects are probably indirect (immune, maybe also glucose drop).

      For metformin and LDN I got a prescription. I printed out few recent articles on positive effects of metformin and LDN and went to a few doctors, when finally I met someone who was prepared to prescribe it. Before I go prescription I did order LDN once from https://www.buyldn.com/ but there were problems on the customs, since naltrexone is a medicine. On top of that it is pretty expensive (45 dollars for 1 month supply + postage costs). Via prescription I now get it for 30 euro for half a year supply.

      Thanks for the suggestion about cycling! I think that most of my supplements are "immune enhancing" and probably don't have much direct effect and I guess cycling wouldn't have much effect either. As usually, hard to say :)

      PS: Stephen thanks for the above answers