Anti-Cancer and Neuroprotective IP6

Xray image of head showing bones and brain

 

IP6, or inositol hexaphosphate, is a natural phytochemical derived from rice bran but also found in grains and vegetables. Also known as phytic acid or phytate, it’s sometimes considered an “anti-nutrient”, meaning that it inhibits the absorption of other nutritional elements. It turns out that those anti-nutrient properties make it anti-cancer and neuroprotective. IP6 is cheap and safe.

IP6 may prevent and treat cancer

IP6 has been known for some time to be anti-cancer.(1)

A striking anti-cancer action of IP6 has been demonstrated both in vivo and in vitro, which is based on the hypotheses that exogenously administered IP6 may be internalized, dephosphorylated to IP1–5, and inhibit cell growth… Besides decreasing cellular proliferation, IP6 also causes differentiation of malignant cells often resulting in a reversion to normal phenotype. These data strongly point towards the involvement of signal transduction pathways, cell cycle regulatory genes, differentiation genes, oncogenes and perhaps, tumor suppressor genes in bringing about the observed anti-neoplastic action of IP6.

In cell culture, IP6 significantly inhibits the growth of pancreatic cancer.(2) “Our findings suggest that IP6 has the potential to become an effective adjunct for pancreatic cancer treatment.”

IP6 has been shown to inhibit the growth of colon, breast, prostate, liver, and skin cancer cells. (See here for a list.)

IP6 shows efficacy against Parkinson’s and Alzheimer’s

IP6 also has been proposed to treat Parkinson’s disease.(4) In Parkinson’s, dopamine neurons progressively decay and die, and this appears to be closely related to the content of free iron in those parts of the brain. IP6 chelates iron in a cell-culture model of Parkinson’s.(5)

It’s been suggested that IP6 may also be able to treat Alzheimer’s disease.(8)

One concern about the use of IP6 for Parkinson’s is that it’s ability to cross the blood-brain barrier is unknown.

We noted in another article on iron and the brain that the dopamine neurons in all humans decay and die at a rate that sets an upper limit to human life at about 115 years. The difference with people who get Parkinson’s is merely that the rate of decay of dopamine neurions is faster: when only 30% of dopamine neurons are left, overt Parkinson’s disease becomes apparent, and when only 10% remain, death ensues. For those who don’t suffer from Parkinson’s, the theoretical point of only 10% of the dopamine neurons remaining comes at age 115.

It follows that IP6, by preventing or perhaps even reversing Parkinson’s disease through iron chelation, could extend human lifespan. Indeed, iron restriction extends lifespan in C. elegans and in mice.(6) Iron supplementation decreases lifespan in C. elegans by promoting protein insolubility.(7) “Increased dietary iron significantly accelerated the age-related accumulation of insoluble protein, a molecular pathology of aging.”

As one can imagine, one reason IP6 is not better known is because it is so cheap and cannot be patented, so drug companies can’t make any money from it; therefore they don’t fund research into it.

The major mechanism of action of IP6 appears to be that it chelates iron: it attaches to free iron atoms and then is eliminated from the body. Cancer cells require large amounts of iron to grow and reproduce, and when iron is taken away from them they can no longer do so. This may help explain the Warburg effect, in which cancer cells preferentially metabolize glucose anaerobically – this could be due to mitochondrial damage from large amounts of free iron.

I’ve added IP6 to my own supplement regimen in my quest to lower my ferritin level, which was 137 last I checked. I got it from Bulk Supplements, which sells a half kilo for $30. (Smaller weights are available.) One-quarter teaspoon is about 500 mg of IP6, and this can be taken first thing in the morning on an empty stomach. The taste is completely innocuous and bland. Taking it on an empty stomach means that the IP6 will not merely chelate minerals in one’s food, but will be absorbed into the body where it can chelate iron already there.

As mentioned above, one concern about IP6 is whether it can cross the blood-brain barrier, a relatively impermeable border crossing that allows only select agents across in order to protect the brain. Whether it can do this or not does not prevent IP6 from chelating iron elsewhere in the body and performing its other anti-cancer functions.

But it’s worth noting that other polyphenols that act as iron chelators do cross the blood-brain barrier. These include EGCG (from green tea) and quercetin.(7, 8.)

Key points

  • IP6 has strong anti-cancer properties
  • IP6 protects neurons from cell death
  • It chelates iron, probably its main mechanism of action
  • It may be able to prevent or treat Parkinson’s and Alzheimer’s diseases
  • IP6 is cheap and safe

For more on this topic, see my book, Dumping Iron.

PS: See also my Supplements Buying Guide for Men.

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47 Comments

  1. Herman Rutner says:

    Most IP6 is sold as the calcium and magnesium salts occupying 4 of its 12 available meal binding sites, the remaining 8 sites are available for binding toxic metal like iron, aluminum, cadmium a along with some beneficial zinc and copper. These can easily be supplemented at a later time of the day along with essential trace metals.

    • P. D. Mangan says:

      Thanks, Mr. Rutner. I just took a look at my supplement label, and it says it’s the calcium-magnesium salt.

    • Joshua says:

      Since magnesium salt is already occupying some of its available metal binding sites, does this mean that IP6 will not chelate magnesium from the body? I had assumed it was doing that, and so have been trying to supplement extra magnesium to account for that.

      • Herman Rutner, M.S. says:

        Commercial IP6, calculated from info on the label of Swanson IP6, is largely an insoluble calcium salt with about 3 calcium and less than 1 magnesium bound to the 6 available phosphates on IP-6, leaving about 3 phosphates available for binding of other metals. Per E. Graf, affinity increases with valency or positive charge, highest with metals like trivalent aluminum, titanium, chromium, iron+3 etc, much less so for bivalent iron+2, zinc, cadmium, calcium, magnesium. And lower valent metals like Ca can be displaced by higher ones like iron+ 3 which forms a very stable complex and thus prevents free radical damage in vivo and in vitro. Furthermore phytases successively de phosphorylate IP6 to IP5 etc down to inositol sugar, all more efficiently absorbed in vivo, further complicating bioactivity of IP6. To answer your question: free magnesium may not displace calcium, both bivalent and of similar affinity, when either is bound to IP6, but may bind to the 3 unoccupied phosphate groups on IP6.

        • Joshua says:

          Thanks, Herman. So, if I’m reading this right, it sounds like:
          1. IP6 is much better at chelating iron than it is at chelating zinc or magnesium (which sounds ideal)
          2. It likely will still chelate some magnesium (and zinc, and perhaps a lot of chromium), so these should still be supplemented when taking IP6.

          • Herman Rutner, M.S. says:

            Correct. As has been recommended by others, it seems best to take IP 6 and eat phytate rich nuts, grains or celerals before noon, and mineral rich supplements at night at least 3 hrs after supper.
            Re chromium toxicity, the warning applies to chromate or Cr-VI not Cr-III, an essential trace element in most multis. If correct as reported, trace amounts of ingested toxic Cr-VI would be rapidly converted to beneficial Cr -III in the presence of ascorbate from supplements or food.

  2. Scott says:

    Terrific site – glad I found it! Just bought your book on anti-aging – I’ve read two others of yours previously.

    IP6 and inositol seem to be a popular combination – comments? Also, re: blood-brain barrier, what do you think of quercetin supplementation (I already drink a lot of green tea)?

    Also, unrelated: I did a search for “phosphatidic acid” and didn’t find anything here – do you have an opinion on it? – it seems to be a hot supplement in fitness circles. Also (probably not the same thing) thoughts on phosphatidyl serine for lowering cortisol? (you have a post on it’s potential for increasing IQ)

    Thanks!

    • P. D. Mangan says:

      Hi Scott, glad you like the site. Inositol is one of the breakdown products of IP6, so I’m not sure that adding inositol would add much value, although it could, I’m still learning about this.

      Quercetin seems like a really good idea to me, though I haven’t tried it yet. I figured it would be good when I learned that researchers had used it to kill senescent cells: https://roguehealthandfitness.com/the-common-supplement-quercetin-kills-senescent-cells/ The fact that it crosses the blood-brain barrier adds to its appeal in my opinion. Fairly large doses are needed, so although it’s the most abundant polyphenol in foods, supplementation is probably necessary to get the benefit.

      Afraid I couldn’t say much about phosphatidyl serine for lowering cortisol.

      Oh, and thanks for buying my books!

  3. Andrew says:

    Is it still advisable to use iron chelating-supplements such as this when I’ve started donating blood quarterly? Related, is some level of iron in the blood still ideal for muscle repair/growth?

    • P. D. Mangan says:

      If you’re donating blood that often, an iron chelator may be a bit much to add to it. Iron is definitely required, and as for an ideal level for muscle growth, I believe that the low normal level I’ve discussed is best for that. Iron overload is likely responsible for anabolic resistance and sarcopenia. You definitely do not want to be iron deficient, although in most cases this is easily recovered from as an adult. (In children, could lead to longer lasting impairment since iron is necessary for growth.)

      Added: in a previous post, I noted a study in which men who donated blood 4 times a year had a ferritin level averaging in the 30s. That’s low enough.

  4. Tuba says:

    IP6 is also called a powerful “antioxidant.” Do you supplement at a particular time to avoid any influence on muscle building? Or, is the term “antioxidant” being liberally used when IP6 does not actually quench oxygen radicals?

    • P. D. Mangan says:

      Yes, antioxidant is a misnomer in this case, as in so many others. It seems the public isn’t capable of understanding how these things work, or journalists and some scientists are too lazy, so they just keep saying antioxidant. IP6 is not an antioxidant and won’t interfere with muscle anabolism.

  5. Herman Rutner, M.S. says:

    Correct, P.D.! IP6 is is not an antioxidant or scavenger of free radicals per se. But it strongly binds and thus scavenges free iron that acts as a catalyst for many free radical systems that cause rancidity by oxidation of fats in grains and meat products. Hence it is a natural stabilizer or preservative. The late Ernst Graf promoted it extensively as a food stabilizer.
    HR, retired industrial scientist

  6. Rob H says:

    This is a fascinating post Dennis, possibly with huge implications for the paleo diet. Maybe the legumes, oats, and organic soya eschewed by the paleo diet can actually be good for us on account of the phytic acid they contain: just so long as the key minerals such as calcium, magnesium, zinc & chromium are taken at different points in the day to prevent their malabsorption.

    The only thing I would add though is that this article: https://chriskresser.com/another-reason-you-shouldnt-go-nuts-on-nuts/
    states that: “It’s important to note that phytic acid does not leach minerals that are already stored in the body; it only inhibits the absorption of minerals from food in which phytic acid is present.” If this is correct, it would indicate that IP-6 is no good for chelating iron already stored in the body: and would only be of use when trying to reduce iron absorption from food being consumed simultaneously. For example, eating your steak with lentils. What are your thoughts on that Dennis?

    • P. D. Mangan says:

      IP6 does indeed chelate iron in the body. For example, here’s an experiment with mice in which IP6 in the drinking water inhibited skin cancer: https://europepmc.org/abstract/med/10625952

      Here’s what Shamsuddin writes in his review (linked in my article) on IP6 and cancer:

      As a first step to that, Sakamoto et al. (38) have demonstrated that contrary to popular misconception, 3H-InsP, when intragastrically administered to rats is very quickly absorbed from the stomach and upper small intestine and distributed to various organs as early as 1 h following administration. The radioactivity isolated from gastric epithelium at this time was associated with Ins and InsP,,, and that in the plasma and urine with Ins and InsP, indicating a very rapid metabolism of the compound (38). The presence of InsP, within the gastric epithelial cells suggests that the intact molecule was perhaps transported inside the cell wherein it was rapidly dephosphorylated. In humans, the small intestine has been shown to have very little ability to dephosphorylate InsP, (39), and thus InsP, should be even more effective against cancer in humans than in rats, as it is likely to be transported to different organ systems, undegraded.

      So IP6 is absorbed and does chelate iron within the body. As for the absorption of other minerals, especially zinc, this doesn’t appear to be a problem.

      I think Kresser got this one wrong.

    • P. D. Mangan says:

      By the way, IP6 also inhibits aortic calcification in rats: https://www.ncbi.nlm.nih.gov/pubmed/16146720

      • Rob H says:

        Very interesting: I had just made the assumption that it would probably be best to take my Vit D/ Calcium/ Magnesium/ Zinc/ Vit K (via grass-fed butter) away from any foods containing phytic acid – in order to avoid the phytic acid binding the calcium useless.. What remains unclear is whether the phytic acid has the effect of directing the calcium to the ‘right’ places in the body, ie the bones & teeth, or whether it just binds it up, making it inert/ ineffective. If it is the latter scenario then I’m guessing it would still be better to take the mineral calcium separately to any foods containing phytic acid. Although from your comment above it appears that taking Zinc with phytic acid containing foods should not be a problem.

        • P. D. Mangan says:

          Yes, I’m not convinced that general mineral chelation is a problem with IP6, but in any case, some zinc supplementation should take care of that.

          By the way, you take a calcium supplement? I can’t recommend that.

          • Rob H says:

            Yep, I have been taking a combined Calcium (low level: 333mg)/ magnesium/ zinc tablet which has been more cost effective than buying them individually. My thinking was that it wouldn’t hurt to have a bit of supplemental calcium so long as it is taken together with magnesium, Vit D and Vit K to ensure that the calcium gets sent directly to the bones and teeth, not the arteries. But I’m now considering switching this combined tablet for just 15mg zinc gluconate (I already take additional magnesium citrate after reading that the magnesium oxide in the above tablet is absorbed very poorly).

  7. Herman Rutner, M.S. says:

    RE the paleo diet, it may have been used in “paleo” times, although I doubt meat was widely available. But in Canaanite Bible times dating back about 6000 years, barley, high in phytate, was the major food source, about 65% of calories, as stone ground barley cakes or bread baked on heated stones. Goat milk based food and seasonal veggies and fruits provided the remaining calories. Wheat was about 3 times more costly, hence not commonly consumed. But during the 40 years Exodus, miracle manna was the only food consumed. Egyptians in pharaoh times ate more veggies and fish.

  8. Herman Rutner, M.S. says:

    True, magnesium taken as a rock hard tablet dissolves slowly in gastric acid, hence is poorly absorbed. But most of the more soluble magnesium or zinc salts are equivalent since they are rapidly converted to the chlorides in digestive juice under normal conditions, except when routinely taking PPI or gastric acidity blockers. And costlier salts like citrate, gluconate etc contain only about 10% Mg compared to milk of magnesia or colloidal USP magnesium hydroxide, my preferred magnesium form. It is best taken as 1 teasp or 150 mg Mg along with 1 tbsp apple cider vinegar in a glass of water which dissolves it to form soluble Mg acetate. A laxative dose is about 5- 10 times larger.

  9. Tuba says:

    I have added IP6 to the daily supplementation (a growing list that is as orchestrated as protein and carbs switch hitting on lift and fast days…) The question was what time of day, or with what meal or foods. My solution? 3 a.m. I’m usually up at that time, bathroom trot or a cup of chamomile tea and some computer busy work. That’s hours after the evening magnesium and on an empty stomach. It’s rather convenient, really.

  10. Herman Rutner, M.S. says:

    Commercial magnesium chloride, best as natural Magnesium Oil applied topically, is another excellent Mg source. It absorbs rapidly through the skin easing muscle cramps and back aches. It also is used for reducing joint pain from inflammation possibly by dissolving painful calcium deposits or spurs.

  11. If IP6 is a phytate / phytic acid and this accounts for its beneficial effect, then why not just eat more nuts & seeds and get the phytate that way?
    FYI – I have noticed that when I periodically go vegan and eat a lot of nuts & seeds, after a certain period of time I start to feel fatigued and cold, as if my iron levels had dropped too low; your theory of phytates binding iron in the body may account for that, and my experience seems consistent with your theory.

    • P. D. Mangan says:

      If I ate like that regularly maybe I would be satisfied. But as with my other supplements, if I decide I need one I want a defined dose. In my case, my ferritin was too high, and so I don’t want to leave this to chance by not knowing how much IP6 I’m getting.

      • I am not 100% convinced that your ferritin was actually too high. Reference ranges are based on a normal, average population. People on low-carb, paleo diets may have different optimal levels for a variety of things. With respect to iron, there are a couple of considerations:
        1) We know that it is inflammatory in excess and causes oxidation, but I imagine that this problem is at least partially offset by the anti-inflammatory effect of avoiding carbs. Therefore, on a low-carb diet, one may be able to have higher iron levels without any ill effect.
        2) People on low-carb diets may have a higher intrinsic need for iron to make hemoglobin and shuttle oxygen to the cells, given that there is less fuel available. In order to keep itself running as effectively as possible and maintain its metabolism despite having a lack of carbs, your body might be intentionally compensating by absorbing more iron, and this might be appropriate for your body given your level of activity. Therefore, if you intentionally try to reduce your iron levels while eating very low carb, then it is possible that either it might not work, or you might end up feeling less energetic and needing to rest more (which might actually be good from a pure anti-aging standpoint).

        • P. D. Mangan says:

          Martin, I appreciate the comment, but there are a few holes in the logic there. High iron could negate any effect of low carb on inflammation and oxidative stress. As for amount of iron needed for carrying oxygen, if one has the minimal level, enough hemoglobin is made, and that’s what carries oxygen. More iron – beyond the minimum needed to make one non-anemic – is not used to make more hemoglobin.

    • Joshua says:

      That feeling of fatigue and cold is probably just symptomatic of a caloric deficit. Any time I diet hard for a while, I get that as well. Even intermittent fasting makes me feel noticeably colder. I get these symptoms despite having rather high ferritin levels (I’m working on that bit).

  12. Pete says:

    Interesting discussion. There has recently been some debate as to whether IP6 does get absorbed into the body and chelates iron or if all chelation occurs in the digestive tract. See here:

    https://rsob.royalsocietypublishing.org/content/5/11/150181

    The authors claim that any chelation that takes place is in the digestive system and does not affect already stored iron.

    I wonder if anyone has any experience with changed ferritin levels after taking IP6 on an empty stomach over a prolonged period?

    • P. D. Mangan says:

      Well, that’s certainly interesting. Goes against virtually everything I’ve read about IP6, particularly what Shamsuddin has written. That doesn’t mean it’s wrong of course, and maybe it lowers iron by preventing absorption; natural (low) iron loss would do the rest. Or maybe inositol is the active ingredient.

      I’ve read reports of people lowering their iron with IP6; anecdotal of course.

  13. Tuba says:

    A couple of points to ponder. In an internet video by Dr. Lonnie Herman (IP6 Cancer 1) he says iron is too well-bound to hemoglobin for IP6 to affect that but it does do so with cancerous cells inside tumors. And there are a smattering of internet sites that say IP6 can lower testosterone dramatically, including free testosterone. Any thoughts on that?

    • P. D. Mangan says:

      On the first point, true, IP6 will chelate unbound iron only. On the second point, I haven’t heard that and can’t think of any reason that it would. Seems more likely the opposite would be true.

  14. Scott says:

    Curcumin is another iron chelator that can cross the blood brain barrier is it not?

  15. Robert says:

    I went from a shockingly high Ferritin level of 1160 ng/ml at the end of August last year to a current level of 141 ng/ml(last Friday).
    A single blood donation is good for about a 23.5% quick drop and I have made 2 blood donations in this period.
    Most of the overall decrease however is the result of taking 2 level teaspoons of IP6(Inositol Hexaphosphate) first thing in the morning with water. (You have to understand “Water” and “Empty Stomach” or it will combine with other minerals and not work as an iron chelator.)
    IP6 is on the FDA’s list of Iron Chelators, it is natural and safe unlike the pharmaceutical chelators which seem more dangerous than high plasma iron levels.
    The iron Disorders institute recomends a ferritin level between 20 and 80, but my research indicates that indications of thyroid dysfunction begin to occur at levels below 50. Also it seems optimum thyroid function is maintained by a ferritin level between 90 and 105. So my conclusion is to strive for a long term ferritin level between 90 and 105.
    The plan now is to continue with the IP6(currently dropping 5 points/day) and to do one last donation this coming Friday.
    In about 1.5 weeks I will be at about 60 for ferritin, and the final donation will help lower my hemoglobin level which is quite high (the Iron Disorders Institute indicates this as a problem also).
    After that I will allow the ferritin to climb back up to about 100 ng/ml(start eating oysters and red meat again…”Deliscious!”) and monitor and maintain that level for the long term.
    It’s been a long haul dealing with Ferro-toxicity and I will be glad to have regained my health and lowered the oxidative stress and predictor of many inflammatory diseases!
    I hope this info helps someone! ?

    • P. D. Mangan says:

      Robert, fantastic information, I’m sure it will help. Congrats on your big-time iron lowering. Thanks for commenting.

      • Robert says:

        Glad to share partner because my doctors, and even the specialist were absolutely useless except for one of them doing a blood panel including Ferritin for an entirely unrelated reason. If I didn’t take things into my own hands…it would not have been pretty for me!
        I just discovered tonight that Green tea catechens penetrate the blood brain barrier and chelate the iron.
        Given that iron accumulates in brain tissue with age and is difficult to remove, is a powerful oxidative agent and that Alzheimer’s Disease is now considered to be Type 3 diabetes;
        My conclusion is that Alzheimer’s is the result of iron related oxidative stress that creates the inflammation that denatures the insulin receptors of the brain! In short “Iron” is the cause of Alzheimer’s Disease!
        ~Remember that neurons cannot store glucose and only have a 2 or 3 minute supply. Alzheimer’s starves the brain from energy!
        https://link.springer.com/chapter/10.1007%2F978-3-211-33328-0_26

        • P. D. Mangan says:

          Many people must have high ferritin like yours and neither they nor their doctors know it. Good thing you took matters into your own hands. I also think iron may be the primary cause of insulin resistance in the brain and overall. Smokers for instance have elevated insulin resistance, and they have high levels of free iron; thus, oxidative stress caused by iron leading to IR. Green tea extract is very underrated and could be an actual cure for Alzheimer’s.

          • Robert says:

            I agree. Interresting article on smoking and the iron concentration that results from it in the lungs. The authors suggest the iron accumulation is why even when a smoker quits the rates of lung disease does not decrease for a long time(the iron stays).
            https://www.atsjournals.org/doi/full/10.1164/rccm.200802-334OC
            …Also read an article that relates iron overload with “Metabolic acidosis!” I have had a urinary PH of about 5 for 20 years and no amount of “green leafies” has been able to change this fact. Makes me assume I have had ferro-toxicty for at least 2 decades and probably longer! Sorry…but I can’t find the link to the article.
            🙂

  16. Prin says:

    Hi Dennis,

    I am now taking 500 mg IP6 first thing in the morning with NAC and a cup of plain tea. Is there any reason why I shouldn’t take collagen at the same time on days I am not fasting that morning? As far as I can tell, IP6 does not chelate amino acids.

    On days when I do fast, I take only IP6 and NAC with my tea, then wait an hour or two before I have coffee with cream and berberine, and sometimes cod liver oil. Is an hour long enough to allow IP6 to be digested before ingesting anything else? How long after I take IP6 should I wait to take any vitamins?

    Also, I think you have said this before: cream or fat does not break a fast, correct? Only proteins and carbs? Does that mean that too much milk could break a fast because of the proteins in it? I drink coffee (sometimes with milk, sometimes with cream) and want to be sure I am not ceasing autophagy when I intermittently fast.

    Thanks for bearing with me as I ask all these questions!

    Prin

    • P. D. Mangan says:

      Hi Prin, it sounds to me like everything you’re doing is fine. IP6 chelates metals only. I think an hour should be plenty long for IP6 to be absorbed from the gut. Too much milk could break a fast, yes. Small amounts are probably nothing to worry about, but milk has protein and sugars.

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