This week brings six updates to Examine.com, two of which are unrelated to nitric oxide metabolism (and will be covered quickly): Arachidonic acid and Serrapeptase.
Arachidonic acid (AA) is the opposite to Fish Oil in plasma membranes, and both AA and fish oil create signaling molecules known as eicosanoids; the ratio of AA eicosanoids to fish-oil eicosanoids mediates the benefits of the omega 3:6 ratio and the benefits of both arachidonic acid and fish oil.
It appears that, in vitro, incubating a muscle cell with higher levels of AA causes production of eicosanoids that can induce muscle protein synthesis. Because of this, plus the fact that it's a relatively novel pathway, AA is touted as a muscle builder. Trials have not yet confirmed these claims, although it does appear that AA can increase joint pain, inflammation, and DOMS.
Serrapeptase is in a similar situation; there's theory behind its actions, but not enough evidence to either recommend it or disprove its efficacy. Serrapeptase is an enzyme that, following (limited) absorption, appears to confer antiedemic and anti-inflammatory properties. Not much of it reaches the blood, although that which does appears to be enzymatically active; no studies have attempted superloading in order to see if the limitations of serrapeptase supplementation can be overridden by merely taking more.
Neither claims about arachidonic acid nor serrapeptase can currently be disproved, but there is not enough evidence to support their supplemental usage either. Arachidonic acid is limited in a sense by antagonizing the benefits of fish oil, and serrapeptase is not well absorbed.
The other cluster of updates involves nitric oxide metabolism. This includes the three commonly used dietary supplements that are in the urea cycle: L-arginine, L-citrulline, and L-ornithine, and the arginine metabolite Agmatine.
As a general statement, ornithine is distinct from both arginine and citrulline as it is not involved with the nitric oxide cycle, and instead just sequesters ammonia while producing urea. Ornithine is an ammonia buffer, and thus is primarily seen as an anti-fatigue agent, or useful in clinical situations where ammonia toxicity is a concern (e.g., renal failure or hepatic encephalopathy).
Arginine is the substrate from which nitric oxide is created, but this may be a false positive; the enzyme that creates nitric oxide is already saturated, and adding further substrate should not logically induce any changes. That being said, arginine does increase nitric oxide at times, and this appears to be due to extracellular arginine concentrations; this leads to the assumption that the ability of arginine to act on the alpha-2-adrenergic receptors stimulates nitric oxide; however, arginine is weak at doing this (the EC50, aka the concentration that half-activates the receptor, is 1mM, but supplemental arginine only reaches roughly half of that). So although required for nitric oxide production, it is mechanistically weak and unreliable at inducing it.
Surprisingly, arginine appears to be quite beneficial for those with impaired glucose tolerance and type 2 diabetes. It appears that in these instances, the arginase enzyme (which converts arginine into ornithine) is increased and may cause a relative deficiency of arginine; thus supplemental L-arginine does appear to fairly reliablu improve blood-vessel health and nitric-oxide production.
Finally, L-ornithine and L-arginine are mimicked and outperformed by L-Citrulline. Citrulline converts to arginine in the body, and arginine can convert to ornithine; citrulline has been noted to increase levels of all three amino acids in the body, is better absorbed with fewer intestinal side effects, and lasts longer in the blood than does L-arginine (as conversion of citrulline to arginine has a rate limit, extra citrulline forms a free floating "pool" in the blood waiting for conversion).
Arginine has unreliable benefits for nitric oxide production, while ornithine has somewhat more reliable benefits for reducing fatigue and ammonia concentrations; citrulline is better at both of these goals and is likely the best supplement option.
Agmatine is a very interesting, novel neurotransmitter. First of all, it activates production of nitric oxide via the alpha-2 adrenergic receptors more potently than arginine does, and is likely to be better for producing nitric oxide.
Agmatine has roles as an NMDA antagonist, a neuronal nitric oxide inhibitor (not related to "the pump" in any way), and a serotonin receptor signal enhancer, and is an activator of both alpha-2-adrenergic receptors and imidazoline receptors. Agmatine may directly block calcium channels, and can indirectly inhibit potassium channels.
The above mechanisms underlie its therapeutic benefits. Agmatine is useful in drug addiction (being shown to abolish anxiety with alcohol withdrawal and fentanyl self-administration, and reducing conditioning effects of meth), is synergistic with opioids like morphine (increases analgesic effects, reduces tolerance and addictive properties), and is synergistic with antidepressants, most notably SSRIs. Agmatine is also highly effective in treating neuropathic pain, and is theoretically synergistic with marijuana for this role as well.
Finally, agmatine is neuroprotective against excitotoxicity and stroke and has inherent anti-anxiety and anti-depressant effects. The latter two are likely due to agmatine enhancing signaling of naturally occurring anxiolytic and antidepressant compounds. There are, finally, some memory-enhancing effects that are context dependent. Behavioral and procedural memory appear to be enhanced, while spatial memory is unaffected; emotional fear conditioning is actually impaired. It was suggested by a few authors that "higher-up" processing is beneficially influenced, which correlates with high concentrations of agmatine in the cerebral cortex and hippocampus.
Neurological effects appear to follow a bell-curve pattern, maxing out at an estimated 500 mg human equivalent for somebody around 150 lbs (based on the limited evidence using oral agmatine in rats). The neuropathic pain reduction is dose dependent.
The limitations of the current evidence for agmatine include:
A ton of studies use injections rather than oral intake. Although the oral studies seem to suggest it has good absorption, a proper bioequivalence study has not been conducted.
Very limited human evidence; a lone study for neuropathic pain.
For many neural effects, it is antagonistic with arginine and citrulline. For neural and cardiovascular effects, it is antagonistic with yohimbine and rauwsolcine; all four are popular supplements.
Overall, agmatine is an incredibly promising dietary supplement for both cognitive health/enhancement as well as an ergogenic, since it is possibly a better nitric oxide stimulator than arginine itself, yet it appears to prevent the toxicity associated with nitric oxide in the brain. Although it requires more human evidence and there are still a few studies that need to be conducted, agmatine appears to be worth looking into.
Beyond a highly uneventful Calcium-D-Glucarate page (there's really nothing remarkable about this "detoxifying agent"), the relevant pages this time around are all based upon sports performance or body composition.
The major update this week is baking soda, more formally known as Sodium Bicarbonate. In a very general sense, it is comparable to Beta-Alanine in regards to both mechanisms and overall effect size, but outperforms it on a few parameters:
However, baking soda is worse than beta-alanine on a few parameters as well:
Finally, the limited studies into bicarbonate and beta-alanine as a combination do not find any additive benefits. If one is already taking beta-alanine, there is likely no need to add in bicarbonate.
Overall, sodium bicarbonate does appear to work, and can potentially be a cheap and widely available ergogenic supplement; yet it requires caution in approaching supplementation.
Beyond bicarbonate, we tackle the Branched Chain Amino Acids, and establish an individual page for all three of them: Leucine, Isoleucine, and Valine. Most information is interspersed within the pages (we attempted to collect it all on the BCAA page, and then opted for a cleaner read on the individual amino acid pages).
Leucine seems to be the standard muscle-building agent, and consuming leucine (either via food, BCAAs, or individual leucine supplementation) does promote muscle protein synthesis; this appears to be more significant in persons with lower dietary protein intake.
Isoleucine seems to be a hypoglycemic agent. It is not as effective as leucine at stimulating muscle protein synthesis, but causes dose-dependent increases in glucose uptake in skeletal muscle. The conversion of glucose to energy is enhanced, but glycogen synthesis is not; thus isoleucine may make a nice pre-workout when taken with carbohydrates. It works via a relatively novel mechanism (shared by leucine, but not by many other supplements) and might work nicely with other hypoglycemic agents such as AMPK activators (like berberine) or muscle contraction itself.
Valine, due to being quite understudied, is actually very unremarkable and does not appear to have any known unique properties.
Finally, the metabolite of leucine known as HMB (beta-hydroxy-methyl-butyrate) has been updated. HMB is less effective than leucine at promoting muscle protein synthesis, yet much more potent at inhibiting muscle protein breakdown (on a gram-per-gram basis). However, the human studies using HMB are all structured to measure the muscle-protein-synthesis effects of HMB, and due to this they are quite lackluster in their results. Preliminary evidence in clinical settings (not in athletes) does suggest a relevant anti-catabolic effect, but although it should work, this is not yet demonstrated in the population most likely to supplement HMB.
HMB is technically a potent anti-catabolic but requires further testing in athletes to confirm.
We previously covered the study that discussed the link between dietary carnitine from meat and TMAO production, which was associated with a higher risk of atherosclerosis. A new study[1] is making the rounds with a similar conclusion, this time about a different molecule.
This study investigates the molecule Phosphatidylcholine. The study was conducted by having subjects eat two eggs, each containing 500mg Choline, alongside 250mg of phosphatidylcholine, which was radiolabeled. Phosphatidylcholine (PC) is a phospholipid (“lecithin” is a term sometimes used to refer to all dietary phospholipids, and will be used in this blog post for simplicity) which contains choline. By using labeled PC, the study’s authors were able to confirm that dietary choline acutely increased serum TMAO, and that this was dependent on intestinal microflora (similar to what occurred with carnitine). It should also be noted that both choline and carnitine are trimethylamine compounds.
Contrary to media reports, there is no molecular link between egg consumption and TMAO in this study. The radiolabeled phosphatidylcholine was consumed via a gelatin capsule alongside two (nonlabeled) eggs, which contained free choline. However, the PC increased serum TMAO dependent on intestinal bacteria, and it is definitely plausible (and likely) that eggs can increase TMAO via the choline content; this cannot be concluded right now though.
Similarly to the carnitine study, this experiment confirmed a correlation between higher TMAO and cardiovascular risk with a cohort study design (4007 persons undergoing coronary angiography) with an adjusted hazard ratio of 1.30 and 95% CI of 1.20 to 1.41 (a weak correlation, but a positive one nonetheless).
There was a higher hazard ratio when looking only at the subset of “death from cardiovascular disease,” which was an RR of 3.37 with a 95% CI, 2.39 to 4.75; this is somewhat notable.
This study also confirmed a correlation between TMAO and cardiovascular disease risk, so it appears that TMAO may be a useful biomarker in the future for cardiovascular disease risk. Whether TMAO is increased by dietary factors or other factors, it appears to be associated with an increased risk for heart disease.
That was basically the study. This study can be used to support the correlation between TMAO and cardiovascular disease, and similar to the previous carnitine study, this was confirmed at least acutely in humans. This study can also be used to further support the link between the microbe capable of choline -> TMAO conversion as a possibly causative link in the pathology of CVD, so identifying this microbe might be therapeutic or preventative in regards to CVD in the future (via modulating the increase of TMAO from the diet).
However, this study is not sufficient evidence to blame eggs for causing CVD. This is especially true when we factor in a variety of studies that explicitly found that egg consumption was not associated with an increase in cardiovascular disease[2][3][4]. It can lend credence to the theory that choline increases atherosclerosis (as there is a plausible mechanism in humans), but is not proof of it; a few factors (having a mixed diet, not having the microbe, other negative regulators of atherosclerosis such as exercise) could make the observations seen here in a clinical setting irrelevant in a practical setting.
More likely, the bacteria that helps convert to TMAO uses the trimethylamine structure (which both choline and carnitine are) to make TMAO. This bacteria (currently unidentified) is the causative agent here, and merely uses sources of trimethylamines (eggs being a source of choline via PC) to do its job.
While one can directly blame eggs for the increase in TMAO, it would be improper to blame egg consumption for increased TMAO (which is correlated with an increased risk for cardiovascular disease). Any blame would better be directed towards the intestinal metabolism and the bacteria that helps convert to TMAO.
Related: are eggs healthy?
We've finally done it. We've been collating research on supplements and nutrition for over two years, and as of this post, we have 17,069 citations in our database.
At the end of the day, we care about answering one question: What does a supplement do?
And today we finally solve that problem. We've replaced the confusing and cumbersome "Human Trials Database" with a "Human Effect Matrix."
For every supplement in our database, a handy table will tell you what effect each supplement has and how noticeable that effect is.
Does Supplement X help with Y? Now you'll know.
Creatine? It has a minor effect in increasing your testosterone, but a strong effect in increasing your power output. What about fish oil? It has actually has a notable effect in decreasing depression!
Best of all, the Human Effect Matrix isn't on the supplement pages only. They are also on the effect pages themselves. Want to know which supplements impact inflammation? Done! Do any supplements help you add muscle? Now you know. (Spoiler: they all have, at most, a minor effect).
What we've done is removed all the mysticism, hyperbole, and marketing-speak used to talk about supplements. It's all tabulated and organized for your perusal, and it's all backed with citations with human-studies.
To get you going, here are a few popular and a few interesting supplements:
Methylsulfonylmethane (MSM) is a joint health supplement that is structurally similar to DMSO, and appears to be used for a variety of health related purposes as well as analgesic. MSM does appear somewhat effective, but there is no robust and repeated evidence to support it as being better than other supplements (Glucosamine sulfate or acetominophen).
The page on MSM as well as glucosamine (where sulfate works, but hydrochloride doesn't) having similar effect size and variability in benefits seem to suggest that the joint health is coming from sulfur provision rather than the vessel by which sulfur is provided. In this case, a high dietary protein intake (via methionine and cysteine) or supplemental N-Acetylcysteine would also be similarly effective. Future trials need to investigate effects of these supplements in persons with or without relative sulfur deficiencies.
Rhodiola Rosea is an Adaptogen compound with the main bioactive of hydroxytyrosol and its glycoside (salidroside); it appears to be highly effective for combating neural fatigue and reducing the side-effects of fatigue (reduction in cognition, increase in depressive or stress symptoms) although it currently does not have much support for improving physical fatigue associated with exercise and is mostly unexplored in chronic fatigue syndrome. Rhodiola appears to be an effective supplement for work-related 'burnout'.
There are other health benefits associated with rhodiola, and alongside Panax Ginseng rhodiola is an adaptogen that is used in research often to merely see the effects of this 'adaptogen' class. Due to this, some evidence links rhodiola to promoting longevity independent of caloric restriction but this requires mammalian evidence.
Guarana is an energy producing seed powder that is the highest naturally occurring source of Caffeine. Guarana is somewhat unique in the sense that 90mg of the seed (conferring a level of caffeine that is commonly seen as inactive) appears to promote cognition. It is not known what molecule is causing this as it has not yet been identified, but something in guarana appears to either inherently promote cognition (perhaps secondary to an anti-fatigue effect) or work synergistically with caffeine.
Despite the popularity of guarana in energy drinks, there is a surprising lack of research available in English, with most being hidden behind language barriers (Spanish) and not catalogued on main databases such as Pubmed.
Olive leaf extract is a supplement with a high concentration of tyrosol-like molecules, and appears to be a very potent antioxidant following oral ingestion of low doses that seems to protect LDL cholesterol from oxidation. There is a large body of evidence on this topic using virgin olive oil against processed (processing destroys the phenolics) where even doses as low as 9mg appear effective.
Olive leaf extract appears to be very promising for perhaps being included in combination supplements (since it is active at a low concentration) and the Examine page can be used as evidence to the benefits of virgin or cold-pressed Olive Oil over processed oil as there does appear to be significant health differences between them due to the olive leaf phenolics.
Salvia hispanica (Chia) is a grain/seed that has traditionally been used as a meal replacement and energy promoting agent. Overall, there is currently no evidence to support chia as being remarkable in any capacity. There is insufficient data on the phytonutrients in chia (so no conclusions can be made there) and human evidence so far is just not remarkable. Anecdotally, however, chia appears to be as nice for promoting good bowel movements as psyllium husk which may be a good use for it.
Krill Oil is a form of Fish Oil fatty acids where, rather than being triglycerides, the fatty acids are present in phospholipid forms (most prominent one being Phosphatidylcholine). Krill oil is better absorbed than fish oil on a per gram basis and thus requires a lower dose (if using the dosing protocols of fish oil from other fish) and supplementation is essentially combination supplement of both fish oil and phosphatidylcholine; the Astaxanthin content of krill oil has not yet been demonstrated to contribute to the benefits.
Currently, the evidence in support of krill oil is very remarkable in the magnitude of benefit (the independent study in hyperlipidemics noting a 50% increase in HDL-C) and although it is independent of any disclosed financial support all studies seem to use 'Neptune Krill Oil' and are a tad too promising. Consider the evidence preliminary, and an independent systemic review would be very valuable in the near future to assess if krill oil is 'just fish oil and PC' or something more.
And three other Ayurveda based brain boosting herbs: Jatamansi, Evolvulus alsinoides, and Convolvulus pluricaulis. The latter two are two of the four herbs referred to as 'Shankhapushpi' (alongside Clitoria Ternatea and Canscora decussata) while the former herb is simply referred to as jatamansi. All three herbs are preliminary in their evidence with no human studies, but animal studies suggest that they can increase learning and memory in otherwise healthy young rodents with potency similar to the reference drug (Piracetam) or, in the case of Jatamansi, may be exceeding Piracetam. Mechanisms are not known for these herbs, but the general phenotype of rodents following ingestion seems to be similar to Bacopa Monnieri (in regards to anxiolysis, antidepression, learning enhancement, neuroprotection, and adaptogenic effects).
This study was recently published, pushing the hypothesis that L-Carnitine in meats could be a connection between meats and cardiovascular disease risk, via TMAO (Trimethylamine oxide).
TMAO is thought to be atherogenic (plaque causing) because it is associated with cardiovascular disease (i.e., people who get heart attacks tend to have more TMAO in their blood). This study itself established a correlation (n=2595 cohort) between cardiovascular disease and greater blood concentrations of TMAO.
TMAO's molecular structure is common to both carnitine and Choline, and thus it is thought they can bioconvert in the body. TMAO is thought to contribute to atherosclerosis by promoting cholesterol influx into macrophages, which then promotes foam cell formation (and then the foam cells themselves become plaque); this was confirmed in ApoE-/- mice (genetically modified mice used for cholesterol research purposes) in this study, and appeared to influence macrophages derived from wild-type mice as well. This mechanism is plausible.
The study above noted that following consumption of l-carnitine (180mg via sirloin and 250mg via radiolabelled capsules), TMAO was confirmed in both the blood and urine. The role of intestinal microflora was confirmed when participants were put on antibiotics (to suppress the microflora), which abolished diet-induced TMAO increases. Furthermore, this increase was detected in omnivores but not long term (more than 5 years) vegetarians and vegans, and seemed to be related to a higher gut population of Prevotella bacteria.
Finally, the researchers conducted a study in APoE-/- mice. The mice fed carnitine had roughly double the plaque buildup vs mice that were not fed carnitine. This was again abolished with antibiotic treatment (to destroy the gut:TMAO link). It should be noted that APoE-/- mice are genetically modified to exacerbate any bad cholesterol effects (for research purposes).
Note: The previous version of this article made note of '1.3% carnitine in the diet' which was a misreading from the paper. Carnitine was supplemented at 1.3% of the drinking water. Quantification of carnitine ingested is difficult, but assuming an intake of 5mL of water daily (somewhat in the ballpark of mouse studies) this would translate to 65mg carnitine in mice (and assuming 25g in weight, which is in the ballpark for a 10 week old female mouse, 2,600mg/kg) and a preliminary human estimate of 208mg/kg. This oral dose is not practically achieved via supplementation or diet despite what the first draft stated; we apologize for any confusion
Overall, what can we conclude from this study?
What cannot be concluded from this study?
What can plausibly be concluded, but requires future research to confirm?
TL;DR?
The study found that in genetically modified mice, a high (but not impossible) dosage of l-carnitine did double plaque buildup. This may or may not be related to TMAO, we cannot say. This may or may not happen in humans, we cannot say. Overall? It's just preliminary research that should only interest other researchers, not the layperson.
At this time, restricting your carnitine consumption is not a prudent response for most people.
Want to learn more? See if red meat causes cancer.
There are four major supplement updates this week, three of which are new additions to the database whereas the final update is a major supplement that has been revamped.
Echinacea has been added as somewhat of a reference for being an 'anti-cold herb.' Echinacea is technically better than placebo for reducing both sickness frequency (in those who are frequently sick) and the duration of sickness, if taken at the first signs of sickness. Echinacea does not appear to do anything to the symptoms themselves.
Overall echinacea appears to be noteworthy, but at the same time the unreliability of it reduces a lot of faith one can put into the supplement. It is likely that some of the alkylamides are more effective than others ('alkylamide' refers to the collection of more than a dozen molecules which appear to be active) and future research may require isolating these alkylamides and seeing which one does what.
So if echinacea's effectiveness is weak, do we have something that shows promise? Kan Jang capsules (a Traditional Chinese Medicine consisting of both andrographis and eleuthero) have preliminary evidence to support a strong reduction in symptoms, mostly affecting the nose, ears, and throat and also reducing sickness length. Andrographic paniculata was added a few weeks back and appears to be the active component, and we have added the other component known as Eleutherococcus senticosus (formerly known as Siberian ginseng and totally unrelated to Panax Ginseng).
Eleuthero (as its common name) does not appear to be very effective for physical exercise performance improvement, although it may possess Adaptogen-like effects and anti-fatigue effects. There are some cognitive protective effects in rats that, while not amazing, are better than other dietary supplement and perhaps deserve some more investigation.
Unrelated to both immunity supplements above is Stevia, the natural sweetener. This one is interesting as it is both bioactive (can exert benefits to the body at fairly normal doses) and is theoretically possible to overdose on stevia. An overdose of stevia is likely to negatively influence fertility before anything else, and although controlled usage of stevia is unlikely to have such negative effects, the dose of stevia that is required to induce negative effects is wholly possible (probably around 8g a day, which is still a fair bit). Other sweeteners (aspartame and sucralose) are mostly inactive until extremely high levels of dosage, which allows a great safety buffer. This appears to be absent with stevia.
Finally, our major update was to Coenzyme Q10. It is highly recommended to supplement with CoQ10 if you are using statin drugs or after a myocardial infarction, and preliminary evidence suggest very effective symptom reduction for fibromyalgia. There are a lot of other disease states that also have lower CoQ10 levels, but have less evidence for their usage. Due to the interaction with heart health, it has been added to our heart health stack.
Beyond select disease states where CoQ10 is astoundingly important, CoQ10 is mostly just a moderately potent cardioprotective agent. It can reduce artherosclerosis somewhat (somewhat novel at the level of the lipoprotein, not novel at all at the level of the blood vessel) and secondary to that may reduce Blood Pressure, but is a bit unreliable in doing so.
Due to the high safety threshold with CoQ10, supplementation is either beneficial or a waste and is likely never adverse or dangerous. Finances may be the determinant if a healthy person wants to use CoQ10 supplementation, as many of the benefits that occur without a disease state may be present but too small to notice.
While it’s hard to define the exact date Examine.com was formed, it’s safe to say that it came about around the middle of March, 2011. What is definitive is our goal is still the same - to be the reference site when it comes to supplementation (and via frequently asked questions, nutrition).
In terms of traffic and reach, we continue to grow. We are on pace to easily crack 200,000 visitors this month. Those visitors will spend over two minutes each on our site, and will generate roughly 450,000 pageviews! We also have over 7000 Facebook likes across our site (not including our fan page), and Claire Yates was our 1000th follower on twitter (perfect timing, she just followed us).
On top of that, we now feature over 15,000 references. Our Human Trials database now has over 1500 studies, of which over 1000 are double blind. The Human Trials database is also getting a significant update, but that's for another day.
We’ve always focused on one goal – to be a reference site. We’ve had no desire to be in the content generation game, and other than tackling hot topics via our blog, we’ve kept to our original mission.
We do need help. While 200,000/month may seem a lot, it’s not to us. We want 10x that. The reality is that the content matter on Examine.com can be dry – we don’t engage in sensationalism and we don’t engage in top 10 lists to drive us traffic. We aren’t afraid of controversy, but by the time we get done covering nuances on any topic, we don’t really generate a lot of anger. We do get an email a day saying how useful Examine.com was, and we love those emails.
So how can you help? Spread the word. Share us on Facebook, tweet about how awesome we are (it's true!), and if you have a blog or site, link to us. We're doing our best to inform the public, but we cannot do it without you.
Have to be honest - we are really excited about the upcoming year and seeing where it takes us (we do have a few things planned ...)
A pair of posts from the author Rob Rhinehart outlining a meal replacement shake referred to as 'soylent' has been travelling around the internet the past few days. Soylent is a shake containing 200g carbohydrate (5g fiber), 50g protein, and 65g fatty acids (totalling around 1,585kcal). For the most part it includes the RDA value of all essential micronutrients. The carbohydrates are derived from starches, and the source of the protein and dietary fats are not stated in the article, though claimed to be from soya and lentil in a VICE interview. Beyond the above standard meal replacement shake, some other nutrients were added including Panax Ginseng (50mcg), Ginkgo Biloba (100mcg), Omega-3 fatty acds (750mg, source not stated), Lycopene (500mcg), lutein (500mcg), Vanadium (100mcg), and alpha-carotene (similar to beta-carotene, a vitamin A precursor).
From what we can tell, the authors intentions are good hearted and prudent:
"I am reticent to provide exact brand names and instructions because I am not fully convinced of the diet's safety for a physiology different than mine"
"I was home for Christmas and saw an elderly family friend get admitted to the hospital after losing an unhealthy amount of weight. He was losing strength in one of his arms and found it very difficult to cook. I started wondering why something as simple and important as food was still so inefficient, given how streamlined and optimized other modern things are. I also had an incentive to live as cheaply as possible, and I yearned for the productivity benefit of being healthy. I'd been reading a lot of books on biology, and I started to think that it's probably all the same to our cells whether it gets nutrients from a powder or a carrot."Yet too simplistic:
"The body is a complex machine. There are a lot of substances and chemicals required for it's optimal operation. However, it is also extremely robust. Many people aren't getting the recommended amount of any of these substances, but the body is able to compensate via complex regulatory systems. This hurts in the long run, though. In fact, turning food in to energy is the primary process that ages the body. By giving it only what it needs, and nothing it doesn't, I am optimistic about the long term effects. The short term effects are already clear."
The closing area of his article where he states:
So...I'll just ship you some of my batch. If you are willing to consume exclusively soylent, and get a CBC, chem panel, and lipid blood test before and after the week and share your results with me it's on the house. Bonus points for getting a psych evaluation before and after. The brain is an organ. I can ship it worldwide but it would be nice if you were in San Francisco so we can meet in person
Leads us to believe that this is more about self-experimentation than anything else. Thus, this seems to be more about good intentions than some kind of money-making scheme.
That being said, there are a few complications with the soylent formulation independent of the author's intentions:
Soylent really needs a reformulation if this takes off and more people decide to 'experiment' with themselves. Bumping the fiber up to 30g and adding some pseudovitamins would be a good start, but honestly the exclusion of food is something not many people should even consider. Once that happens, then it would likely just become another standard meal replacement shake.
The inherent problem with micromanaging foods down to their molecules is that there is a remarkable amount of molecules that you need to keep track of - the essential vitamins and minerals are not enough. Meal replacement shakes have, up until now, thrived as they replace one or two meals in the day and then mention that the consumer should 'eat a healthy well balanced meal' otherwise; absolute exclusion of food has never been recommended traditionally.
Soylent is not a new concept, although the idea of a meal replacement shake may be getting a second wind due to soylent. It needs a reformulation as the current one is very loosely based on what the RDA of micronutrients. It's quite deficient in several areas, and needs a much more thorough evaluation on its contents.
The last two weeks have seen numerous popular supplements added to the Examine database, with quite a few of them also doubling as food products.
Hemp Protein is a protein source derived from hempmeal (seeds after the oil has been extracted) and is mostly marketed for its 'balanced' fatty acid content of omega-3 and omega-6 fatty acids. It does appear to have a balanced profile, but the benefit of this in practical terms is doubtful due to the omega-3 source being alpha-linoleic acid rather than the Fish Oil omega-3s (EPA and DHA). Although there is no THC content in hemp protein like there is in Marijuana, there does appear to be some limited cannabinoid content; the practical relevance of these cannabinoids in hemp protein is currently not known (and it is unsure whether one can extrapolate data from marijuana onto hemp protein).
Psyllium has been added and is the first in the new Dietary Fiber category page. Psyllium appears to be quite effective and proven as a 'bulk laxative' (laxative secondary to forming stool) and due to its low fermentability in the colon it resorbs a fair bit of water and possible gas to increase fecal mass, softness, and regularity. At least one study has noted decreases in flatulence associated with psyllium ingestion, and although there are health effects associated with psyllium (reduced serum glucose and cholesterol) these do not appear to be unique to psyllium and instead just common to any gel-forming fiber.
Coconut Oil is a highly saturated source of medium chain triglycerides (MCTs), and appears to be somewhat effective as both a skin and hair moisturizing agent when directly applied (although the greasiness of coconut oil might need to be accounted for. When used as a part of a fat loss diet, there appears to be sufficient evidence to support the role of coconut oil in place of other fatty acids to increase the amount of fat lost over a period of time. The effect size is not remarkable, and sometimes the benefit is small enough that the difference is not significant; however, there does appear to be a beneficial effect of coconut oil MCTs on fat loss.
Of supplements that are not food products:
Noopept was finally added, and based on limited evidence it does appear to be very similar in mechanism to Piracetam while requiring a much lower dose. Similar to piracetam, however, it does require more evidence in otherwise healthy subjects or animals to confirm a cognitive boosting effect
Lavender was added to round out our Aromatherapy section, and actually appears to be a much more supported aroma than all the others. The aroma of lavender appears to be able to induce a reduction in anxiety and some limited sedation in numerous trials, and oral ingestion of lavender essential oil has some surprisingly robust evidence for it for reducing generalized anxiety disorder.
7-Keto DHEA was taken from the DHEA page and given its own entry due to the low hormonal activity of it. While 7-keto DHEA appears to be an anti-stress molecule and mitochondrial uncoupling agent, it requires more evidence and some larger studies to validate its usage in humans as the limited evidence right now is highly confounded with conflicts of interest or other nutrient inclusion. That being said, 7-keto DHEA may be able to increase the metabolic rate or at least attenuate the rate of decline during dieting.
Nattokinase is a dietary enzyme found in some fermented soy products that is said to be cardioprotective by reducing fibrin binding and thus reducing the risk of thrombus formation. The evidence to support this claim is very limited and currently there isn't any evidence to support the usage of nattokinase over simply eating natto (which may actually be more effective, as nattokinase is but one of many enzymes created during the fermentation process)
The major update this week is:
Beet Root, but more precisely its active ingredient known as inorganic Nitrate. Nitrate is commonly ingested in vegetables and appears to also be endogenously produced in the body to a limited degree (almost meeting the nonlegitimate criteria of our Pseudovitamin category if it can be linked back to a disease state associated with a deficiency). Nitrate's metabolite, nitrite, circulates in the blood and is readily converted to Nitric Oxide with preferential conversion in deoxygenated areas of the blood and microcirculation.
It appears to quite reliably reduce blood pressure in persons with elevated blood pressure, and although blood pressure in healthy persons at rest in unaffected it seems to attenuate the rise in blood pressure during exercise.
Nitrate supplementation at or around 500mg reduces the oxygen cost of exercise and appears to be able to make mitochondria more efficiently work (secondary to nitric oxide). Due to this, usage of nitrate supplementation before exercise that is not maximal exertion but more glycolytic in nature (sprinting, prolonged resistance training upwards of 12 reps or so, crossfit) is able to prolong time to exhaustion, improve performance on time trials, and sometimes reduce the rate of perceived exertion. The effect size of nitrate is larger in these trials, nonexistent in maximal power output, and lesser in prolonged endurance exercise but appears to be greater than that of Beta-Alanine supplementation.
Finally, nitrate is converted to nitric oxide independently of the NOS enzyme (mediates conversion of L-Arginine into nitric oxide). This suggests that nitrate supplementation would be potentially additive with L-Arginine or L-Citrulline as they do not interfere with one another, but this requires some testing.
Nitrate appears to be a potential pseudovitamin compound with cardioprotective and performance enhancing effects, with the latter being slightly more effective than beta-alanine.
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