Weight and the Microbiome

Often people have weight issues — despite rigorous diets. With CFS, many patients are skinny and unable to gain weight while others eat only celery and stay obese. The fat CFSer often has their fatigue ascribed to being obese by physicians and ascribe the issue to the patient’s attitude and lack of wiliness to change.

There can be DNA and epigentic causes (for example, my weight increase with stress and reduces when the stress is significantly reduced). For example, my own DNA report from 23andMe shows:

weight

In this post, I am going to look at bacteria that are associated with being obese or lean.

  • “So far, evidence of an antiobesity effect of different lactobacilli and bifidobacteria has been mainly obtained from animal models of dietary-induced obesity. Using these experimental models, a substantial number of studies have reported reductions in weight gain and, in particular, fat tissue mass at different locations following administration of bacteria, as compared with controls.” [2016]
  • ” Of the four probiotic candidates, the bifidobacteria B. longum BORI and B. bifidum BGN4, developed in our laboratory, and L. acidophilus AD031 showed excellent anti-obesity effects and suppressed lipid deposition in liver.”[2016]
  • “Members of the Firmicutes phylum, and Bifidobacterium longum, were more abundant in the lean group.” [2016]
  • “Cross-sectional studies have shown that certain bacterial populations – such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Methanobrevibacter smithii and Christensenellaceae – are better represented in lean individuals compared to those who are overweight or metabolically unhealthy.” [2016]
  • “The Bacteroides fragilis group were found at high concentrations in obese and overweight children when compared with the lean ones (p 0.015). The obese and overweight children harboured higher numbers of Lactobacillus spp. than lean children (p 0.022)…. Furthermore, a negative correlation between BMI and Bifidobacterium spp.  (r = -0.22; p 0.039) was observed. ” [2016]
  • “Our results suggest that the Mediterranean diet could be a useful tool to restore potentially beneficial members of the gut microbiota [reducing obesity], although the stability of these changes over time still remains to be assessed… better than a low fat high carbohydrate diet” [2016]
  • “… suggesting a causal role of gut bacteria in development of obesity-related metabolic diseases and a potential for microbiota modulation as a strategy to improve host health…the positive association with a healthy metabolic profile suggested for B. longum and F. prausnitzii” [2015]
  • “The obese children have a lower amount of Bifidobacteria and higher amount of E.coli (smaller B/E ratio) compared to normal non-obese children.” [2015]
  • Potential probiotic Bifidobacterium animalis ssp. lactis 420 prevents weight gain and glucose intolerance in diet-induced obese mice [2014].
  • “These results may contribute to explain the body weight gain reducing effects of the Rosemary Extract.” [2014]
  • “The results show that resveratrol (200 mg per kg per day) significantly lowers both body and visceral adipose weights, and reduces blood glucose and lipid levels in HF mice. Resveratrol improves the gut microbiota dysbiosis induced by the HF diet, including increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Enterococcus faecalis, and increasing the growth of Lactobacillus and Bifidobacterium.” [2014]
  • “The acquired obesity observed in patients treated with [antibiotic] vancomycin may be related to a modulation of the gut microbiota… Vancomycin was associated with a 10% BMI increase ” [2013]
  • “Analysis of the eligible articles pointed out that Lactobacillus gasseri SBT 2055, Lactobacillus rhamnosus ATCC 53103, and the combination of L. rhamnosus ATCC 53102 and Bifidobacterium lactis Bb12 may reduce adiposity, body weight, and weight gain.” [2014]
  • “The fecal concentration of Lactobacillus reuteri was positively correlated with BMI (coefficient=0.85; 95% confidence interval (CI) 0.12-0.58; P=0.02) in agreement with what was reported for Lactobacillus sakei.” (i.e. more means fatter!) “As reported, B. animalis (coefficient=-0.84; 95% CI -1.61 to -0.07; P=0.03) and M. smithii (coefficient=-0.43, 95% CI -0.90 to 0.05; P=0.08) were negatively associated with the BMI. Unexpectedly, E. coli was found here for the first time to negatively correlate with the BMI (coefficient=-1.05; 95% CI -1.60 to -0.50; P<0.001).” [2013]
  • Obesity-associated gut microbiota is enriched in Lactobacillus reuteri and depleted in Bifidobacterium animalis and Methanobrevibacter smithii.[2012]”

Bottom Line To Reduce Weight

There is likely no magic formula in the research above. Most diet focus on reducing calories and not trying to shift the bacteria towards the lean mixture. For another author’s view, see this on DietVsDisease.org

Lactobacillus is often associated with obesity for many strains. Yogurt and other lactobacillus food are likely good for increasing weight but not decreasing weight.

  • ENCOURAGE faecalibacterium prausnitzii, see this earlier post.
  • Lactobacillus gasseri  – which Swanson sells ($15 for 120 capsules of 3 BCFU)
    swa027
  • Bifidobacterium longum – you want it to be without any lactobacillus.
    71oy8qkmqpl-_sy679_
  • Bifidobacterium animalis subsp. lactis (BB-12®)

    7534_en_large

  • For a list of Bifidobacteri mixtures and their contents, see this post. Phillips Colon Health Probioplus DDS Five Strain looked like a good choice, but appears to be off the market now 😦
  • Change of diet towards Mediterranean Diet
  • Increase use of Rosemary in cooking
  • Resveratrol – Grapeseed, red wine, or as a supplement
  • Reducing Bacteroides fragilis — using the post on OTC medicines, we see taking Calcium supplements (including laxatives) reduces this group.

 

Typical OTC medicine and the Microbiome

Recently I discover a nice study that show how various over the counter medicines alters the microbiome. Taking various ones may help or hinder restoring a dysfunctional microbiome.

The article was published in October 2016 and the full text is available. The chart below show the changes reported. Note that that “None” means no OTC and a healthy person (i.e. what we likely want to strive for)
nihms-731256-f0001

Later in this article, we have more details on how combinations influences the microbiome. Unfortunately, Abx – antibiotic do not specify which ones.

  • “Medication use in our study was similar to what was found in the Mayo Clinic study using data from the Rochester Epidemiology Project [26].”
  • “Because our study was not experimental in design, we cannot ascertain whether the gut microbiome is a reflection of the medications per se or of the underlying disease that the medications were intended to treat. There is ample evidence that antibiotics will reduce bacterial abundance [27,28] but for some medications (NSAIDs, antidepressants), it is possible that the bacterial composition could partly reflect the underlying condition.”

Bottom Line

I am not going to draw any conclusion as to what to use or avoid. There are too many combination used by CFS patients, so I will have to leave it to the readers to reach their own conclusion. Just consider changing some of them to see if that will cause an improvement.

What I found very interesting is that I recall around 2001 on the Yahoo Group, CFSFMExperimental, that one member claimed to have gone into remission for almost one year by drinking cough syrup everyday.  He then relapsed. There was much speculation as to why.  It is now apparent that he was successfully altering his particular microbiome shift — but failed to re-establish a normal one. The bacteria eventually adapted to the cough syrup.

Calcium Channels and CFS?

A reader wrote:

“Need your brain. 

GastroCrom and Tramadol are both mild calcium channel blockers. Both vasodilate.  They are my 2 best meds. With the new Australia study and connection to this calcium ion function issue – how does this connect? Also appears to be activated by pregnenolone. My level were very low. I have been taking it for about a month and it’s helping things in so many ways. 
The dysfunction of this causes inflammation and pain. Both of which are my worst symptoms. It also has connections to muscarniaric receptors. Both 1 and 2 have been found with POTS and 3 with Sojourn. This is my next thing to have checked. 
I’ve been saying for years that there is some sort of issue in calcium channels. If I try to stop either med, my POTS(Postural Orthostatic Tachycardia Syndrome) and MCAS( Mast cell activation syndrome) gets worse.
I had a MCAS attack on my heart (called Kounis Syndrome), after chewing too much sugar free gum. Aspartame possibly creating too much glutamate -activating sympathetic system, degranulating mast cells. Tramadol also works on NMDR (glutamate channels). “
With the cognitive issues with CFS (which I know first hand) and being well recovered, I am glad to lend a cognitive hand when needed to understand why something may work.

Basic Actors

  • GastroCrom  is Cromoglicic Acid ” is traditionally described as a mast cell stabilizer, …prevents the release of inflammatory chemicals such as histamine from mast cells.”
    • Since excessive histamine is common with CFS patients, I would ascribe that this is why it helps you so much. Earlier posts on histamine –Mar 14, Mar 15Mar 16
  • Tramadol ” is an opioid pain medication
    • “As of 2015 tramadol was not approved in the United States for fibromyalgia.[16] Based on three small trials with weak study design, there is fair evidence for tramadol as a second line treatment.[16]”  It also “increase central serotonin neurotransmission. “[2016]
    • “Earlier studies suggest that CFS may be associated with genetic variability in genes important for serotonin (5-HT) signaling [3,4].” [2015]
    • “Chronic fatigue syndrome (CFS) or Myalgic Encephalomyelitis (ME) is characterized by…autoimmunity to serotonin” [2015]
  • Aspartame ==> glutamate: I could only find studies indicating no evidence [1980] [1986] [1987], but did find
    • ” Plasma phenylalanine concentrations were significantly higher (p less than 0.05, paired t test) after ingestion of meals containing aspartame” [1982]
    • Aspartame has conflicting evidence with two positive and two negative provocation studies [for causing headaches]. Observational studies provide modest evidence that gluten- and histamine-containing foods as well as alcohol may precipitate headaches in subgroups of patients.” [2016]
Next, let us look at a graphic of what pregnenolone is involved in (Note that Cortisol and Aldosterone quantities are increased by it).
preg

POTS

  • “Selective serotonin reuptake inhibitors (SSRIs) are often prescribed in patients with postural tachycardia syndrome (POTS), and act at synaptic terminals to increase monoamine neurotransmitters.” [2014]
  • ‘Pharmacologic treatment is recommended on a case-by-case basis, and can include… , mineralocorticoid agents to increase blood volume, and serotonin reuptake inhibitors.” [2010] (for mineralocorticoid see above diagram)

Bottom Line

The two drugs acts strongly on two different aspects of CFS:

  • Excessive histamine is reduced (probably, microbiome associated)
  • Improved serotonin signalling (possibly DNA associated), which may also impact POTS

They may act on other aspects but that is difficult to evaluate given the dominant aspects that they are known to act upon.

Second Question  – Calcium Channels

Now the explicit question about Calcium Channels.

  • “It is suggested that chronic fatigue syndrome/fibromyalgia is caused by virus injury to the calcium channels leading to larger quantities than usual of calcium ions entering the striated muscle cells.”[1994]
  • “Circulating autoimmune antibodies may produce symptoms of muscular fatigue by reacting with acetylcholine receptors or calcium binding channels … We were unable to detect any pathogenic antibodies.” [1997]
  • ” We also report for the first time,… as well as decreased intracellular calcium within specific conditions in CFS/ME patients.” [2016]
  • “Given the important roles of calcium (Ca2+) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients…. identified a number of SNPs and genotypes in genes… These may …. suggest a role for Ca2+ dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.” [2016]
  • “TRPM3 activity and function in NK cells in CFS/ME patients is impaired, resulting in changes in Ca2+ ion concentration in the cytosol and intracellular stores which may, in turn, change the NK cells’ activation threshold.” [2017]

My take is that the impact of the two drugs mentioned above with calcium channel (still speculative, the “may” keyword) is far less than their impact on two established aspects of CFS.  It may be there, but these two drugs are not suitable to demonstrate that calcium channels (versus other things) is involved or effective for treatment.

 

 

Cholestyramine

In my last post, Cholestyramine appear as a good supplement based on surveys. Wikipedia describes it as ” a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrenedivinylbenzene copolymer.” – a description likely above most CFS cognitive ability.

In terms of CFS, R.C. Shoemaker, M.D. first proposed it in his 2001 article on possible estuarine-associated syndrome (PEAS)   citing ” resolution with cholestyramine treatment suggests a neurotoxin-mediated illness.” as well as from Sick Building Syndrome [2005], [2006].

  • [Chronic Lyme] “Patients coinfected with B burgdorferi and B microti derive measurable clinical benefit from prolonged treatment with atovaquone and cholestyramine” [2006] – 20% became asymptomatic, 64% improved.

On the negative side, 2010 study on a condition that often had fibromyalgia, found “Fatigue was associated with greater use of prescription medication (P < 0.01), in particular for antipruritics (cholestyramine: P < 0.001; rifampin: P < 0.001), proton pump inhibitors (P < 0.002), beta-blockers (P < 0.02), and antidepressants (P < 0.001), whereas those taking calcium and vitamin D appeared less fatigued (P < 0.05).” There are a number of articles on Irritable Bowel Syndrome with Diarrhea.

  • Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea.”[2015]
  • ” An estimated 70% to 96% of chronic diarrhea patients with Bile acid malabsorption respond to short-course cholestyramine.” [2013]

Microbiome Impact

  • “In vitro studies have shown that some bile salts inhibit the growth of intestinal bacteria…the number of ileal anaerobic microorganisms decreased significantly after both bile salt and cholestyramine treatment.”[1975] This is good because
    • “A significant increase of Gram positive facultative anaerobic faecal microorganisms in 108 CFS patients as compared to 177 control subjects (p<0.01) is presented in this report.” [2009] In other words it appears to counter one aspect of the microbiome shift seen in CFS.
  • “Certain organisms such as Bacteroides fragilis are stimulated by bile acids and the activity of such bacteria may be decreased by the unavailability of bile acids bound to the resin [cholestyramine].  Secondly, certain bile acids exert a pronounced bactericidal effect at pH 5-6 and this decreases as the pH rises to 7-2 (Percy-Robb and Collee, 1972). ” [1978]

Bottom line: this is a prescription drug which appears to work well when prescribed, typically for Irritable Bowel Syndrome with Diarrhea. It does impact growth of different bacteria and may shift the population closer to normal in CFS patients.

If your MD is willing to prescribe it for 12+ weeks, around 80% of CFS patients may see improvement. Of course, it would be nice to an actual study on CFS patients with microbiome samples done before and after.

 

 

 

Surveys on Supplements

In my last post, I gave a Cookbook based on PubMed articles and some surveys on this site.  CFS patients often ask on support groups — what to take, and the quality of recommendations vary greatly! The ideal response or guidance for any supplement, probiotics or anti-infection agents would be:

  • Probability of improvement
    • Degree of improvement is often very subjective
  • Probability of problems / deterioration
  • Quantity taken (many pubmed studies have no effect seen until a certain dosage was reached)

IN this post I will list survey sites that I found and list items that were not included in the Cookbook or the Surveys. Items need at least 10 responses in the survey to be included

  • ME Association of UK 2010 Survey:
    • CORTICOSTEROID eg HYDROCORTISONE: Better 33% Worst 21.6%
    • THYROXINE: Better 41% Worst 10.8%
    • MODAFINIL/PROVIGIL: Better 37% Worst  29.6%
    • EICOSAPENTAENOIC AID (EPA) OMEGA 3 OIL: Better 36.3%  Worst 4%
    • L CARNITINE: Better 30.8% Worst 6.3%
    • INOSINE PRANOBEX/ IMUNOVIR: Better 25.8% Worst 24.2%
    • Enada/NADH: Better  19.9% Worst 16.8%
    • EVENING PRIMROSE OIL: Better  28.4%  Worst 5.4%
  • https://beta.groups.yahoo.com/neo/groups/CFSFMExperimental/polls/close
    • EDTA (thylenediaminetetraacetic acid): 32.5% improved 12% worst
    • my experience with getting a saline drip has been (short term): Better 72% Worst 0%
    • low dosage naltrexone www.lowdosenaltrexone.org): Better 26%  Worst 26%
    • ImmunoPro (non-denatured whey): Better:  47%  Worst 24%
    • Alfred Blasi protocol (http://health.groups.yahoo.com/group/Al fredblasiprotocolFMSCFS/ ): Better: 46%  Worst: 11%
    • Salt/C Protocol (http: www.lymephotos.com):  Better 36%  Worst: 12%
    • Gookinaid: Better: 54%   Worst: 46%
    • the Hemex Protocol (anticoagulants, ISAC panel Mocha Panel): Better: 48%   Worst:  27%
    • Cholestyramine: Better: 58%   Worst: 8%
  • http://www.storiesoutloud.co.uk/supplements/pollresultsall.py
    • Coconut Oil: Better: 81% Worst: 6%
    • Probiotics (not specific): Better: 69% Worst: 0%
    • Vitamins
      • B Vitamins: Better: 69% Worst 0%
        • B12: Better 59%, Worst 5%
        • Folic Acid or Methylfolate: Better 40%  Worst 15%
        • NADH: Better  27%, Worst 9%
      • Vitamin C: Better: 66%  Worst 0%
      • Vitamin D: Better  54%, Worst 14%
    • Minerals
      • Magnesium (Not Epsom Salts): Better: 74%  Worst 6%
      • Epsom Salts (Magnesium Sulfate):   Better: 92% Worst 0%
      • Calcium: Better  25%, Worst 17%
      • Sea Salt: Better: 83% Worst 0%
      • Selenium: Better 60%,Worst 10%
      • Zinc: Better 56%, Worst 6%
    • Digestive Enzymes: Better: 55% Worst 6%
    • Garlic: Better: 50%, Worst 0%
    • Turmeric/Curcumin: Better 60%, Worst 7%
    • Dehydroepiandrosterone (DHEA): Better 60% ,Worst 10%
    • Omega 3 (No Particular Oil): Better 47%, Worst 0%
    • N-Acetyl-L-Cysteine (NAC): Better  60%, Worst 13%
    • Spirulina: Better 40% , Worst 0%
    • Co-enzyme Q10 or Ubiquinol: Better 55%, Worst 19%
    •  Melatonin:  Better  56%, Worst 20%
    • Acetyl-L-Carnitine (ALC): Better  48%,Worst 9%
    • D-Ribose: Better 51% , Worst 18%
    • Evening Primrose Oil: Better 38%, Worst 8%
    • Ginkgo: Better 45% , Worst 18%
    • Milk Thistle: Better 46% , Worst 23%
    • Valerian:  Better 64% , Worst 29%
    • Chocolate or Cocoa:  Better 48% , Worst 24%
    • Ginseng (American or Asian/Korean/Panax or Siberian): Better  25%, Worst 8%
    • 5-HTP: Better 33% , Worst 40%
    • Echinacea:  Better  6%, Worst 25%

Bottom Line

If you know of additional surveys/polls please pass their URL along.

A lot of items are sitting around 50% for helping…   so the first choice should be items with a low percentage of harming (i.e. 10% or less…) and at least a  50% for helping.. This gives a 5:1 risk factor. The top picks from above are:

  • Zero risk of worst
    • Saline Drip – usually not practical
    • Sea Salt
    • Magnesium Sulfate
    • Probiotics (any)
    • Vitamin C
  • High benefit to risk ratio ( with > 50% of being better)
    • 13.5 Coconut Oil
    • 12  B12
    • 8.6 Turmeric/Curcumin:
    • 7.25 Cholestyramine:
    • 7 Zinc
    • 6 Selenium
    • 6 Dehydroepiandrosterone (DHEA):

Dosages?  Most of the surveys do not say anything about dosages. I know a few dosages from studies, cited in this post. My rule of thumb is that the dosage on bottles are not-therapeutic dosages, and do not consider mal-absorption seen in CFS/FM/IBS. Take vitamin B1 (thiamine) as an example: This 2013 study found no improvement below 1500 mg/day and then a major improvement. The typical B1 dosage is:

  • “For adults with somewhat low levels of thiamine in their body (mild thiamine deficiency): the usual dose of thiamine is 5-30 mg daily in either a single dose or divided doses for one month. The typical dose for severe deficiency can be up to 300 mg per day.”  [MedLinePlus.Gov]

IMHO, malabsorption is a major major factor — resulting in effective dosages being much higher than is normally accepted.

 

Cookbook Summary for the Brain Fogged

 

 

Many readers have asked for a simplify summary…

Supplements by Proven Benefits Level

  1. Magnesium:  600-800 mg /day (Post)
  2. Vitamin D3: 15,000 IU/day (post)
  3. Neem (rotate)
  4. Oregano (rotate)
  5. Resveratol – 1000 mg/day
  6. Licorice – 2 gms/day
  7. Zinc
  8. B12
  9. CoQ10
  10. L-carnitine 500mg x 3 times a day – improvement after 4 weeks
  11. NAC – 3 times a day

Cognitive (Brain Fog) Aids

  1. bacopa-monnieri
  2. piracetam

Probiotics

2 weeks on one, then move to the next

 

  1. Miyarisan — Clostridium butyricum –converts d-lactic to butyric acid
  2. Equilibrium – soil based organisms
  3. Lactobacillus fermentum ME3 – converts lactic acid to acetic acid (some people have reported that they smell like vinegar when they start it)
  4. Symbioflor-2  – E.Coli strains –documented to persist
  5. L. Reuteri – produces B12
  6. Mutaflor — E.Coli Nissle 1917
  7. Prescript Assist soil based organisms
  8. Align — Bifidobacteria infantis (B. infantis) 35624

Note that only 2 of the above are Lactobacillus probiotics – most Lactobacillus have negative or no effect.

Postlogue

weight-loss-pills-1

With CFS, I have picked carefully when I put my energies. My main focus is to develop a model, constantly validate if it is consistent with new research and find candidate supplements and prescription drugs.  For each item, I research on PubMed to get the latest findings.

I use the terms candidate because, without actual (well done) studies on humans with CFS/IBS/FM, we do not know it they really have significant benefits. How long do studies take? Often 2-5 years if some researcher become passionate about it.

The model defines what we are wanting supplements and prescription drugs to do. The ideal is something that:

  • Reduces all of the overgrowth of bacteria reported
  • Increase the undergrowth of bacteria reported
  • Does not increase, but decrease d-lactic acid levels
  • Does not increase, but decrease histamine levels

The degree that I drill into everything is well above many CFS-suffers cognitive processing levels.A protocol is what a MD produces, I am a citizen scientist so I can only give suggestions to the best of my analysis.

There are really no good well-constructed studies of probiotics and CFS/FM/MCS. The few studies that there are,  use commercial mixtures often contain L.acidophilus which is contraindicated(bad) for CFS.

  • “The aim of the study was to evaluate the effect of Lactobacillus paracasei ssp. paracasei F19, Lactobacillus acidophilus NCFB 1748 and Bifidobacterium lactis Bb12 on fatigue and physical activity in CFS patients…there were no significant changes in fatigue and physical activity scores.” [2009]

IBS has many studies (see this post). I worked off [Surveys] to a large extent. With these, the pattern is rotation: 2 weeks on one, then move to the next (so we have 16 weeks listed above).

There are many excellent candidate items not cited above.


As always, consult with a knowledgable medical professional before starting or changing supplements.

Bacopa Monnieri – Revisited

A reader wrote:

“Another thing I take to eliminate brain fog is Bacopa Monnieri. It’s sometimes called Brahmi too but Brahmi can also be another thing in Indian medicine (I think?). I don’t claim to be an expert on Ayuveda but all I know is there are several brands that call it each name and all of them work for me. Its effect is almost as strong as modafinil. However, it’s definitely using some other pathway because it’s subjectively different and it also stacks with other stimulants. Caffiene and modafinil both pair well with it and magnify the effects.

This is remarkable since I’m a nonresponder to almost all nootropics and herbs. And whenever I give Bacopa to friends of mine who don’t have CFS, it does nothing for them. But I have a friend with diagnosed fibro and an aquitance with diagnosed cfs. They both got strong subject mental clarity from bacopa too. I’m not sure why it would work so well for people in our cluster? Do you have any guesses?”
I actually did a post on it 13 months ago, and concluded “There are no studies with CFS/FM/IBS patients which would be ideal. My gut feeling (subjective) is that it is worth trying at 500-1000 mg/day.” It is relatively cheap on Amazon, so what is newly found about this? “Safety and tolerability data was well reported for 80% of studies with only 2.3% of all participants reporting mild side-effects.” [2016]

Bottom Line

There was been human studies and the reader report of dramatic improvement is very viable! Brain inflammation is common with CFS (typically seen in 75% of SPECT scans of CFS patients) and that this is effective in reaching the brain. A definite recommendation for anyone with brain fog.