I don’t want to just mess with your head. I want to mess with your life. I want you to miss appointments, burn dinner, skip your homework. I want you to tell your wife to take that moonlight stroll on the beach at Waikiki with the resort tennis pro while you read a few more chapters.
If you have always believed that everyone should play by the same rules and be judged by the same standards, that would have gotten you labeled a radical 50 years ago, a liberal 25 years ago, and a racist today.
Quemadmoeum gladis nemeinum occidit, occidentis telum est. (A sword is never a killer, it’s a tool in the killer’s hands.)
—Lucius Annaeus Seneca “the younger”
(ca. 4BC - 65AD)
The American Republic will endure, until politicians realize they can bribe the people with their own “money.”
—Alexis de Tocqueville
(D & S comment: The above is a fine epitaph for the former American Republic, now the American administrative state.)
You can’t possibly hear the last movement of Beethoven’s Seventh and go slow.
—Oscar Levant, explaining his
way out of a speeding ticket
The censors wouldn’t even let me sit on a guy’s lap, and I’ve been on more laps than a table napkin.
Memory and Learning, Sexual Desire (LIBIDO), Reduction of Pain
Galantamine Enhances Cognitive Performance in Aged Ovariectomized Rats
One of the best ways to protect your aging brain is to get adequate amounts of choline, either through the diet (eggs, liver) or via supplements. As we have pointed out before, some 92% of Americans do not get even the minimal amount of choline recommended by the U. S. Institute of Medicine in their diet. Moreover, older women (past menopause, hence, with lower levels of estrogen in their system) require even more choline than premenopausal women. (Fischer, 2010) A food industry trade publication called this “Choline: The Silent Deficiency” and pointed to an opportunity for food companies to find ways to fortify their food products with choline. (See the January 2015 issue of “Prepared Foods.”)
As we have also reported before, cholinergic nervous system activity in the brain is vitally important for, among other things, cognitive performance. In women, it has been found that estrogen enhances the effects of cholinergic activity in the brain involved in learning and memory. With age in humans, the ability of the brain to take up choline declines. (Cohen, 1995)
Galantamine is a cholinesterase inhibitor, a class of compounds (in the case of galantamine, this is a natural substance despite being offered in a prescription form) that increases the length of time that the signal for cholinergic nervous system activation remains turned on in the neuronal synapse. Mounting evidence indicates that estrogen enhances brain function in women by increasing cholinergic nervous system activation. For example, a recent paper (Dohanich, 1989; reviewed in our last newsletter) showed that in rodents androgen-inhibited estrogen induced sexual receptiveness (LIBIDO) was prevented by choline, indicating that estrogen acted via a cholinergic mechanism to prevent androgen inhibition of libido or, another way of putting it, androgens had an anticholinergic effect in the female brain thus inhibiting libido induced by estrogens.
A recent paper (Gibbs, 2011) shows that galantamine plus estradiol enhanced cognitive performance in aged female rats with reduced levels of estrogens (as compared to young female rats). (This paper was previously reviewed by Will Block in the Dec. 2012 issue of Life Enhancement.) Especially interesting here was the fact that galantamine was able to enhance the effects of estradiol in the acquisition of a cognitive task (called the DMP, delayed matching to position, task—see paper for details of this, for a rat, fairly complex task) even after an extended period of reduced estrogen levels following ovariectomy. The rats were ovariectomized at 16-17 months of age. At 21-22 months of age, rats received daily galantamine treatment or vehicle by subcutaneous injection, then after a week, half the rats also received estradiol subcutaneously. Interestingly, neither galantamine nor estradiol alone had any effect on the rats after this extended period following ovariectomy.
Nevertheless, the COMBINATION of galantamine and estradiol significantly improved the animals’ ability to perform the DMP task, but not a different cognitive task, the stimulus discrimination/reversal learning task. Still, this is a very impressive enhancement of cognition in female rats after an extended period of very low estrogen in the brain and systemically. The authors suggest that this might indicate that “older women who have not used hormone therapy for many years and are beginning to show signs of mild cognitive impairment” could benefit from such a regimen. This is indeed good news for older women who have previously passed on hormone replacement because of concerns about it and are reaching the point where cognitive decline is becoming noticeable.
From a classic book on nutrition and the brain by three of the pioneering scientists in that field (Barbeau, 1979), we read the following on the effects of lithium on the cholinergic nervous system in the brain: “...manic behavior can be suppressed by giving physostigmine, a drug which, by inhibiting acetylcholinesterase [GALANTAMINE also inhibits acetylcholinesterase], increases intrasynaptic acetylcholine concentrations.”
The researchers (Millington, McCall, Wurtman, 1979) report in the classic book cited in the paragraph above that they investigated possible interactions of exogenous lithium and choline on choline’s entry into the brain. The researchers stated: “To our surprise we found that chronic treatment with lithium enhances the effects of exogenous choline on brain choline and acetylcholine, probably by preferentially suppressing choline’s efflux from the brain.” Although the researchers found that lithium inhibited the uptake of choline into the brain, it also suppressed the efflux of choline from the brain, the overall effect being an enhancement of choline levels in the brain. These scientists also found that lithium suppresses choline influx into erythrocytes (red blood cells). Moreover, another group found that chronic lithium treatment increases the synthesis of brain acetylcholine. The researchers commented: “The neurochemical effects of lithium and choline may thus be complementary ...”
This very early finding on the effects of combining choline and lithium seems to still be somewhat little known, as is so commonly the case with unpatentable nutrients that cannot be used to make blockbuster moneymakers for market sales. Although lithium itself is sold for the treatment of manic-depressive disorder because no good substitute has yet been found for it, the combination of choline and lithium remain in limbo, with no visible presence in mainstream medicine as a way to counteract declining choline levels in the brain with age that may lead to age-associated cognitive impairment.
Another fascinating section of the book (reference given just above) was written by A. G. Karczmar. Entitled “Overview: Cholinergic Drugs and Behavior—What Effects May Be Expected from a ‘Cholinergic Diet’,” it contained a remarkable report on a very early (1972) paper on the effects of the cholinergic system on sexual activity. “The significance of supraspinal cholinergic mechanisms was dramatically illustrated by Heath [reference given below] when he demonstrated that intraseptal administration of ACh [acetylcholine] evoked orgastic behavior in several patients that was indistinguishable overtly, subjectively, and electroencephalographically from spontaneous coital behavior ...” Note, however, that Heath also reported a similar action of norepinephrine. “Generation of hippocampal theta waves by cholinergic agonists and anti-ChEs [anticholinesterases] should be emphasized, as this pattern is a concomitant of coital behavior. It must be added that the hippocampus and other limbic sites such as the amygdala known to control sexual behavior are innervated cholinergically.” WOW!!
The amazing array of subjects covered in the 1979 book referred to above includes very early data on the effect of the cholinergic system on pain. In the same section of the book in which the discussion of sexual behavior is contained, there is this fascinating material on pain and cholinergic agonists: “For almost 40 years now [the book was published in 1979] it has been apparent that cholinergic agonists (particularly muscarinic agonists) and anti-ChEs [anticholinesterases] exert analgesic actions; these compounds, initially shown to potentiate the analgesic actions of morphine and codeine, also exert antinociceptive [pain suppressive] actions of their own ...” Choline, however, was reported to attenuate morphine analgesia in the rat. “Since cholinergic agonists and anti-ChEs markedly increase serotonin levels, this effect could underlie the cholinergic analgesia.” In fact, a 2012 paper (Byung-Sang Lee, 2012) supports the link between increased serotonin signaling and pain relief.
Aggression is part of human nature, not to be considered something harmful in itself. It all depends on what the aggression is used for. A mother protecting her infant is a type of well-known aggression and can serve a beneficial effect. Active self defense in the face of attack is another type of aggression that you had better have or you’re a sitting duck. In fact, I think it’s fair to say that if people didn’t have the ability to be aggressive in their own defense, the human species (or any species, for that matter) would have died out long ago. So aggression is a type of behavior that is necessary and is under the control of a number of neurotransmitters that both promote it and inhibit it, These includes serotonin, noradrenaline, and the cholinergic nervous system, among many others. Yes, it is very complicated and it is a wonder that people are able to live in a generally peaceful way among large numbers of other people. Not as peacefully as bonobos, for example, but perhaps (I (Sandy) speculate) the cholinergic system can offer a clue in that respect since it regulates both aggression and sexual activity and might act as a switch between these to the benefit of bonobos that would rather f__k than fight.
Early recognition of the cholinergic nervous system’s connection to the regulation of aggression was discussed in the classic book we have been talking about here. This is a 36 year old book and just shows you what three genius editors could do in giving an overview of a field that it seems these many years later has hardly penetrated the consciousness of many scientists, let alone laypeople.
The author of this section of the book (same author of the material on sexual activity we have discussed here) has this to say about aggression and the cholinergic nervous system: “Whether applied to several brain structures, particularly limbic brain structures or administered systemically, cholinergic (mostly muscarinic) agonists and/or anti-ChEs [anticholinesterases] cause aggression or facilitate experimentally induced aggression, whether of affective [emotional aggression that can be induced in small rodents by footshock or isolation] or predatory type [like the mouse killing behavior of rats]. Of interest in this context is the recent investigation of aggression induced in monkeys by small intravenous doses (6.25-25 μg/kg) of physostigmine [a cholinesterase inhibitor].” Long story short, a dominant monkey and a subordinate monkey were paired together, and one of the pair received physostigmine, which enhanced the aggressive action of the animal receiving it, whether that was the subordinate or the dominant animal, though it is reported that the effect was greater in the dominant animal. When the subordinate monkey got the drug, it reversed the hierarchical status of that animal. If this sounds familiar to you, like much more recent experiments that have produced similar results in monkeys treated with serotonergic drugs, it is likely due to the fact that activation of the cholinergic system increases the release of serotonin. But the old study with cholinergic drugs has been around for decades and seems to have been pretty well forgotten.
The author concludes this section of his part of the book by saying, “...it may be predicted that when ACh [acetylcholine] accumulation results as a consequence of a cholinergic diet, facilitation or induction of aggression should follow, as in this situation ACh would act as a cholinergic agonist.” A cholinergic diet might include a lot of eggs (with the choline largely contained in the yolks as phosphatidylcholine) or liver (yech).
Indeed, there is a very large scientific literature on the influence of cholinergic agonists on aggression, though there seems to be no general awareness of what this might mean in particular instances of human aggression. For example, a 2015 paper (Chen, 2015) reports that plasma butyrylcholinesterase regulates ghrelin to control aggression. Butyrylcholinesterase is an enzyme that also hydrolyzes acetylcholine (as does acetylcholinesterase) but at a higher concentration. Male BALB/c mice that had high levels of plasma butyrylcholinesterase (and thus decreased acetylcholine) as a result of gene transfer exhibited sharply reduced plasma ghrelin and surprised the paper’s authors by fighting less, both spontaneously and in a resident/intruder provocation model. On the other hand, mice with the BChE gene deleted had increased ghrelin and had a lot more fights. There was no mention of the early studies on the cholinergic system and aggression. It is almost as if the very early studies on aggression and the cholinergic system had been lost somewhere.
As I indicated before, emerging links may be emerging or they may have been hiding out in the immense scientific literature waiting for you to run across them, but in any event, I am now aware of papers that provide a plausible link between the cholinergic nervous system, fish oils (EPA and DHA), and estrogens. (Don’t think this just applies to women; men have estrogens, too.)
Docosahexaenoic acid (DHA, an omega-3 fatty acid because of estrogenic effects. This may link estrogen, the cholinergic nervous system, and cognition (as reviewed above). Gilray et al. Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects. Am J Clin Nutr. 80:1167-74 (2004) inflammation and the cholinergic system and DHA.
“The soluble form of amyloid protein (sAPP) released from neurons activates microglia [a type of immune cell in the brain] and induces excessive microglial expression of IL-1 [an inflammatory cytokine]. IL-1 increases the production and activity of the acetylchol-degrading enzyme acetylcholinesterase, which results in a decrease in brain acetylcholine levels.” Here, part of the Alzheimer’s disease process is revealed to be an increased expression of an inflammatory cytokine, which decreases brain acetylcholine levels. The cholinergic nervous system in which acetylcholine is the neurotransmitter is a major antiinflammatory regulatory system in the brain and body. DHA, on the other hand, is also an antiinflammatory molecule in the brain when converted to Neuroprotectin D1. DHA inhibits the formation of proinflammatory molecules such as the prostaglandin PGE2 (Das, 2008).
“Prostanoids represent another key component of neuro-inflammation. Particularly, PGE2 is highly synthesized in the brain during inflammation.” (Laye, 2003) For more on PGE2, see the two-part paper by Sandy Shaw on the niacin flush at www.life-enhancement.com.
It has been reported in recent papers that there is an average decrease in methylation levels in the regulation of genetic expression, an epigenetic change that has become a very hot area of research in aging and in the occurrence of a large variety of inflammatory and other diseases. Average decrease in methylation means just that, most genetic methylation decreases but there are some areas, such as the expression of some tumor suppressors that are overmethylated and, hence, less expressed, increasing the risk of cancer.
A very new paper (Veldhoven, 2015) reports that an epigenome-wide association study found there was an average decrease in methylation levels years before breast cancer was diagnosed. The authors suggest that this is a good biomarker for very early detection of possible breast cancer.
PGE2, a powerful inflammatory prostaglandin (discussed extensively in my paper (Part I) on the cause of the niacin flush—see at www.life-enhancement.com, “Why the Niacin Flush May Be Surprisingly Beneficial to Your Health” in the August 2015 issue—may be involved here. Importantly involved in inflammatory diseases, PGE2 has recently been reported (Venza, 2012) to induce interleukin-8 derepression (restores IL-8 expression from tight regulatory suppression) in human brain astrocytoma cells, where the increased IL-8 expression recruits and activates immune and inflammatory factors, increasing the spreading and invasiveness of the deadly glioma brain tumor.
The paper (Venza, 2012) reported that the PGE2 induced derepression of PGE2 took place through coordinated DNA demethylation and histone hyperacetylation. Interestingly, there are some other inflammatory diseases, such as COPD (chronic occlusive pulmonary disorder) where histone deacetylation is decreased (that is, there is hyperacetylation of the histone) at HDAC-2, histone deacetylase 2. (NOTE: Importantly, some diseases are associated with increased levels of histone deacetylases and others with increased levels.) In the second part of my paper on how the niacin flush may benefit your health there is a section at the very end of natural substances that, like the niacin flush, reduce the activity of PGE2. That includes substances such as omega-3 fatty acids, curcumin (constituent of turmeric root), and ginger, for example.
An interesting early paper (1994) reported that the synthesis and release of prostaglandins D2 and E2 by rat uterine tissue takes place throughout the sex cycle. Pulsatile PGD2 (as occurs in the niacin flush) is antiinflammatory while chronic release of PGD2 (as occurs in Alzheimer’s disease, for example) is proinflammatory. PGE2 is generally inflammatory but can under some circumstances be antiinflammatory (perhaps depending upon dose and time course of its release). Prolactin, released during orgasm, regulates levels of PGD2 and PGE2. Somewhere in this complex stew is the magic switch that might be useful for producing orgasm and increasing its strength. Just for fun, you know. Might make a moneymaking formula, too, but the fun comes first.
Could An Orgasm At the Same Time As the Niacin Flush Result in a Stronger Orgasm?
A possible clue is an observation Durk made many years ago that having a niacin flush at the same time as having an orgasm would increase (I noticed this, too) the strength of the orgasm, which hints that pulsatile PGD2 (the cause of the niacin flush) may be part of the orgasm process. If you can tolerate the niacin flush, you might give it a try and let us know if you notice anything (write to us c/o Life Enhancement Products about this but please do not ask for medical advice. We can get into serious legal problems (prison, legal expenses that bankrupt us, etc.) doing that and we simply cannot reply to such requests.
Great source of choline (mostly from the egg yolks)
Good source of isothiocyanates from fermented cabbage
Also get isothiocyanates from horseradish
One dozen hard-boiled eggs, cut lengthwise in half after cooking
Place all ingredients in a medium bowl, the yolks removed from the eggs after hard boiling the eggs
6 tablespoons mayonnaise
1 tablespoon prepared horseradish or two tsp. powdered horseradish
1⁄4 tsp salt
1⁄2 cup finely chopped corned beef
1⁄4 cup finely chopped corned beef
1⁄4 cup finely chopped sauerkraut, drained well
Mix all ingredients for the filling until well blended.
Spoon the filling mixture into the egg white halves.
Top each egg-half with a teaspoon of the topping. You might want to make more of the topping, as a teaspoon may not be enough!
Serve to your friends and wait for the compliments!
A paper (Shimada, 2014) Durk found in a search provides an excellent summing up of how inflammatory prostaglandins, products of the omega-6 fatty acids through their conversion to arachidonic acid, are critically involved in epilepsy and what takes place during a seizure, whether it is tonic-clonic or temporal lobe epilepsy (the latter may have no convulsive features at all, resulting in sometimes subtle changes in mental state, to a sort of disassociated state, akin to the infamous “split personality” of schizophrenia, which may make it difficult to diagnose).
The paper describes the process as follows: “In addition to inflammatory cytokines, prostaglandins (PGs) are major factors that stimulate inflammation processes. PGs are known to markedly increase following seizures and they contribute to epileptogenesis and reduction in seizure threshold.” “The enzyme cyclooxygenase (COX) converts arachidonic acid to PGH2 and the specific PG synthase converts PGH2 to various PGs such as thromboxane A2, PGF2alpha, PGE2, PGI2, or PGD2.”
“Because PGs play an important role in inflammatory responses, the function of PGs in epileptogenesis have been studied for a considerable amount of time” One thing the researchers pointed out is the discrepancy in effects of COX inhibitors in the treatment of epilepsy, with some having positive effects, while others can even increase damage and mortality. The reason for this discrepancy is, I believe, due to failing to recognize that the release of prostaglandins in pulses can be antiinflammatory (with PGD2 being an excellent example, discussed at length in my niacin paper) while their release over an extended period of time is likely to be proinflammatory. So the time course of the release of prostaglandins resulting from the inhibition of COX is not being considered, so far as I have seen in the literature on prostaglandins. As prostaglandins are crucially involved in inflammatory diseases, which include just about every important disease afflicting man, this time course of the release of prostaglandins by COX inhibitors is itself critical to the outcome of treatment.
This information fits nicely into the paper I wrote on the niacin flush (which is caused by a pulsatile release of a particular prostaglandin, prostaglandin D2 (PGD2) and which has powerful antiinflammatory effects) and I have added it as part II of my niacin flush/inflammatory diseases paper at the Life Enhancement website www.life-enhancement.com. (See “Why the Niacin Flush May Be Surprisingly Beneficial to Your Health” in the August 2015 issue.)
The researchers go on in their analysis of epilepsy: “...PGD2 and PGF2alpha can exhibit anticonvulsive functions. PGD2 synthase H-PGDS knockout (KO) mice [they cannot make PGD2] or PGD2 receptor DP1R-KO mice showed more severe seizures after pentylenetetrazol (PTZ) treatment than wild type mice whereas deficiencies of the other synthase L-PGDS or receptor DP2R did not alter seizure severity.” “By contrast, PGE2 mainly functions as a promotor of epileptogenesis and ictogenesis.” “...COX2 coupled PGE2 production can promote seizures through mechanisms that drive epileptogenesis.”
It is very interesting to note that PGD2 can act as a counter-regulatory factor to PGE2 but only when it is released in pulses, as occurs during the niacin flush. See my niacin flush paper PART I near the start of the text, just after the discussion of “What Is the Niacin Flush.”
Prostaglandin D2 release as an antiinflammatory pulse can be effected by a number of dietary supplements, including curcumin (and other constituents of turmeric root), niacin (in the immediate release form that causes flushing), selenium (shunts arachidonic acid production to antiinflammatory prostaglandins such as PGD2), EGCG (inhibits PGE2 production, possibly by releasing PGD2 in a pulse), ginger, sulforaphane (as found in cruciferous vegetables; stable metabolites with potent antiinflammatory activity also contained in the herb Moringa oleifera). These are just a few examples.
The data in a paper I was reading (Rafi, 2007) indicated potent antiinflammatory effects of the carotenoid lycopene that as part of a natural chemical pathway inhibits COX, which, via its two forms COX1 and COX2, converts arachidonic acid to inflammatory prostaglandins, such as the powerful inflammatory prostaglandin E2 (PGE2) (under some conditions it can be anti-inflammatory). PGE2 is a known factor in virtually all inflammatory diseases, including cardiovascular disease, cancer, diabetes type 2, arthritis, inflammatory bowel disease, epilepsy, and many others.
COX-1 is constitutively expressed, while COX-2 is an inducible enzyme that “mediates acute and chronic inflammation, pain, and cellular repair mechanisms.” (Rafi, 2007) The authors believe that the results of data from studies of lycopene “suggest that inhibition of COX2 may be effective in preventing inflammatory-associated cancers.” (This suggestion, from 2007, was supported by later work.) The authors concluded: “Therefore, using lycopene or [lycopene-containing] tomato-based products to regulate the production of NO and COX-2 may be classified as a therapeutic approach for the treatment or prevention of chronic inflammatory disease.”
DURK AND SANDY GET RELIEF FROM THE PAIN OF
THEIR ARTHRITIC KNEES WITH LYCOPENE
Unfortunately, both of us have moderate cases of knee osteoarthritis, with Sandy’s knees significantly more painful. We had run out of lycopene and after a few days to a couple of weeks we both noticed more pain in our knees. The day we went back on lycopene (we started on 15 mg. a day, though Sandy has upped hers to 30 mg. a day now that she has felt the difference), we were both aware of much more comfort in walking. The best way to take it is with the fattiest meal of the day, as it is absorbed best with fats.
It is also interesting that lycopene is another one of the natural products that inhibits for formation of inflammatory prostaglandins. See (Shaw, 2015) “Why the Niacin Flush May Be Surprisingly Beneficial to Your Health” by Sandy Shaw for a discussion—in Part I under the subheading “What Is the Flush?”—of inflammation and the prostaglandins that play such a major role in it, particularly PGE2 and PGD2. PGD2 is prostaglandin D2 that is the cause of the niacin flush and which counters the effects of inflammatory PGE2 when released as a pulse, but there are many ways other than taking niacin to interfere with PGE2-induced inflammation. Lycopene is one such effective antiinflammatory nutrient.