December 2015 Blog with Durk and Sandy



You’d better watch out,
You’d better not cry,
You’d better not pout,
I’m telling you why,
Santa Claus is tapping
Your phone.

He’s bugging your room,
He’s reading your mail,
He’s keeping a file,
And running a tail,
Santa Claus is tapping
Your phone.

He hears you in the bedroom,
Surveils you out of doors,
And if that doesn’t get the goods,
Then he’ll use provocateurs.

So—you mustn’t assume
That you are secure,
On Christmas Eve
He’ll kick in your door,
Santa Claus is tapping
Your phone.

Our thanks to Eugene Volokh,
posted 9 Sept. 2013

When I played drunks I had to remain sober
Because I didn’t know how to play them
when I was drunk.
— Richard Burton

LSD is a drug that causes psychotic and aberrant behaviors in people who have not taken it.
— tyr

If that’s an army, they are too few. If it’s a diplomatic embassy, they are too many.
— Tigranes the Great of Armenia at Tigranocerta in 69 BC, surveying the 12,000 Roman soldiers who were about to tear apart his army of some 135,000 men (from The Classical Compendium by Philip Matyszak, Thames & Hudson, 2009)

Love is not altogether a delerium, yet it has many points in common therewith.
— Thomas Carlyle

Love is a great beautifier.
— Louisa May Alcott

There is pleasure in the pathless woods.
— Lord Byron

Joy is not in things; It is in us.
— Richard Wagner

Random processes produce many sequences that convince people that the process is not random after all. You can see why assuming causality could have evolutionary advantages. It is part of the general vigilance that we have inherited from our ances- tors. We are automatically on the lookout for the possibility that the environment has changed. Lions may appear on the plain at random times, but it would be safer to notice and respond to an apparent increase in the rate of appearance of prides of lions, even if it is actually due to the fluctuations of a random process.

— Daniel Kahneman, Thinking, Fast and Slow (Farrar, Straus and Giroux, 2011) (pg. 115)

(D & S Comment: The automatic vigilance is described in the book as being part of System 1, the intuitive way of thinking. So while it is certainly good to be vigilant of marauding lions even if you think their appearance is caused by the boogie man, the fly in the ointment is that the belief in an incorrect assumption of a cause can, in the world of politics, end up costing a huge amount of money if the process is random rather than caused by what people believe intuitively. And, unfortunately, as the author points out earlier in the book (pg. 91) the people who are most likely to make snap (intuitive) judgments of the competence of political candidates on the basis of whether they have a “competent” face were those that were most politically uninformed and who watched a lot of television.

Francis Crick (Nobel Prize Winner, Medicine, 1962) must have been bom- barded with mail following his receipt of the Nobel Prize. Here is a response he is reported to have sent out: Dr. Crick thanks you for your letter but regrets that he is unable to accept your kind invitation to: send an autograph/ help you in your project/ provide a photograph/ read your manu- script/ cure your disease/ deliver a lecture/ be interviewed/ attend a conference/ talk on the radio/ act as chairman/ appear on TV/ become an editor/ speak after dinner/ write a book/ give a testimonial/ accept an honorary degree.

— reported in David Frost’s The Impossible Takes Longer the 1,000 wisest things ever said by Nobel prize laureates (Walker & Co. 2003)
(D & S Comment: We think we know how he felt. After the publication of “Life Extension, a Practical Scientific Approach” and our very extensive publicity tours in 1982 and 1983, we received over 500,000 letters with nearly all of the above requests.)

To be secure, take the advice of a 19th century Boston politician, Martin Lomasney: “Never write if you can speak, never speak if you can nod, and never nod if you can wink…“

I was asked at a lecture by someone in the audience who said, why can’t I clone myself and keep the copies as spare parts? And my answer was, be careful, one of the copies might keep you for spare parts.
—Sydney Brenner, Nobel Prize for Medicine, 2002

A common principle often invoked in scientific discourse is Occam’s Razor. This principle dictates that the simplest or most parsimonious explanation should be favored. However, one shouid keep in mind that a simple explanation that does not explain the facts is to be discarded. Sydney Brenner introduced the concept of “Occam’s Broom,” which is used to sweep inconvenient truths under the rug to salvage the ‘simplest’ explanation. Recognizing when to use the razor and avoid the broom is a use- ful reflection in evaluating scientific models as the subtle Mendel and McClintock examples attest.
— pg. 11, Birchler, Mendel, Nechanism. Models, Marketing, and More in the Sept. 24, 2015 Cell

The philosopher Friedrich Hayek, who led the debate against social and economic planning in the mid-twentieth century, noted a paradox that applies today. As science advances, it tends to strengthen the idea that we should “aim at more deliberate and comprehen sive control of all human activities.” Hayek pessimistically added, “It is for this reason that those intoxicated by the advance of knowledge so often become the enemies of freedom.“
— Nico Stehr, in an oped (“Democracy is not an inconvenience”) in the 24 Sept. 2015 Nature

(D & S Comment: Scientific journals are disproportionately full of opeds propos ing regulations before, during, and after any technology not fully understood (as they all are). In the end, their agenda ends up attempting to regulate nearly all human activities, thus supporting Hayek’s pessimistic suggestion above.)


In another move toward police state medicine, the FDA has notified Pathway Genomics that it cannot market a blood test to screen for various cancers in healthy people because the company didn’t get the FDA’s permission to do so. In a 21 Sept. 2015 warning letter, the FDA declared the company’s test blood collection tubes a “medical device” and therefore, their use comes under the agency’s jurisdiction. The test, which would have allowed the public to determine whether they had cancer cells circulating in their bloodstream at a cost of $299 to $699 will probably never become available because the cost of getting FDA approval is prohibitive. Meanwhile, the FDA calls the test, which simply collects blood for analysis by their Pathway Cancer Intercept Detect service, the results to be sent to the patient’s doctor (who has to order the test), a “high risk test that has not received adequate clinical validation and may harm the public health.”

Where is the “high risk” the FDA claims exists here and how might it “harm” the public health, provided a disclaimer truthfully explains limits to the test’s ability to provide conclusive proof of having or not having cancer, a disclaimer we would be amazed if the company didn’t already provide for legal protection, if for no other reason.

The FDA is a dangerous entity backed by little more than government force that is immensely harmful to the public health. The agency pursues a vigorous agenda of extending its jurisdiction by decree (they simply proclaim authority over whatever suits their fancy), without Constitutional or statutory basis, to more and more of new medical technologies, effectively eliminating most of them from public access. In the meantime, courts regularly “defer” to the FDA and other regulatory agencies, providing little in the way of an effective check to their power-seeking. The result is the shrinking of choices available in the medical marketplace. And for THIS, we pay taxes??? We’d be better off shredding the money.

  • FDA warning on cancer test reported in the 2 Oct. 2015 Science, pg. 12


The researchers of a paper studying the above subject (Li, 2010) wanted to learn whether hydrogen could reduce inflammation and improve cognition in a rat model of Alzheimer’s disease. The 84 rats were divided into three groups: sham operated (icv injection that did not include amyloid beta1-42), amyloid beta 1-42 icv, and amyloid beta 1-42 icv plus hydrogen saline. Hydrogen saline was injected into the third group of rats for 14 days after intracerebroventricular (icv) injection of Amyloid beta1-42. They were tested for inflammatory cytokines IL-6, and TNFalpha and the lipid peroxidation product malondialdehyde (MDA), as well as testing the rats in the (uh oh) Morris Water Maze and open field trial to test for learning and memory function.

The hydrogen-enriched saline significantly improved animal performance in the Morris Water Maze and enhanced LTP (long term potentiation), an important process in learning, in the hippocampus, where LTP is blocked by amyloid beta1-42. The treatment also reduced levels of the inflammatory cytokines and the malondialdehyde, as well as reducing the hyperactive immune response to HNE and GFAP, which was induced by amyloid beta1-42.

So far, the experiments with hydrogen treatment for various medical conditions have used only hydrogen gas or hydrogen in saline or water. Why nobody is using hydrogen generated by the hydrogen producers residing in the gut microbiota for this purpose is not clear. It is possible that the reason is that a test for evaluating how much hydrogen is generated by the microbiota and which then diffuses into the tissues has not yet been developed; it is much simpler to know how much hydrogen the animals were administered when it is done by gas or by water or saline saturated with hydrogen.

Unlike hydrogen administered by gas or in water/saline, the ingestion of fermentable fibers, such as long chain fructooligosaccharide (long chain inulin), which is a particularly good fuel for the hydrogen producers in the gut, is a simple inexpensive way to get hydrogen into your system, PLUS it is not limited to the short time following the breathing of the gas or the drinking of the hydrogen containing liquid for exposure to hydrogen.

We are both enthusiastic users of our hydrogen power supplement. It is a powder that is not miscible in water, but mixes in very well when added to oatmeal, which is one way we use it. You could also add it to smoothies, casseroles, thick soups, etc. It is stable when cooked.

  • Li, Wang, Zhang, et al. Hydrogen-rich saline improves memory function in a rat model of amyloid beta-induced Alzheimer’s disease by reduction of oxidative stress. Brain Res. 1328:152-61 (2010).


Recently it has become a focus of much attention in Alzheimer research on the lesions in white matter that are so strongly associated with the disease. White matter is the myelinated tracts that connect neural networks of the brain that are found in gray matter, such as the visuo-spatial processing area that is severely impaired in Alzheimer’s disease. In our last newsletter, Sandy hypothesized that Alzheimer’s might not be a disease where memories are lost, but where the areas containing memories are disconnected from being accessed by other brain areas. If this is the case, then the white matter tracts that constitute these connections might be the key to Alzheimer’s via their vulnerability to damage. White matter lesions have been found in imaging studies of Alzheimer brains and are attracting scientific attention as an important factor, possibly a key factor, in the disease (Godin, 2009; den Heijer, 2006; Stebbins, 2009). Interestingly, depression in older individuals is often accompanied by white matter abnormalities. An earlier paper (Alexopoulos, 2005, cited in Alexopoulos, 2010) proposed that, “white matter abnormalities compromising frontolimbic circuitry may predispose to geriatric depression and interfere with its response to pharmacotherapy.”

One scientist who has done considerable work on the white matter changes in Alzheimer’s disease, George Bartzokis, M.D., has proposed that “white matter may be the primary origin of the complex process that comes to present as AD [Alzheimer’s disease]. That is, white matter involvement may precede, not follow, cortical degeneration. In a series of thoughtful papers, Bartzokis has presented the ‘myelin model’ as an alternative to the traditional conceptualization of the pathogenesis of AD.” “Although still theoretical, the myelin model draws support from many neuroimaging studies.” For example, individuals at familial risk of AD or late onset AD associated with the ApoE4 allele have been found to have white matter abnormalities in memory-related tracts, such as the parahippocampal white matter, cingulum, inferior occipitofrontal fasciculus and splenium of the corpus callosum. “A particularly intriguing DTI study of normal ApOE4 carriers found decreased microstructural integrity of temporal lobe tracts with normal hippocampal and entorhinal cortical volumes.” (quotes in this paragraph come from pp. 305-306 of Christopher M. Filley’s book The Behavioral Neurology of White Matter, 2nd edition, (Oxford University Press, 2012).


A 2014 paper (Littlejohns, 2014) reports the interesting finding that severe deficiency of Vitamin D (<25nmol/L) and deficiency of Vitamin D (≥25 to <50 nmol/L) was associated with a substantially increased risk of all-cause dementia and Alzheimer disease.

Vitamin D has been shown to mitigate age-related cognitive decline, possibly by reducing inflammation and decreasing amyloid beta burden (Briones and Darwish, 2012). Another paper reported that vitamin D prevents cognitive decline and enhances synaptic function in the hippocampus in aging mice (Latimer, 2014). A recent paper (Mizwicki, 2014) reported that vitamin D3 promoted the recovery of impaired amyloid beta phagocytosis by Alzheimer’s disease macrophages. This is important because the rate of production of amyloid beta in Alzheimer’s brains has been found not to differ from that of normal brains, but the ability of the Alzheimer’s brain to clear amyloid beta is impaired compared to that of normals.

Interestingly, multiple sclerosis is also a disease where damage to myelinated white matter tracts is responsible for failure of linkages between areas of the brain that send commands to motor areas and the motor areas that are supposed to receive those messages. The damage to the white matter tracts blocks these communication pathways. Moreover, multiple sclerosis is known to be increased at higher latitudes, that is the farther north you live, the higher the risk of getting multiple sclerosis. Vitamin D deficiency is associated with that higher risk and, of course, people at higher latitudes are exposed to less sunlight and consequently get less vitamin D via its manufacture in the skin. It may be a stretch but it is still tempting to extend the vitamin D association to Alzheimer’s disease as well.

Moreover, a paper (Huebbe, 2011) has shown that the apoE4 allele, which increases the risk of Alzheimer’s disease, is associated with higher vitamin D levels in targeted replacement mice (where the human apoE4 is substituted for their apoE) and in humans. This is consistent with the fact that in Europe, the apoE4 allele distribution is positively correlated with geographic latitude, with a greater than 4-fold greater frequency in the north than in the south (e.g., 22.7% in Finland vs. 5.2% in Sardinia. The authors (Huebbe, 2011) interpret this to possibly mean that the apoE4 allele may be beneficial early in life but then have a cost in later life (beyond reproductive age). Another paper (Norberg, 2011) also found that there was a north-south difference in the cognitive impairment resulting from apoE4 in non-demented subjects, with data coming from 16 centers across Europe. The latter study showed apoE4 carrier prevalence was 62.7% for the northern region, 42.1% in the middle region and 31.5% in the southern region. “Similar to AD [Alzheimer’s disease], APOE4 status is also associated with white matter (WM) abnormalities that may contribute to age- and disease-related neurodegeneration.” (Foley, 2014).

Durk hypothesizes that taking high dose vitamin D to get into the higher concentration of vitamin D that is still safe may be a way to reduce the damaging effect of having an apoE4 allele, because the gene’s expression may be plausibly assumed to be increased when vitamin D levels are low. Taking high dose vitamin D may, therefore, decrease the expression of apoE4 and reduce its deleterious effects thereby. This is an exciting possibility and one we hope will be tested soon. In the meantime, taking vitamin D at levels up to 4000 iu per day may be reasonable for most.


  • Littlejohns et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 83:920-8 (2014).
  • Huebbe, Nebel, Siegert, et al. ApoE4 is associated with higher vitamin D levels in targeted replacement mice and humans. FASEB J. 25:3262-70 (2011).
  • Latimer, Brewer, Searcy, et al. Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats. Proc Natl Acad Sci U S A. 111(41):E4359-66. (Sept. 29, 2014).
  • Briones and Darwish. Vitamin D mitigates age-related cognitive decline through the modulation of pro-inflammatory state and decrease in amyloid burden. J Neuroinflammation. 9:244 (2012).
  • Mizwicki, Menegaz, Zhang, et al. Genomic and nongenomic signaling induced by 1 alpha,25(OH)2-vitamin D3 promotes the recovery of amyloid-beta phagocytosis by Alzheimer’s disease macrophages. J Alzheimers Dis. 29:51-62 (2014).
  • Stebbins and Murphy. Diffusion tensor imaging in Alzheimer’s disease and mild cognitive impairment. Behav Neurol. 21:39-49 (2009).
  • Godin, Tzourio, Maillard, et al. Apolipoprotein E genotype is related to progression of white matter lesion load. Stroke. 40:3186-90 (2009).
  • den Heijer, Sijens, Prins, et al. MR spectroscopy of brain white matter in the prediction of dementia. Neurology. 66:540-544 (2006).
  • Norberg, Graff, Almkvist, et al. Regional differences in effects of apoE4 on cognitive impairment in non-demented subjects. Dement Geriatr Cogn Disord.32(2):135-42 (2011).
  • Alexopoulos, Glatt, Hoptman, et al. BDNF Val66met polymorphism, white matter abnormalities and remission of geriatric depression. J Affect Disord. 125(1-3):262-8 (2010).
  • Alexopoulos. Depression in the elderly. Lancet. 365:1961-70 (2005).
  • Foley, Salat, Stricker, et al. Interactive effects of apolipoprotein e4 and diabetes risk on later myelinating white matter regions in neurologically healthy older aged adults. Am J Alzheimer’s Dis Other Demen. 29(3):222-35 (2014).


The physiological functions of bile acids have been found to extend beyond that of regulating the absorption and catabolism (breakdown) of fats such as cholesterol and triglycerides. It is reportedly involved in the liver’s metabolism of fatty acid and triglyceride synthesis and VLDL (very low density lipoproteins) production mediated by sterol-regulatory-element-binding protein 1c and bile acids have been shown to inhibit high fat diet induced hyperglycemia and obesity in C57BL/6J mice (Ikemoto, 1997). Not too long ago, a paper (Watanabe, 2006) reported that bile acids increased energy expenditure in brown fat (this was in mice) and prevented obesity and insulin resistance. Remarkably, they found that cholic acid, a bile acid, induced the enzyme (D2, iodothyronine deiodinase type 2) that converts the biologically inactive thyroid hormone T4 to its active form T3. Cholic acid increased D2 activity and oxygen consumption in brown fat, preventing obesity and increasing fat oxidation (thus increasing insulin sensitivity). Incidentally, as an aside, niacin (via the pulsatile release of prostaglandin D2) also increases the oxidation of fats by signaling the conversion of cellular energy use from glucose to fats (Virtue, 2012); this appears to be one of the mechanisms by which niacin beneficially affects the metabolism of lipids.

Iodothyronine diodinase type 2 (D2) is also expressed in skeletal muscle. The researchers (Watanabe, 2006) found that skeletal muscle cells from the mice treated with cholic acid also had increased D2 activity and therefore served as a source of the active form of thyroid hormone.

D2 Is a Selenoprotein

One way to improve the function of D2 is to take adequate amounts of selenium as the enzyme is a selenoprotein (Curcio, 2001). Inadequate selenium intake is one way that people can be hypothyroid even when they secrete adequate amounts of T4 because D2 is needed to convert that T4 to its active form T3.


  • Curcio et al. The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line. J Biol Chem. 276:30183-7 (2001).
  • Watanabe, Houten, Mataki, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 439:484-9 (2006).
  • Ikemoto, Takahashi, Tsunoda, et al. Cholate inhibits high-fat diet-induced hyperglycemia and obesity with acyl-CoA synthetase mRNA decrease. Am J Physiol. 273 (Endocrinol Metab 36): E37-E45 (1997).
  • Virtue, Feldmann, Christian, et al. A new role for lipocalin prostaglandin D synthase in the regulation of brown adipose tissue substrate utilization. Diabetes.61:3139-47 (2012).

Protection Against Autoimmune Diseases In the Brain

Short Chain Fatty Acids (acetate, propionate, butyrate) Protection Against Autoimmunity (especially by propionate) in the Central Nervous System (in an animal model of multiple sclerosis)

Interestingly, the fermentation of beta glucans takes place in the large intestine (in contrast to many other more readily digested fibers that are usually fermented in the small intestine) as a result of the action of colonic microflora (Kim and White, 2010). Here, the fermentation of beta glucans results in the formation of short chain fatty acids—acetate, propionate, and butyrate—which are now known to provide protection to the gastrointestinal (GI) tract by inhibiting the growth of pathogenic bacteria, reducing cholesterol, as well as helping in the absorption of essential minerals including calcium and magnesium (Kim and White, 2010).Barley and oats are two excellent sources of beta glucans, a component of fiber, that has been shown to reduce cholesterol by lowering the reabsorption of bile acids, thus increasing the excretion of cholesterol (which is converted to bile acids) in the feces (Kim and White, 2010). Bile acids are described as “physiological detergents that play important roles in facilitating the absorption of dietary lipids and fat-soluble vitamins and biliary excretion and disposal of endogenous metabolites and xenobiotics.” “In the liver, bile acids inhibit both triglyceride synthesis and gluconeogenesis.” “…bile acids activate a G protein coupled receptor TGR5, which stimulates energy expenditure in brown adipocytes. TGR5 agonists have been shown to improve obesity and insulin resistance.” (last three quotes from Li, 2010). [More on the effect of bile acids on obesity in the article just following this one.]

A very new paper (Haghikia, 2015) now reports that long chain fatty acids enhanced the formation of T helper 1 (Th1) and/or Th17 cells that are involved in autoimmune diseases (Haghikia, 2015). Short chain fatty acids, particularly propionate, were shown in the Haghikia et al paper to ameliorate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. The mechanism involved the ability of the short chain fatty acids to beneficially influence the creation of T regulatory (Treg) cells that restrain excessive immune system activity as seen in autoimmune diseases. As the authors note, the Treg cell effector cell balance “is disturbed in MS [multiple sclerosis] patients.” They also point out the exceptional effect of propionate, “[o]f particular interest is the ability of PA [propionic acid] to beneficially influence the generation of Treg cells. Our study posits PA as a potent compound with the capacity to restrain CNS [central nervous system] autoimmunity via restoration of the altered Treg cell effector T cell balance, which is disturbed in MS patients.” Moreover, the researchers note “growing evidence for the lasting dietary effect [of propionic acid] on microbiome composition” and indicate their opinion that “a rapid translation of PA therapy from clinical studies to clinical trials in MS patients seems reasonable.”

We agree that clinical trials with propionate seem reasonable, but as propionate is an unpatentable compound, widely available and inexpensive, it is unlikely to interest pharmaceutical companies in investing millions for research and with economic conditions as bad as they are, government money is unlikely to be forthcoming for this research either.

How to Get More Propionate from Your Diet

One way to get increased amounts of propionate (which cannot be taken orally as a supplement because it will not survive passage through the liver) is to ingest digestive resistant fiber. Our hydrogen power formulation is a fructo-oligosaccharide or long chain inulin and the published literature indicates it as an extremely good source of fiber that is fermented to short chain fatty acids, with especially large amounts of propionate as compared to other fibers (Kim and White, 2010). Of course, the hydrogen power formulation is specifically intended to be used as a fuel by hydrogen producing gut microbes in the lower digestive tract, where the hydrogen diffuses throughout the body, passes through the blood-brain barrier and into mitochondria, and provides protection against hydroxyl radicals, the most dangerous biological radical, and peroxynitrite (Ichihara, 2015). Our barley nuggets, flour, and flakes are from a special barley strain that is very high in beta glucans. Our resistant starch is also a good precursor to propionate.)

Interestingly, there may be autoimmune components to Alzheimer’s disease (AD) (as indicated by a literature search we did on October 20, 2015; also see Bartzokis, 2011) and, thus, there is the possibility that a fiber that is fermented to propionate and other short chain fatty acids might also help prevent or mitigate the autoimmune involvement in AD. We have not seen a paper specifically testing this hypothesis.


  • Kim and White. In vitro bile-acid binding and fermentation of high, medium, and low molecular weight beta-glucan. J Agric Food Chem. 58:628-34 (2010).
  • Haghikia, JIorg, Duscha, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity. 43:817-29 (2015).
  • Li, Chanda, et al. Glucose stimulates cholesterol 7 alpha-hydroxylase gene transcription in human hepatocytes. J Lipid Res. 51:832-42 (2010).
  • Ichihara, Sobue, Mikako Ito, et al. Beneficial biological effects and the underlying mechanisms of molecular hydrogen—comprehensive review of 321 original articles. Med Gas Res. 5:12 (2015), 21 pp.
  • Bartzokis. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging. 32(8):1341-71 (2011).



In the course of writing the paper, she learned a lot about how the niacin flush works (a major effect is the pulsatile release of prostaglandin D2, which suppresses the inflammatory prostaglandin E2, which appears to be a factor in every inflammatory disease. She also learned that finding out what was known at any particular time was very difficult, requiring many extensive literature searches, due to the disseminated understanding of a particular aspect of science, the “balkanization” of science (where many areas of science are not very well connected to other areas), and the level of understanding differing from one scientist to another. Sometimes it seemed that a particular fact that had been discovered years ago had to be rediscovered due to a sort of failure of the earlier knowledge to be kept alive in ongoing discussions. This is why the disclaimer “we are the first to discover what we report in this paper, to the best of our knowledge” has become ubiquitous, because you can never be entirely sure.When Sandy wrote her paper on the niacin flush (see the July, August, and September issues of the Durk & Sandy newsletter at the Life Enhancement website (, her purpose was to find out whether it was a good idea to eliminate the niacin flush in order to make niacin supplementation more pleasant for those who didn’t like the flush. It was not self-evident whether the flush played a part in the protective effects of niacin (the immediate release form that causes flushing) or whether it could be suppressed without reducing the very powerful beneficial effects of niacin in protecting against non-fatal heart attacks (the most common kind) and reducing the risk of a variety of diseases associated with dyslipidemia and inflammation, such as diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and many others.

A good example of the last point, that you can find work that predates new research and anticipates its findings is the following: Sandy just found a 1998 paper (Prasad, 1998), a review that proposed that “PG [prostaglandin] induced elevation of Abeta [amyloid beta] may lead to an increased binding of Abeta…” and they report their prior work in which they show that “prostaglandins (PG), which are [] released during inflammatory reactions, cause rapid degenerative changes in differentiated murine neuroblastoma (NB) cells in culture.”

Sandy became very interested in prostaglandins D2 and E2 and their apparent ubiquitous appearance in inflammatory diseases. It seemed that the papers she read did not distinguish between the PULSATILE release of PGD2, which appeared to be an important anti-inflammatory signal, as compared to CHRONIC release of PGD2, which was pro-inflammatory, as she learned was the case in Alzheimer’s disease. Even now, this distinction does not seem to be mentioned in papers.

A recent paper (Das, 2011) describes inflammation and its resolution as follows: “During the early phase of inflammation, COX-2 derived PGs [prostaglandins] and TXs [thromboxanes] and lipoxygenase-derived LTs [leukotrienes] initiate exudate formation and inflammatory cell influx. TNF-alpha causes an immediate influx of neutrophils concomitant with PGE2 [prostaglandin E2] and LTB4 [leukotriene B4] production, whereas during the phase of resolution of inflammation, an increase in LXA4 [lipoxin A4, a pro-resolution molecule derived from arachidonic acid], PGD2 [prostaglandin D2] and its product 15deoxydelta12-14PGJ2 formation occurs that induces resolution of inflammation with a simultaneous decrease in PGE2 synthesis that stops neutrophil influx and enhances phagocytosis of debris.”


  • Das. A defect in the activities of delta6 and delta5 desaturases and pro-resolution bioactive lipids in the pathobiology of non-alcoholic fatty liver disease. World J Diabetes. 2(11):176-88 (2011).
  • Prasad, Hovland, La Rosa, et al. Prostaglandins as putative neurotoxins in Alzheimer’s disease. Proc Soc Exp Biol Med. 219:120-5 (1998).


A paper (Das, 2011) reviews changes with age that result in reduced levels of arachidonic acid and the long chain omega 3 fatty acids (found in fish oils) EPA and DHA and, consequently, low-grade systemic inflammation due to a reduced level of the important antiinflammatory, inflammation resolving molecules that are derived from them, lipoxins, resolvins, and protectins, respectively. It may surprise you to learn that arachidonic acid, which is the source of highly inflammatory prostaglandins, can also be converted to lipoxins, that have antiinflammatory effects. The chemical pathways are described in Das, 2011: “TNFalpha [tumor necrosis factor alpha, a major inflammatory cytokine] causes an immediate influx [to the inflamed tissues] of neutrophils concomitant with PGE2 [prostaglandin E2, a powerful inflammatory prostaglandin] and LTB4 [leukotriene B4] production, whereas during the phase of resolution of inflammation, an increase in LXA4, PGD2 [prostaglandin D2, which can function as an important antiinflammatory molecule via pulsatile release, as in the niacin flush] and its product 15 deoxydelta 12-14PGJ2 formation occurs that induces resolution of inflammation with a simultaneous decrease in PGE2 synthesis that stops neutrophil influx and enhances phagocytosis of debris.” The authors explain that this is a process in which there are two waves of release of arachidonic acid, one in which it and its metabolites are involved in inflammation and one in which they are involved in the resolution of inflammation. They note that high fat diets, trans-fat, and cholesterol block the action of the enzymes (delta5 and delta6 desaturases) that are required to produce GLA (gamma linolenic acid), DGLA (dihomogammalinolenic acid), AA (arachidonic acid) EPA, and DHA, thus exacerbating inflammatory conditions.


Another paper (McGahon, 1997) described how the age-associated decrease in membrane arachidonic acid (AA) observed in the dentate gyrus of the hippocampus of rats resulted in impaired long-term potentiation, an important process in learning and memory. Giving the aged animals a diet supplemented with arachidonic acid and its precursor, gamma-linolenic acid, resulted in reversal of the decreased membrane AA and sustained long term potentiation “indistinguishable from four month controls.”

We both take supplemental gamma linolenic acid.


  • Das. A defect in the activities of delta6 and delta5 desaturases and pro-resolution bioactive lipids in the pathobiology of non-alcoholic fatty liver disease. World J Diabetes. 2(11):176-88 (2011).
  • McGahon et al. The ability of aged rats to sustain long-term potentiation is restored when the age-related decrease in membrane arachidonic acid concentration is reversed. Neuroscience. 81(1):9-16 (1997).


The phenolic acids (including the important polyphenols you get in your diet and probably also take in supplement form), found ubiquitously in the plant kingdom, have been reported in a recent paper (Ren, 2009) to suppress lipolysis via activation of the same receptor by which niacin also suppresses lipolysis, one of the major protective effects of niacin against cardiovascular disease.

The phenolic acids tested and reported (Ren, 2009) to inhibit adipocyte lipolysis were shown in Table 1 and included (showing the dose that inhibits lipolysis by 50%, the IC50): niacin (nicotinic acid) at 0.2, caffeic acid at 14, gallic acid at 30 and others less well known, such as protocatechulc acid at 20. Note that niacin is much more effective at inhibiting lipolysis, but keep in mind that the dose of niacin being reported here is the pharmacological dose used in conventional therapy for reducing LDL cholesterol and increasing HDL cholesterol and is far higher than the physiological amount of niacin found in a good diet. The other compounds are presumably reported at doses closer to the physiological amounts one can get in a diet.

The authors explained how they became interested in the possible activity of phenolic acids at the niacin receptor: “ …both phenolic acids and nicotinic acid are small carboxylic acids with close structural similarity. We also note that application of certain phenolic acids, such as benzoic acid, also induces a flushing response and prostaglandin D2 release in a manner similar to that of nicotinic acid treatment. We thus asked whether phenolic acids could act as GPR109A agonists [activators].”

The authors conclude in their paper’s abstract: “Activation of GPR109A by phenolic acids may thus contribute to a cardiovascular benefit of these plant-derived products.” They also note in the text of the paper that, “while considered on an individual basis, the amount of a given phenolic acid may be low, and a combined phenolic acid content could be quite high.” They give as an example of combining different phenolic acids, “…addition of 80 mm of trans-cinnamic acid, p-coumaric acid, or benzoic acid alone led to a suppression of lipolysis by 17, 26, and 3%, respectively. However, when the same concentrations of these three compounds were combined, a suppression of 53% was observed.”


  • Ren, Kaplan, Hernandez, Cheng, et al. Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA-G). J Lipid Res. 50:908-14 (2009).


In a 2006 paper (Saraswathi and Hasty, 2006), researchers studied the effect of incubating mouse peritoneal macrophages with 100 μg/ml VLDL for six hours, finding that it resulted in 2.8 to 3.7 fold increases in intracellular triglycerides and free fatty acids, respectively, via intracellular hydrolysis (lipolysis). There were significant increases of at least two fold in inflammatory proteins as well, including TNFalpha, IL-1beta, MCP-1 (monocyte chemoattractant protein-1, intercellular adhesion molecule 1, matrix metalloproteinase 3 (MMP3), and macrophage inflammatory protein 1alpha. The authors suggest that these changes point to a direct proatherogenic effect of VLDL. The increases in triglycerides and free fatty acids was eliminated by Orlistat, an OTC weight-loss drug.

Interestingly, VLDL is known to be the lipoprotein carrier for apoE4. “ApoE3 binds preferentially to HDL and apoE4 to VLDL.” (Tetali, 2010). The fact that the ApoE4 gene is being carried by a potentially proinflammatory lipoprotein suggests the possibility of an interplay that may increase the adverse effects of apoE4. Suggestion: keep your VLDL level down. Niacin is very effective at this, as is fish oils.


  • Saraswathi and Hasty. The role of lipolysis in mediating the proinflammatory effects of very low density lipoproteins in mouse peritonial macrophages. J Lipid Res. 47:1406-16 (2006).
  • Tetali, Budamagunta, Simion, et al. VLDL lipolysis products increase VLDL fluidity and convert apolipoprotein E4 into a more expanded conformation. J Lipid Res. 51:1273-83 (2010).



Quinine in the form of tonic water, a very popular mixer with spirit alcohol, has been found to have the very interesting effect (Talavera, 2008) of inhibiting the TRPM5 channel-dependent response of taste receptors to sweet taste. This is part of a recently discovered facility of bitter compounds to frequently inhibit the sweet taste transduction pathway.

Dr. xxxx, the new editor/author of the “Nutrition & Healing” newsletter, formerly written by Jonathan V. Wright, M.D., suggests that 2-4 ounces of tonic water with quinine may be able to stop ongoing restless legs in some. I’ve tried it. Sometimes it helps. But don’t drink too much of it. Though there is no warning on a bottle of tonic water, there is about 75 mg of quinine in a bottle (1 liter) and some people have been reported to be sensitive to as little as 30 mg. (See “Wikipedia” article on quinine.) Those sensitive to it can end up having a kind of hangover that includes lower blood pressure (even to the point of fainting), lightheadedness, and difficult in walking (as if you were drunk on alcohol). This may possibly be due to the decreased response of the taste receptors to sucrose, which is supposed to release insulin that then releases noradrenaline. Reduced noradrenaline can lower blood pressure and might lead to lightheadedness, fainting, memory problems, and motor clumsiness.

Scaring Away Restless Legs

A possibility (per an experience of Sandy’s) is that a scary incident can frighten away restless legs, just as hiccups can also be eliminated that way. (You may have to be totally unprepared for the surprise fright.) This suggests (but doesn’t prove) that a bolus release of (probably) noradrenaline/adrenaline might be what counteracted the restless legs in this case. On the other hand, a chronic release (as compared to a bolus release) of noradrenaline/adrenaline might make restless legs worse so don’t take a long-acting adrenergic agonist and necessarily expect it to give you longtime relief.

Sandy has found agonists of the adrenergic alpha2 receptor to be usually effective at suppressing restless legs. Such agonists include the anti-hypertensive/sedative drug clonidine and dopamine (with L-dopa as its precursor). Alpha 2 adrenergic agonists suppress noradrenergic neurons in the locus coeruleus; these neurons “fire during waking, fire less during sleep and their activity increases just before waking, suggesting they promote wakefulness.” (Zhang, 2015). The scientists who produced that paper (Zhang, 2015) found that a drug with alpha 2 adrenergic receptor agonism produced sedation that resembled closely recovery sleep following loss of sleep.


  • Talavera, Yasumatsu, et al. The taste transduction channel TRPM5 is a locus for bitter-sweet taste interactions. FASEB J. 22:1343-55 (2008).
  • Zhang, Ferretti, Guntan, et al. Neuronal ensembles sufficient for recovery sleep and t he sedative actions of alpha2 adrenergic agonists. Nat Neurosci.18(4):553-61 (2015).


After not getting enough sleep, recovery sleep is an induced state that helps restore normal waking feeling and behavior. A paper (Zhang, 2015) reports that, “…recovery sleep and alpha 2 adrenergic receptor-induced sedation were not only similar behavioral states, but were both induced by activating similar neuronal populations in the PO [preoptic] hypothalamus.” The researchers found that GABAergic neurons in the LPO (preoptic hypothalamus) were required for the onset of dexmedetomidine-induced sedation. Desmedetomidine is an alpha2 adrenergic agonist used in clinical practice as an anesthetic.

This might be useful for people who have lost sleep and want to try using an alpha2 adrenergic receptor agonist to help them recover. Clonidine is such an agonist, a prescription drug that has been widely used as a sedative and is safe for most normal people at usual dosage prescribed. It will put you to sleep, so don’t take it when you plan to be working or driving. This drug may help relieve restless legs, but in Sandy’s experience it helped only when taken at night before bedtime. Natural products that act as agonists at alpha 2 adrenergic receptors are arginine and possibly agmatine (decarboxylated arginine found naturally in human serum) (Joshi, 2007). Clonidine potently lowers blood pressure, so be very cautious about dizziness-induced falls.

Interestingly, the authors (Zhang, 2015) note that, “candidate homeostat molecules, which accumulate proportionally to the amount of sleep deprivation and act locally in the preoptic area, include PGD2 [prostaglandin D2] and adenosine.” PGD2 is released in a pulse by immediate release niacin at doses of 50 mg or more, depending on individual sensitivity. We have found niacin to have a calming, sometimes nap-inducing effect.


  • Zhang, Ferretti, Guntan, et al. Neuronal ensembles sufficient for recovery sleep and the sedative action of alpha2 adrenergic agonists. Nat Neurosci. 18(4):553-61 (2015).
  • Joshi, Ferguson, Johnson, et al. Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells. Proc Natl Acad Sci U S A. 104(24):9982-7 (2007).

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