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Friday, 17 November 2017

Beetroot - Cold Hands, Leukoaraiosis, Psychosis and Anxiety in Schizophrenia





Karimnagar, India, where Schizophrenic Rats respond well to Beetroot Juice

If you are not old enough to be interested in dementia, skip through those parts of this post and read about schizophrenic mice and beetroot juice.
There have been earlier posts regarding using nitric oxide (NO) to improve circulation and derive a cognitive benefit.
Many sportsmen have followed up on the research studies that show exercise endurance is improved after taking beet root juice. Since it is not a banned substance they are free to benefit from it.
We know that beet root does not only reduces blood pressure but it actually can increases perfusion, or blood flow, to the brain. Reduced blood flow to the brain is a feature of some dementia. Studies have used MRI to show that circulation is increased. A follow up study has recently been published which shows that beet root juice combined with exercise produced MRI results that resemble those of much younger adults.
In a previous post we saw that cocoa flavanols improved memory in older people and in effect brought them back to where they used to be 20 years previously. With cocoa the mechanism is not fully understood by is believed to “activate the nitric oxide system” in the brain. Cocoa does not produce nitric oxide in the way beet root does. Foods like beetroot and spinach contain large amounts of nitrates and they cause a measurable increase in circulating nitrites in the blood. The nitrites can later on become nitric oxide.
There is a lot of research into cocoa flavanols, mainly in relation to its benefit for those heart disease and more recently dementia. It also has benefits for anyone with diabetes, because it increases insulin sensitivity, as some readers of this blog have confirmed.
Cocoa flavanols appear to indirectly increase eNOS which then leads to more Nitric Oxide (NO). In addition there are antioxidant effects. eNOS reacts with L-arginine to produce NO.
But there is another way to make Nitic Oxide (NO), via nitrite that is circulating in your blood.  To increase nitrite you just eat nitrates, green leafy vegetables and beetroot.
It appears that eNOS does affect nitrite levels, so perhaps more eNOS means more NO is produced and then nitrite stays as nitrite and so the level of nitrite increases. Everything is inter-related.




Interestingly, statin drugs increase circulating nitrite levels just like beetroot.
NO bioavailability is determined by the balance between NO biosynthesis and its degradation by reactions with hemoglobin and reactive oxygen species (ROS).



So in people with oxidative stress there will be less NO. 

Nitric oxide (NO) is a potent signaling molecule that influences an array of physiological responses. It was traditionally assumed that NO was derived exclusively via the nitric oxide synthase (NOS) family of enzymes. This complex reaction requires a five electron oxidation of L-arginine and is contingent on the presence of numerous essential substrates (including O2) and co-factors. Recently an additional, O2-independent, NO generating pathway has been identified, where nitrite (NO2 ) can undergo a simple one electron reduction to yield NO. NO2 is produced endogenously from the oxidation of NO and also from the reduction of dietary nitrate (NO3 ) by facultative bacteria residing on the tongue. Recent data show that dietary NO3 supplementation, which increases the circulating plasma [NO2 ], reduces the O2 cost of submaximal exercise in healthy humans. This finding is striking given that efficiency during moderate-intensity exercise has been considered to be immutable. Therefore, dietary NO3 supplementation may represent a practical and cost-effective method to improve exercise efficiency and exercise tolerance in humans. Given that a NO3 -rich diet may have numerous cardiovascular and other health benefits, dietary NO3 intake may have important implications for human lifelong health and performance.
   
Cold hands
People with poor circulation tend to have cold hands and feet. From the comments in this blog it appears that many people with autism have cold hands/feet.
Do the many Nitric Oxide producing therapies used by sportsmen “warm up” cold hands?
Well we do actually now have some data on this subject. 


At least in the case of beetroot the answer is no.


L-arginine, L-citrulline, eNOS and NO    
It does appear that more eNOS can be beneficial. More eNOS means more NO as long as there is enough L-arginine. If you want to make more L-arginine, the most effective way is to eat L-citrulline, which is abundant in water melon.
It looks like some people lack arginine while others lack eNOS.  The males in clinical trials of citrulline and water melon, as a Viagra alternative, must lack L-arginine.
I think in autism the problem is lack of eNOS.
I thought L-citrulline might increase the positive effect of Agmatine that is very evident in Monty, aged 14 with ASD, but it has no additional effect.
Maybe some people do lack eNOS and l-arginine.
You do not need eNOS to make nitric oxide from the nitrites produced by beetroot juice.

Agmatine
We previously saw that the OTC supplement Agmatine increases eNOS, but it also actually affects BDNF.

Taken together, the findings of this study show that long-term agmatine administration increases the BDNF levels in both the hippocampus and amygdala, and also peripherally the NO synthesis and/or bioavailability, and corrects the age-related endothelial dysfunction, and hence may help in recovering vascular aging and vascular dementia.


Leukoaraiosis
Leukoaraiosis is a new word to this blog, it is very relevant to dementia, but it would likely only be relevant to autism if there has been hypoxia (lack of oxygen). Two readers of this blog do report hypoxia.
There is a lot of information in this blog about treating dementia and so for the sake of completeness I will elaborate further.
It appears that most people with Mild Cognitive Impairment (MCI) or dementia have lsome eukoaraiosis.
Leukoaraiosis also referred as ischemic demyelination or age-related white matter disease, is a radiological term given to white spots that appear on your MRI scan.

It is commonly observed in elderly people, and it is often a finding related to vascular dementia.  Histology from these lesions show atrophy of axons and decreased myelin. It is thought that localized hypoxia is what caused the damage.

On both CT and MRI, leukoaraiosis is characterized by bilateral patchy or confluent white matter changes.
So if your “autism” resulted from hypoxia, you might expect to see white spots on your MRI scan.
What is interesting is that leukoaraiosis may contribute to ongoing mild hypoxia.
It always seemed odd that people might benefit from HBOT (hyperbaric oxygen) years after they suffered acute hypoxia; but if the acute hypoxia left leukoaraiosis, perhaps this then reduces ongoing blood flow and thus leaves mild localized hypoxia, which does respond to treatment.
When blood flow is interrupted to part of the brain your doctor would call that a stroke.  A mini-stroke occurs when that blood flow is only temporarily interrupted.  These so-called transient ischemic attacks (TIA) are a warning sign of what may come shortly afterwards.
It appears in many people mini-strokes occur but remain unreported.
As a result of mini-strokes and/or leukoaraiosis perfusion in older people is not as good as in younger people and so cognition and memory suffer.
This can be partially addressed by making your blood more “slippery” using low dose aspirin, but the risk is that over the years blood vessels have narrowed and become brittle.  You then risk micro bleeds where the blood vessel cracks and the “slippery” blood can leak out.  This does happen in the brain
Cerebral microbleeds are not rare and are seen as another cause of cognitive impairment.





The conclusion for adults is that prevention is much better than cure. A diet rich in nitrates (spinach beetroot etc) and flavanols (cocoa etc) plenty of exercise and avoiding half a century of high cholesterol looks a wise choice. 

Emerging evidence suggests that silent strokes or lacunar infarctions, leukoaraiosis, and vascular diseases may be associated with cognitive impairment including dementia. We assessed the occurrence of these risk factors among various spectrum of cognitive dysfunction. A retrospective review of patients evaluated in Guam with the diagnosis of Memory Loss, Mild Cognitive Impairment (MCI) and Dementia from August 2006 to December 2014 was conducted. The history of stroke and co-morbid vascular diseases was identified. The neuro-imaging studies were reviewed to determine the presence of silent strokes and leukoaraiosis in patients without history of a clinical stroke. There were 585 patients included in the analysis. One hundred forty two patients having a diagnosis of memory loss, 95 have MCI and 348 have dementia. A history of stroke was present in 29% of patients with Memory Loss, 20% of patients with MCI and 30% of patients with dementia. Silent strokes without a history of clinical stroke were present in 10% of patients with memory loss and MCI, and 15% of patients with dementia. The presence of Leukoaraiosis was present in 50% of patients with memory loss, 56% of patients with MCI, and 60% of patients with dementia. Occurrences of vascular diseases were higher in patients with dementia than patients with Memory Loss and MCI. In conclusion, silent strokes, leukoaraiosis and vascular diseases are found to be more prevalent in patients with Dementia than those with Memory Loss and MCI.  

Oxygen deprived areas of the brain can change the way the brain functions in older adults. These areas of the brain were thought to be just a normal part of aging and could lead to other diseases such as Alzheimer's or stroke.
Leukoaraiosis is described as a condition where brain scans (CT or MRI) show bright white dots. These areas of the brain are deprived of oxygen and were considered to be a normal part of aging process.
"There has been a lot of controversy over these commonly identified abnormalities on MRI scans and their clinical impact. In the past leukoaraiosis has been considered a benign part of the aging process, like gray hair and wrinkles," said Kirk M. Welker, M.D., assistant professor of radiology in the College of Medicine at Mayo Clinic in Rochester, Minn., in a press release.
The condition is common in people who are above the age of 60. Recently, leukoaraiosis has been linked to diseases like Alzheimer's, hypertension and stroke.
"We know that aging is a risk factor for leukoaraiosis, and we suspect that high blood pressure may also play a role," Dr. Welker said.
Researchers from the Mayo Clinic obtained brain scans from 18 participants over the age of 60. The brain scans of these participants were matched against those obtained from a control group. Researchers found that these participants had lesions in the brain that were 25 millimeters long while some lesions in the brains of control group participants were about five millimeters long.
The participants were given tests based on words and visual patterns. All the participants were connected to brain scanners during the tests.
The participants of control group and study group completed the task with similar speed. However, researchers found that the brains of people who had moderate leukoaraiosis worked differently than people who had mild lesions.
They found that areas of brains that performed word-association tasks weren't activated during the test but areas that process visual patterns were highly activated.
"Different systems of the brain respond differently to disease. White matter damage affects connections within the brain's language network, which leads to an overall reduction in network activity," Dr. Welker said.
Welker said that diagnosing leukoaraiosis is important in people who are above 60, especially those who have to undergo brain surgery and those who are part of scientific research study.
Previous research shows that the probability of stroke increases with increase in leukoaraiosis spread.
"Our results add to a growing body of evidence that this is a disease we need to pay attention to Leukoaraiosis is not a benign manifestation of aging but an important pathologic condition that alters brain function," Welker said.  

Finally, now you know all about leukoaraiosis, back to beet root juice.


Background:
Exercise has positive neuroplastic effects on the aging brain. It has also been shown that ingestion of beet root juice (BRJ) increases blood flow to the brain and enhances exercise performance. Here, we examined whether there are synergistic effects of BRJ and exercise on neuroplasticity in the aging brain.
Methods:
Peak metabolic equivalent (MET) capacity and resting-state magnetic resonance imaging functional brain network organization are reported on 26 older (mean age = 65.4 years) participants randomly assigned to 6 weeks of exercise + BRJ or exercise + placebo.
Results:
Somatomotor community structure consistency was significantly enhanced in the exercise + BRJ group following the intervention (MBRJ = -2.27, SE = 0.145, MPlacebo = -2.89, SE = 0.156, p = .007). Differences in second-order connections between the somatomotor cortex and insular cortex were also significant; the exercise + BRJ group (M = 3.28, SE = 0.167) had a significantly lower number of connections than exercise + placebo (M = 3.91, SE = 0.18, p = .017) following the intervention. Evaluation of peak MET capacity revealed a trend for the exercise + BRJ group to have higher MET capacity following the intervention.
Conclusions:
Older adults who exercised and consumed BRJ demonstrated greater consistency within the motor community and fewer secondary connections with the insular cortex compared with those who exercised without BRJ. The exercise + BRJ group had brain networks that more closely resembled those of younger adults, showing the potential enhanced neuroplasticity conferred by combining exercise and BRJ consumption.  
BRJ is clearly an encouraging nutritional supplement that may improve functional health in older adults, and the proposed primary mechanism of benefit of BRJ is the rise in plasma nitrite caused by the high levels of dietary nitrate in BRJ (32). Consumed nitrate, once absorbed from the intestine, is taken up from the plasma by salivary glands and concentrated in saliva; nitrate is subsequently reduced to nitrite by oral bacteria and ultimately absorbed into the circulatory system (32,33). Nitrite appears to be reduced to NO during hypoxia. NO is an antioxidant and a potent vasodilator (34,35), is a critical relaxation factor synthesized in endothelial cells (36,37), and is key to vascular compliance. For this study, we hypothesized that reductions in brain blood flow associated with hypertension and aging associated leukoaraiosis result in low-grade hypoxia (38) and that these reductions might be offset by the NO-mediated vasodilation in hypoxic regions due to the increased amount of circulating nitrite from the BRJ ingestion. Indeed, results from our lab have shown that 24 hours of a high nitrate diet supplemented with a single dose of BRJ leads to increased regional CBF in older adults (39). Coupled with exercise (a hypoxia-inducing activity), we propose that the biological mechanism underlying the neural plasticity shown in Figure 1 resulted from increased NO bioavailability after drinking BRJ





Supplementation with nitrate (NO3)-rich beetroot juice has been shown to improve exercise performance and cardiovascular (CV) responses, due to an increased nitric oxide (NO) availability. However, it is unclear whether these benefits are greater in older adults who have an age-related decrease in NO and higher risk of disease. This systematic review examines 12 randomised, crossover, control trials, investigating food-based NO3 supplementation in older adults and its potential benefits on physiological and cognitive performances, and CV, cerebrovascular and metabolic health. Four studies found improvements in physiological performance (time to exhaustion) following dietary NO3 supplementation in older adults. Benefits on cognitive performance were unclear. Six studies reported improvements in CV health (blood pressure and blood flow), while six found no improvement. One study showed improvements in cerebrovascular health and two found no improvement in metabolic health. The current literature indicates positive effects of dietary NO3 supplementation in older adults on physiological performance, with some evidence indicating benefits on cardiovascular and cerebrovascular health. Effects on cognitive performance were mixed and studies on metabolic health indicated no benefit. However, there has been limited research conducted on the effects of dietary NO3 supplementation in older adults, thus, further study, utilising a randomised, double-blind, control trial design, is warranted.
  
Beet Root and Schizophrenia
Having read about cocoa and beet root a long time ago, I did try both on myself. I think beet root has effects that go well beyond lowering blood pressure.
There are of course no trials of beet root in autism, but there is one in the next closest thing, schizophrenia. Unfortunately it was in rats, but nonetheless the findings are interesting.
   
In recent years, there has been much focus on the apparent heterogeneity of schizophrenic symptoms. By contrast, this article proposes a unifying account emphasizing basic abnormalities of consciousness that underlie and also antecede a disparate assortment of signs and symptoms. Schizophrenia, is fundamentally a self-disorder or ipseity disturbance is  characterized by complementary distortions of the act of awareness, hyper reflexivity and diminished self-affection. Anxiety impacts people in ways that they are unaware. In the presence of anxiety, attention is highly directed towards threatening information. Recently, anxiety was found to impact task switching performance when threatening stimuli were present. In the current study, we examined the Anxiolytic and antipsychotic activity of Beet Root Juice (BRJ) in rats. This study reveals that the BRJ has showed decreased effects of turning behaviour, weaving behaviour, head bobbing and falling behaviour. It also showed decreased effect of loco motor activity and increase in catalepsy scoring. Thus it shows anti psychotic and anti anxiety effects.

Ketamine-Induced Stereotypic Behaviour in Mice
Animals were divided into five groups and each group consisted of four animals. The control animals received normal diet and treated with Ketamine (50 mg/kg) for 15 consecutive days. The animals of standard groups received Olanzapine (5 mg/kg) after 30 min Ketamine was given, (50 mg/kg) for 15 consecutive days. The animals of test groups received different concentrations of BRJ (2 , 4, 8% w/w) through a specially prepared diet and after 30 min Ketamine was given (50 mg/kg) for 15 consecutive days. Each rat was individually placed into plastic cages (37 × 24 × 30 cm3) divided into quadrants by lines on the floor and allowed to acclimatize for at least 30 min before the testing began. Behavioural tests were performed between 10 a.m. and 4 p.m. The stereotypic behaviour was assessed by counting the number of turning, weaving, head-bobbing and ataxia. Turning was measured by counting turn around every 15 min over 60 min. Weaving and head-bobbing were measured by counting its neck wave right and left, and go up and down every 15 min over 60 min. Ataxia was assessed by counting the number of falls of each rat on the floor of the cage every 15 min over 60 min period

Beet root juice was as effective as Olanzapine, an antipsychotic medication used to treat schizophrenia and bipolar disorder. (Ketamine is what creates the stereotypy)



Beet root juice was more effective than Haloperidol, a typical antipsychotic medication used in the treatment of schizophrenia, tics in Tourette syndrome and  mania in bipolar disorder


Beet root was as effective as Diazepam (aka Valium), is a medication of the benzodiazepine family that typically produces a calming effect 



I found the above paper very surprising. It certainly supports my feeling about the effects of beet root juice being beyond just lowering blood pressure. It definitely has a calming effect on me, so it is not just in rats.

Beetroot Juice for Autism?
Why not try just try it?
It does taste better when it is 25% apple juice and 75% beetroot.
You can also use freeze dried beetroot powder, which can be put in capsules.
It is not clear the amount of powder you need.
>150 ml a day of juice gives the exercise endurance effect and the calming (Diazepam) effect.  I would guess 2 or 3 fresh beet root would be equivalent.
Freeze dried beet root powder appears to remove 90% of the weight. So 3g of powder equals about 30g of beetroot.
Some people use a teaspoon of beetroot powder to control blood pressure. 
I expect there are studies on beetroot powder and blood pressure.
I concluded in Monty, aged 14 with ASD, that while Agmatine has a significant effect from the first day citrulline has no noticeable effect whatsoever (so no lack of L-arginine).  Having just read about the rats from Karimnagar, India in the above study I started offering Monty some of my beetroot juice. I have filled some large gelatin capsules with freeze dried beetroot, but it is not clear how much you would need.  Better to stick with the juice and see if it does anything.
Beet root is rich in betaine, which is also good for you.
I think Agmatine increases eNOS and also NO, by increasing dietary nitrate we make more nitrite which is available to make more NO as it gets depleted by oxidative stress (Reactive Oxygen Species). It looks like some people with autism have no shortage of L-arginine and so there is no effect from arginine or citrulline supplementation.
I think there is a rationale to consider Agmatine and Beetroot juice. We do have the surprising results from the schizophrenic rats, which do suggest there can be a benefit. 
I have to say that after a year of drinking 150ml of beetroot juice a day, I am a convert. You do get used to the taste. 
Beetroot, cinnamon and cocoa flavanols are quite potent potential non-drug therapies for dementia and not forgetting where you left your car keys.







60 comments:

  1. Another great post -- especially for dementia feeling older parent :) Could you just take beetroot in a capsule. Not endorsing these, but there are a fair number of options in the U.S.

    Solgar Beetroot Extract 500 mg Vegetable Capsule

    Natures Way Beet Root Capsules, 500 mg - 100 count

    Thanks Peter!

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    Replies
    1. It looks like 500mg of beetroot capsule equals just 5g of beetroot. Some vendors suggest 6 tablets a day which would be 30g of beetroot. A food serving of beetroot is 50-100g.

      There are big gelatine capsules (000 size) which I used for cinnamon and cocoa. A teaspoon of cinnamon or high flavanol cocoa is all you need. I think you will need more beetroot.

      My conclusion was you will need so many capsules, it is better to eat/drink the real thing, if at all possible.

      Delete
    2. Peter, I know beets contain other substances than just nitrates but what would you think that nitrates would yield similar benefits?

      Delete
    3. Aspie1983, vegetables contain sodium nitrate, which is also added as preservative in processed meat. While nitrates in vegetables are seen as good, it looks like sodium and potassium nitrate/nitrite added to processed meat may be harmful. It looks like processed meat should be avoided, since there may be a chemical reaction taking place that can be cancer causing, this is quite well known.

      So best to buy 1 liter of beetroot juice and drink it over 5 days. See if you feel and different at the end of the five days. Check blood pressure before and after. In Europe beetroot juice is usually inexpensive.

      Delete
    4. Hi Peter,

      Ive been eating beets and occassionaly the juice, it is somewhat part of the common diet where I live, so I allready got that area covered, also beets do seem better than spinach as a source of nitrates considering eating alot of spinach has the problem of oxalates, or is this also a problem with daily eating beets/drinking beetjuice.

      With regards to clostridicum butyricum I have digged up a bit more it seems this is a very promising strain for those with autism, especially with those with high il-6/tnf-a and low il-10. On top of that I just found it lowers uric acid levels too, whoop!, seems my body wasnt lieing to me after all that I felt so good on it:

      [Effects of Clostridium butyricum on serum uric acid and inflammatory mediators in rats with hyperuricemia].
      https://www.ncbi.nlm.nih.gov/pubmed/28539294

      A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice.
      https://www.ncbi.nlm.nih.gov/pubmed/23768495

      An important role of interleukin-10 in counteracting excessive immune response in HT-29 cells exposed to Clostridium butyricum
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410821/

      A breakthrough in probiotics: Clostridium butyricum regulates gut homeostasis and anti-inflammatory response
      https://www.ncbi.nlm.nih.gov/pubmed/25940150

      The hepatoprotective effect of the probiotic Clostridium butyricum against carbon tetrachloride-induced acute liver damage in mice.
      https://www.ncbi.nlm.nih.gov/m/pubmed/28933492/

      Clostridium butyricum in combination with specific immunotherapy converts antigen-specific B cells to regulatory B cells in asthmatic patients
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746628/

      "Treatment with SIT and CB (clostridicum butyricum) increased p300 and STAT3 activation, UP REGULATED THE IL-10 GENE TRANSCRIPTION and increased the frequency of peripheral antigen specific B cells."

      Immunomodulatory effects of Clostridium butyricum on human enterocyte-like HT-29 cells (induces il-1 AND hsp70 = like sulforaphane)
      http://www.tandfonline.com/doi/full/10.1080/19768354.2013.789075

      "Therefore, since the production of anti-inflammatory cytokines Hsp70 and IL-10 is a protective response, we suggest that one mechanism for beneficial attributes of C. butyricum is the ability to induce the expression of Hsp70 and IL-10."

      Delete
    5. Aspie1983, what dose of Miyairi doe you use? What effect do you notice?

      Delete
    6. Hi Peter,

      Im currently not on it (it should be arriving within 1-2 weeks now), but have used it for about 3 months in the past anywhere from 1 tablet after each meal, all the way up to 15 tablets after each meal (yes thats 45 tablets a day and have noticed absolutely zero negative effects), what I remember from it is that I had perfect stools on it (and I believe even when I am off the clostridicum butyricum I have maintained lots of its positive effects as I stated before in other posts of mine), on top of that it has a very calming feeling (feels very much like it affects gaba, I didnt find it stimulating at all) in that it makes me 'relaxed but not sedated'.
      It also seemed to put me in a better mood, allthough at the same time the clostridicum butyricum also eliminated my bloating after meals (could be indirect mood enhancement due this possibly).

      For me personally its one of the more effective supplements, where as things like ritalin, chocamine (cocoa extract) simply seem to raise mood by being stimulating which I do not like.
      Ashwagandha is calming too, but this felt very different from miyairi, I prefered the calming effect from miyairi, it feels somewhat the same 'type of calm' as skullcap gave me.

      Im sometimes astonished that different gaba like drugs can feel soooo different, I guess this is due to the different receptor subtypes being targetted?

      Delete
    7. Aspie1983, it would be useful to know at what dose there is a behavioral/mood effect. If you could start at a low dose and record the effects that might be useful for others.

      The tablets are really tiny, for those who are wondering how someone can swallow 45 tablets.

      Delete
    8. Will do that Peter, I got the mysari strong version this time I couldnt find any decent seller of the 630 'normal' version on ebay anymore when I ordered.
      From what I remembered 1 tablet of strong equaled about 2-3 of the tablets that were in the 630 pill package.

      It seems like a very promising add-on therapy for autism if you ask me, especially those with il-6 and low il-10, especially the zero side effects that I noticed.

      Delete
  2. With regards to the post, I seem myself to have indeed a mild form of raynauds (purple/red-ish color at the upper part of my fingers and some minor 'scar like' lines that other people of my age do not seem to have.
    It would only make sense that this genetic micro bloodflow problem that I have is either due to adrenoreceptors or some VEGF issue.
    I do not have this scar tissue in my toes by the way eventhough I always used to have cold feet as a kid this seemed to have normalized somewhat but my hands have always remained cold.

    Citrulline helps a very small bit but not much and my 75mcg levothyroxine that does infact normalize my TSH levels doesnt help at all for this, only ginkgo seemed to have some effect.

    I have gotten permission from my psych. to go get my d3, tsh, t4, urea and lipids tested again by the way, she did recommend me to not go to the lab straight away but wait till mid december because I have gotten my d3 and urea levels tested just over a month ago, will be good to see if cordyceps can take my urea down even further, so far it has gone down from like 10.6 to 8.6.

    ReplyDelete
  3. Hi Peter,
    I juiced some beetroot today (about 3) and gave the drink to my son. Wasn't sure how to make it tasty. Any suggestions on a juice recipe?
    Is it possible to just buy the juice? It's going to be about $4 a drink (just the organic beets) to do the juice myself.
    Stereoptypy is an issue so hoping to see some calming effects possibly. Any idea how long a "dose" might last in terms of effect?
    Thanks.
    Nancy

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    Replies
    1. Nancy, in Europe it is easy to buy the juice and it is not expensive. You can also by bulk (freeze dried) beetroot powder and add back the water. I think beet root is much less popular in North America. They are easy to grow in your garden.

      To make it tasty use 1 part apple juice and 2-3 part beet root juice. So you could just add beet root powder to apple juice.

      I think juice once a day is fine. I would try it for a week.

      When I tried it on myself I measured my blood pressure and the effect took place within a day or two. It remains even if you skip a day or two. I only noticed the calming effect when I stopped taking it.

      It does look to be the nitrates which are why it has an effect and you can also get these from dark green broad-leafed vegetables (eg spinach), which are incidentally an important part of the Mediterranean Diet.

      I think you can add nitrates to your diet cheaply, which vegetable depends on where you live.

      Delete
  4. Question for all:
    Has anyone tried low dose naltrexone (LDN)?

    Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia.
    https://www.ncbi.nlm.nih.gov/pubmed/28536359

    "We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF)."

    https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5489802_biomedicines-05-00016-g001.jpg

    ReplyDelete
  5. HI Peter,
    Is the bulk freezedried beetroot the same as the beetroot capsules you spoke of, where it 5 mg of beetroot would be a 500mg capsule? Or tis the freezedried more concentrated?
    I'm also wondering if the juice was not fresh (same day) if the potency would decrease.
    Thanks
    Nancy

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    Replies
    1. Nancy, I imagine that fresh beetroot is best, but most sportsmen, and cyclists particularly, use store-bought beetroot juice.

      You can buy liquid beetroot concentrate, which I imagine is what they use to make store-bought juice. Either that or use the freeze dried powder (also sold in the US).

      In the US this is one product:-

      https://www.amazon.com/Juice-Concentrate-Filled-QUART-Supply/dp/B01KKATK2I

      The cost is about $1 a day.

      I imagine that the capsules are the least potent option.

      Delete
  6. Peter, I never use benzodiazepines with or without Bumetanide.
    In fact my son only tried alprazolam and clonazepam in various dosage and found out that there is always a paradoxical response.
    Even saffron, which is supposed to exert its anxiolytic effects, according to some papers I viewed, through the benzodiazepine binding site, can make him aggressive and restless.
    I just wait to see what the Bumetanide wash out period would be.
    However, I am quite sure that something profoundly helps my son with obsessive and rigid thinking which I could partially attribute to vitamin D3 supplementation. I am satisfied with it but I am alert to find ways to overcome possible loops.
    With respect to your theory, if we wish to positively affect chloride levels and L-type calcium channels, vitamin D3 is being researched as an antiepileptic alternative to AED's.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143473/

    " Rather, it is more likely that Vitamin D3’s rapid, anticonvulsant effect results from its ability to fine-tune Ca2+ and Cl− currents across neuronal membranes (54, 55). Vitamin D3 initiates non-genomic signal transduction pathways that ultimately alter the conductance of L-type calcium channels and chloride channels, therefore affecting neuronal excitability and seizure susceptibility at the threshold level"

    Whether AED's or vitamin D3 is more toxic and when to stop giving is an issue I have to deal with and of course I wouldn't like to get into discussions about the industry that is being made up of it as long as it helps my son.

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    Replies
    1. Petra, alprazolam clonazepam and valium are all benzodiazepines.

      The original idea behind the French research into bumetanide for autism came because a psychiatrist told the researcher how odd it was that his patients with autism often had a paradoxical response to valium (no bumetanide used). In other words the normally inhibitory GABA was excitatory.

      If your son has a paradoxical response to alprazolam and clonazepam he would be similar to the patients of that French psychiatrist. This is a marker for who is likely to respond to bumetanide.

      I think L-type calcium channels play a role in the autism of people who have allergy, mast cell activation and probably some of those with GI problems. If your son has none of these issues, a calcium channel blocker may well have no positive effect.

      Vitamin D3 does many clever things, but you can have too much of it, that is what you have to be careful with.

      Delete
    2. Hi Peter, muy son has a paradoxical response to diazepam,he has strong allergies and GI problems.Apart from bumetanide and verapamil which would be my options.Valentina

      Delete
    3. Valentina, did you try bumetanide?

      The allergies can be treated conventionally with mast cell stabilizers. Cromolyn Sodium is very widely used.

      An interesting option to ask your doctor about is Azithromycin, which seems to have some immuno-modulating properties, in addition to being an antibiotic. In some people with autism and allergies it helps a great deal and is used long term.

      Delete
    4. Peter,I thought many times about trying bumetanide, since I write here,some years ago. Now, I could have the possibility to get it from Mexico, as my cousin who lived in France, moved there because of his work, he is a classical music composer.He is coming here for Christmas, but the question is that I couldn´t have a regular supply, as I have with my son´s godfather.I don´t know how many Miccil boxes should i get to cover one year.Besides I wouldn´t have the security of being able to get it for the next year. Don´t know what to do. With respect to azithromycin, here I can get it in 250 mg tablets, but are 6 in total per box, very little amount of tablets.Could i split the tablet in quarters, to get 60 mg more or less per day or is too little?
      Valentina

      Delete
    5. Valentina, Miccil should be very cheap. I would assume you need 2 x 1 mg tablets per day. My bumetanide comes with 20 x 1mg tablets. I think it should cost about $2 a pack in Mexico, but you have to check. My Bumetanide has 3 years to its expiry date. I use 36 packs a year a pay about EUR 80, so about $100.

      If it works, you either find someone to mail it to you, or you go to Mexico every 3 years.

      Regarding Azithromycin, Agnieszka is the person to ask.

      Delete
    6. In Spain, for 20 x 1mg tablets of Fordiuran you will pay less than 3 EUR. You can buy it without RX.

      Delete
    7. Peter, I will try with 10 packs, then, if the improvement is notorious, I will ask my cousin to mail me some more.I would have to see how I manage to enter them. Valentina

      Delete
  7. Peter,

    What about a CB1/ananadamide type of approach to social deficits?
    A very recent study (september 2017), and I know there has been lots more research about cb1 and cb2 receptors.
    Also what I posted about oleoylethanolamide, seems to be somewhat highlighted in the study.

    https://examine.com/supplements/oleoylethanolamide/

    The Endocannabinoid System and Autism Spectrum Disorders: Insights from Animal Models
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618565/

    "Conversely, a study by Jung and colleagues [41] demonstrated the presence of marked deficits in metabotropic glutamate receptor 5 (mGlu5)-dependent 2-AG release and EC-mediated long-term depression (LTD) at excitatory synapses of the forebrain of Fmr1 knockout mice. The authors showed that Fmr1 deletion resulted in an incorrect targeting of DAGLα to dendritic spines, reducing mGlu5-DAGLα functional coupling and ultimately leading to a loss of 2-AG-dependent retrograde signaling at excitatory synapses of the mouse forebrain."

    They mention LTD, now I have mentioned before in autism some people including myself seems to also be unable to forget some things (something that bothers me for example, I have the inability to 'let go', once again alcohol hangover fixes this and feels like a reset for my brain, alcohol also strongly influences LTD/LTP)

    "Furthermore, the effect of FAAH inhibition on social approach in BTBR mice was strictly dependent on enhancement of AEA (anandamide aka bliss molecule) signaling at CB1 receptors, as URB597-mediated recovery of sociability was prevented by concomitant administration of the CB1 receptor antagonist AM251 and it was not associated with alterations in 2-AG contents [45]. This finding in BTBR mice, although preliminary, supports the hypothesis that enhancing AEA signaling could ameliorate ASD-related social impairments."

    I have read mixed results URB597 on safety/efficiacy in some other papers.

    Pharmacological inhibition of fatty acid amide hydrolase attenuates social behavioural deficits in male rats prenatally exposed to valproic acid.
    https://www.ncbi.nlm.nih.gov/pubmed/27592249

    "It should be noted that
    in addition to AEA, FAAH inhibition also results in increased brain
    levels of the related N-acylethanalomines, oleoylethanolamide
    (OEA) and palmitoylethanolamide (PEA) [39,52]. Although the contribution
    of these N-acylethanalomines to social and emotional
    behavioural responding remains to be been investigated, it is possible
    that increased OEA and PEA may compete with AEA at the
    FAAH catalytic site leading to reduced catabolism of AEA, maintained
    increased levels and subsequent enhanced activity at the
    CB1 receptor. Thus, it is possible that the enhancement of AEA in
    discrete brain regions following FAAH inhibition, and consequential
    activationof CB1 receptors,modulatesneuroanatomical circuits
    regulating social behaviour in male VPA exposed rats."

    PEA also targets CB1 and CB2


    Maca (which is an aphrodisiac/used for high altitude sickness) also has FAAH-inhibiting qualities:

    The macamide N-3-methoxybenzyl-linoleamide is a time-dependent fatty acid amide hydrolase (FAAH) inhibitor
    https://www.ncbi.nlm.nih.gov/pubmed/23853040

    ReplyDelete
    Replies
    1. Aspie1983, there are many possible ways that might improve social deficits in Asperger's. These are not issues I have to deal with in my son, he has more basic issues.

      I would imagine α7 nAChR agonists would help many people with Asperger's feel happier. The obvious one is nicotine, but that has some well known drawbacks, as most things do.

      Half a century ago Lovaas was experimenting at UCLA with LSD on patients with autism. It is not surprising to me that it had an effect and now medical research into LSD has restarted. LSD can make irreversible changes, although I do not think that is why it is a banned substance.

      I imagine within the Asperger's on-line community they will have found some answers. As usual what works for one may not help another.

      Delete
    2. Im concerned about the decreased 5ht2a binding that happens once LSD leaves the body, in aspergers there allready are low 5ht2a receptors.

      I suspect this is one the reasons why inositol benefits me aswell as ashwagandha.

      Chronic inositol increases striatal D(2) receptors but does not modify dexamphetamine-induced motor behavior. Relevance to obsessive-compulsive disorder.
      https://www.ncbi.nlm.nih.gov/pubmed/11267629

      ALTERATIONS IN THE SENSITIVITY OF 5TH RECEPTOR SUBTYPES FOLLOWING CHRONIC ASVAGANDHA TREATMENT IN RATS
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331105/

      Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study.
      https://www.ncbi.nlm.nih.gov/pubmed/16648340

      With regards to alpha7 nicotinic receptors, ive tried low dose galantamine with little to no effect.
      However I might try memantine in the future (been wanting to try this for ages), long term use of it can upregulate alpha7 nachr's and I suspect long term NMDA inhibition will make the NMDA receptor work better.

      Delete
  8. Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535916/

    ReplyDelete
    Replies
    1. Aspie, places like reddit and youtube are full of adults on spectrum sharing their experiences, very often life-and-symptom-changing, with various psychodelics and opioids like LSD, MDMA, ketamine, here is one such account https://www.youtube.com/watch?v=PJgWKl_vss0

      This is in addition to 'official' research like this on e https://www.youtube.com/watch?v=KCIoOu3ygYc

      Delete
    2. Hi Nat,

      Thanks for telling me :), but ive been using reddit for over 2 years allready and have done various stronger substances, such as DXM a few times (seems to produce an afterglow which I like, nmda antagonism wearing off? alcohol hangover also benefits me and alcohol is an nmda antagonist on top of a gaba pam).

      Ive also done magic mushrooms (im from holland so very easy to get the dried strong stuff), did a whole bag (~15gr dried) and all I got was some more insight when looking at objects and people, while the rest of my friends were tripping like mad on the same amount. I 100% sure have low 5ht2a function.

      MDMA im scared to try because its can have permanent neurotoxic effects on serotonin cells.

      Ketamine has bladder issues, so im not taking that either, but im open to ideas of other strong nmda antagonists, was thinking of discussing memantine with psych.

      It seems all the supplements I take have made me tons more health than I was years ago (somewhat fixed my mitochondrial dysfunction and strong improved my gut function).
      This has repaired 2 things for me: dramatic improve in cognitive function and my irritability is completely gone.

      However the anhedonia type symptoms remain (allthough they have improved by 30-40% compared to 3 years ago), Im sure I still need a strong med that affects my (social)reward system.

      Another thing that I have been considering is Kratom (yes I know it affect opioids), but from what ive read on forums and reddit there is also a dose related response where lower doses are more stimulating without being sedating and high doses being dulling and sedating.

      Delete
    3. Aspie@"Ive also done magic mushrooms (im from holland so very easy to get the dried strong stuff), did a whole bag (~15gr dried) and all I got was some more insight when looking at objects and people, while the rest of my friends were tripping like mad on the same amount. I 100% sure have low 5ht2a function."

      If this was me I'd be looking into longer-term micro-dosing.

      Delete
  9. Peter, I've been posting a lot about vitamin D3 and since your blog has 1,078,712 total pageviews, I feel responsible to add that all I am saying is absolutely based on my short term subjective observation which is certainly far from scientific approval.
    It's only for your personal information and would under no circumstances advise parents with children affected by relevant disorders to use vitamin D3 unless they consult their doctor first. My son is supervised by several doctors and since he was found deficient he had to be supplemented with until his serum levels optimise.

    ReplyDelete
    Replies
    1. Petra, your comments are always welcome. Just today my decaffeinated coffee (Svetol) pills arrived as my OAT3 inhibitor, based on your original comments about coffee + bumetanide.

      Delete
  10. Thank you Peter, good luck with your OAT3 inhibitor+Bumetanide.

    ReplyDelete
  11. Here is some new research on cinnamon which elucidates its roles in combating obesity and regulating blood sugar:

    Press Release:

    https://www.sciencedaily.com/releases/2017/11/171121095145.htm

    Paper:

    http://www.metabolismjournal.com/article/S0026-0495(17)30212-3/fulltext

    In summary they found that one effect of cinnamaldehyde is that it induces the expression of several proteins that induce thermogenesis which is important both for maintaining body temperature when challenged with cold, as well as maintaining glucose homeostasis.

    With respect to autophagy, FGF21 is part of the AMPK signaling pathway which is very important in autism research (metformin does as well).

    Dr. Naviaux has a nice little chart displaying FGF21/AMPK activities about mid way down here in this PDF:

    https://iacc.hhs.gov/meetings/iacc-meetings/2014/iacc-workshop/september23/slides_robert_naviaux_092314.pdf

    ReplyDelete
    Replies
    1. Tyler, very interesting and further support for having a teaspoon of Ceylon cinnamon a day.

      More support today for coffee drinking:

      Three cups of coffee a day 'may have health benefits'
      http://www.bbc.com/news/health-42081278

      We want a cinnamon, cocoa and coffee flavanol combination.

      Delete
  12. Peter, have you written anything on myelination (and how to repair or enhance it)?

    /Ling

    ReplyDelete
    Replies
    1. There are things I referred to here and there, Multiple Sclerosis (MS) comes up. If I had a remyelination problem I would use a PDE4 inhibitor. Just google "PDE4 myelin".

      Dr Kelley wrote somewhere that as you recover from mitochondrial disease one of the key issues is the extent to which remyelination occurs. He seems to think that using various antioxidants things will gradual settle and myelin sheathes will get repaired.

      Delete
    2. The best non-drug option for PDE4 inhibition is probably resveratrol and maybe pterostilbene. Here is a paper showing resveratrol to have comparable effects to rolipram which is the primary drug used for PDE inhibition research purposes.

      Press Release:

      https://www.sciencedaily.com/releases/2012/02/120202151133.htm

      Delete
    3. Hi Tyler,

      I see 2 different resveratorol's one is the trans- version and the other one a normal one, is the difference between the two really as big as the price is?

      Delete
    4. Resveratrol is thought to be poorly absorbed by the digestive tract and trans-resveratrol is thought to be better absorbed. Just take more of it if you ask me just like oral methyl-B12 is poorly absorbed so the dose you usually take is 12000% of the RDA. The product I have used is called Resvinatrol Complete.

      The plant resveratrol is harvested from is an invasive species in North America called Japanese Knotweed so it is not like it is super hard to farm and process.

      Delete
    5. Thank you Peter, Tyler, Aspie!
      This took me down a pathway I haven't looked into before. It made a really good lesson! What I learned regarding better remyelination:

      Inhibit PDE4. The reason rolipram wasn't developed as a medicine for this and now only is used in labs is because it induces nausea and vomiting. What you'd really want is its R-enantiomer that only targets the part of PDE4 called HARBS (high-affinity rolipram-binding state), but this doesn't exist yet. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997278/figure/fig08/)

      Wikipedia lists Ibudilast and Luteolin as PDE4 inhibitors among others.

      Going further downstreams (see link) we have some other alternatives:
      cAMP elevating drugs. (suggestions?)
      Agonists of Epac and PKA.
      Inhibitors of Rho (to enhance neurite outgrowth) and
      Inhibitors of ROCK (to increase myelination)

      Beside this, it looks like some MS research is looking into high dose biotin (MD1003) and vitamin D (works together with something called RXR gamma in brain and could increase myelin making cells by 80%). Also clemastine, an OTC antihistamine, was mentioned mainly as an immune suppressing drug for MS.

      /Ling

      Delete
    6. Ling, I think Ibudilast is best. It has been used in Japan for many years as an asthma drug, requiring long term use. Not surprisingly, it is now being trialed in the US to treat MS. At least one reader of this blog is using it.

      Delete
    7. I'll check up both pterostilbene and Ibudilast, though Luteolin also has a very nice range of effects.

      It seems underdeveloped corpus callosum and delayed myelination are things I'll have to address according to the new diagnose.

      Tyler, was it your son who had some "inappropriate laughing" or something similar? Children with my daughters diagnose are mostly very happy-go-lucky, sometimes to the point of going silly... I just wonder what that could mean in medical terms. Of course it is much better than having a depressed kid, I'm not complaining, just trying to understand what pathways might be affected.

      /Ling

      Delete
    8. Ling, if it is UBE3A there is Gaboxadol.

      Delete
    9. Thank you Peter, but it is not Angelman. My daughter has an even rarer syndrome with less than 200 people diagnosed in the world. All of them have ID and 90% remain non-verbal even with years of education. No known treatment options...
      ..we'll see about that.

      Might not look too good, but there are some positives:
      + Now I am even more motivated
      + Genetics can show more exactly what is going wrong
      + I have N>1 to look at for typical biomarkers

      Actually, what I did want to ask you for is if you ever tried Ibudilast yourself, and why you have chosen a statin instead?
      Ibudilast really looks worth trialling, not only as a PDE4 inhibitor but also as a NRF2 activator.

      /Ling

      Delete
    10. Ling, I have not used Ibudilast. I came across the idea that a statin might beneficial very early on in my investigation.

      I did try once to order some Ibudilast, but the order did not work.

      Based on the paper below, it seems that a fifth of a Roflumilast pill is another option (no side effects).
      https://www.ncbi.nlm.nih.gov/pubmed/29098341

      The second option is probably easier for me or organise.

      One reader has a disorder even more rare (100 cases reported) called Andersen-Tawil syndrome.

      I think many cases of rare syndromes never get reported, so they are more common than we realise.

      I know of a girl who went for genetic testing 10 years ago and the parents were then told she would never talk. Having been told the news, they then give up trying to get her to talk. She does not talk today.

      There is another case reported of a mother who kept on trying to get her daughter to talk and was successful. Later she had genetic testing which showed speech was not going to come. This was put forward by her doctor as a reason NOT to do genetic testing.

      Delete
    11. Ling, look into the non-drug things you can do to encourage speech. You can first encourage communication with PECS and AAC Devices (Augmentative and Alternative Communication). This does not mean you have given up on speech, it just gives your child a means to communicate now. Once a child realizes all the benefits communication gives, there is much more reason to talk. I know that PECS is widely used in Scandinavia, I saw it once on exhibition in Sweden. PECS is quite fun for children, but you need to learn how to use it.

      https://www.youtube.com/watch?v=-Bzli1iC_w8

      I went on a two day course to learn PECS, it is the best way.

      Delete
    12. Yes, we are looking into communication devices and have recently done a sign language course with quite some success... This weekend during dinner I signed "First, eat - then, iPad" and my daughter happily signed back "First, iPad?". Motivation is the key, but also having fun together. :)

      Getting a genetic diagnose has made me - for the first time - appreciate the autism concept. I would never have dreamed of there being answers or treatments for this rare condition if I had known about it from the start. But, at this point, I already know successful interventions exist.

      I would almost say that I know more than those very few doctors researching this gene haploinsufficiency, because they are starting from scratch and do not take into account the bigger picture of existing autism science.
      It is good with a medical diagnose, but bad if it means that everyone is trying to solve the big questions in their own tiny little cluster.

      /Ling

      Delete
  13. Peter, I will get bumetanide soon, 100mg potassium a day is enough? I will start with 1 mg, also wanted to know why is needed an OAT3 inhibitor along with bumetanide and wich would be? Valentina

    ReplyDelete
  14. Valentina, if possible measure potassium in your son's blood before starting. Then you know his baseline position. I would add 200mg of potassium with each 1mg of bumetanide and increase dietary potassium (bananas, kiwis etc). Then you have to make sure that fluid intake increases to replace that lost by diuresis. This means drink more water, so if he has bumetanide before school drink .75l of water. Some people give the potassium in .25l of water as an effervescent tablet. So it is not hard to get to .75l. Just give your son time to get to the WC, so don't leave home in a rush or you will just create stresses later.

    It may take more than two weeks to lower chloride levels and see any effect.

    Measure potassium levels a week or two after starting to check they are within the usual limits. If taking blood is easy you can do it earlier. If you adjust diet and add potassium it looks like most people have no problems. Some 20% or so seem to lose more potassium and those people need to be careful.

    An OAT3 inhibitor should just makes bumetanide work better, by slowing it being excreted. You do not need that at this stage.

    ReplyDelete
    Replies
    1. ok, I will be carefull,fortunatley it is the best moment, as my son starts summer vacations on december 8, I will get it by december 3. When can I expect the diuresis to decrease?
      Valentina

      Delete
    2. Valentina, if you give bumetanide shortly after your son wakes in the morning, he will probably needs the WC one extra time in the next hour and then again later in the morning. People all react a little differently, but for my son it was never a problem. Just apply common sense.

      Delete
  15. Cold Shock Protein - an underdog with jaw dropping potential?
    Probably never heard of cold shock proteins right? Neither had I untill today.
    So the question is why has cold shock stress barely given any attention so far? given that we are exposed to the elements of nature daily such as the freezing cold and the blistering heat from the sun. On top of that, everyone knows deep down inside what an immense effect darkness and cold, light and warmth have on our moods and even on our motivation.

    What I found extremely striking is that during the darker and colder months, despite it being a more depressive period on average than lighter days I also seem to be in the need for more social contact. Throughout the years I have always noticed this, but somehow I never really did a search for it on pubmed/google.
    I had this minor eureka moment on reddit today after seeing some reports of people (with all sorts of problems such anhedonia, depression and god knows what) taking cold showers a few times per week with alot of benefits.
    Rhonda Patrick (well known for bringing media attention to brocolli sprouts/sulforaphane with her charming smile and now recently also cold stress exposure) has a paper that discusses how this system works.
    https://www.foundmyfitness.com/reports/cold-stress.pdf

    Now alot of people seem to confuse cold showers with for example showering at a nice warm temperature for 5minutes, then 30sec to 1minute cold water and usually finishing off with atleast some warm water to warm you back up.
    This is where it goes wrong, after reading all these reports it is apparantly essential to atleast be showering for 15minutes at 14celcius. Why is this important? Well it seems that only then the body's core temperature is lowered enough to have a noticable effect.
    As many can imagine a cold shower a few times a week would be a struggle and a hell for anyone and not exactly something you would look forward to, especially for kids with autism this would be an impossible approach.

    Enter menthol... menthol cigarettes, chewinggum, toothpaste, mint tea and essential oils. As you can see it is in alot of stuff these days.

    Role of cold receptors and menthol in thirst, the drive to breathe and arousal
    https://www.ncbi.nlm.nih.gov/pubmed/10744889

    Differential distribution of Y-box-binding protein 1 and cold shock domain protein A in developing and adult human brain.
    https://www.ncbi.nlm.nih.gov/pubmed/24817634
    "Cold shock domain protein A was typically observed in astrocytes, oligodendrocytes, choroid plexus epithelia and nerve fibers. However, in circumscribed brain regions as hypothalamus, habenula, and cerebellum, this protein was also expressed in neurons. In the prenatal brain, both proteins were found to be abundantly expressed in radial glial cells, neuroblasts and neurons, which might be an anatomical correlate of the proposed roles of both proteins in cell proliferation and differentiation. In addition, Y-box-binding protein-1 was identified in cultured, lipopolysaccharide-stimulated microglial cells, WHICH UNDERSCORES ITS PUTATIVE ROLE AS A MEDIATOR IN IMMUNE AND INFLAMMATORY PROCESSES."

    Neurodegeneration: Cold shock protects the brain
    https://www.nature.com/articles/nature14195?message-global=remove

    Cooling-Induced ER Stress is Good for Your Brain
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535306/

    Cold Shock Proteins Are Expressed in the Retina Following Exposure to Low Temperatures
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996528/

    Cold/menthol TRPM8 receptors initiate the cold-shock response and protect germ cells from cold-shock–induced oxidation
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001517/

    Cold shock response in mammalian cells.
    https://www.ncbi.nlm.nih.gov/pubmed/10943555

    ReplyDelete
  16. Mild hypothermia facilitates the expression of cold-inducible RNA-binding protein and heat shock protein 70.1 in mouse brain.
    https://www.ncbi.nlm.nih.gov/pubmed/22609236

    "After mice were exposed to cold for 24 and 48 h, their rectal temperature reached 33°C-35°C. Then, using real-time quantitative PCR, we analyzed the mRNA expression levels of c-fos, cold-inducible RNA-binding protein (CIRP), heat shock protein (hsp) 70.1, oxytocin, and representative inflammatory cytokines, i.e., tumor necrosis factor (TNF)-α and interleukin (IL)-6 in target organs. Importantly, we found that the expression levels of CIRP and hsp70.1 were elevated in the olfactory bulb within 48 h. In the hypothalamus, CIRP expression levels increased and were followed by an increase in hsp70.1 expression. Meanwhile, TNF-α and IL-6 expression decreased gradually over 24 and 48 h in the olfactory bulb and hypothalamus. These specific expression profiles, i.e., enhanced CIRP and hsp70.1 expression and depressed cytokine expression, suggest that they could regulate apoptosis related to the cytokine signaling."

    Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783498/
    "We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway.
    "SIGNIFICANCE STATEMENT Menthol, the most popular flavorant for tobacco products, has been considered simply a benign flavor additive. However, as we show here, menthol alone exerts several neurobiological changes. We are among the first to show that menthol, by itself, increases the number of nicotinic acetylcholine receptors (nAChRs) in the mouse brain. It does so at a dose that matches nicotine in its ability to increase nAChR number. At this same dose, menthol also alters midbrain dopamine neuron function and prevents nicotine reward-related behavior. Together, our data show that menthol is more than an “inert” flavor additive and is able to change the function of midbrain dopamine neurons that are part of the mesolimbic reward pathway."

    Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability
    https://www.nature.com/articles/npp201772
    "Using mouse models, we show that menthol enhances nicotine-induced changes in nicotinic acetylcholine receptors (nAChRs) expressed on midbrain DA neurons. Menthol plus nicotine upregulates nAChR number and function on midbrain DA neurons more than nicotine alone. Menthol also enhances nicotine-induced changes in DA neuron excitability. In a conditioned place preference (CPP) assay, we observed that menthol plus nicotine produces greater reward-related behavior than nicotine alone. Our results connect changes in midbrain DA neurons to menthol-induced enhancements of nicotine reward-related behavior and may help explain how smokers of menthol cigarettes exhibit reduced cessation rates."

    So to those like me who have an extreme aversion for cigarette smoke, menthol might hold some promise in improving social functioning and hopefully even in those who could use more IQ.

    Now, im planning on experimenting with this is in the future, it would be very interesting to see how I will respond to 'cold shocks' either induced by cold showers or menthol like substances (camphor for example also hits this system) during the warmer months such as late spring and the entire summer.

    Camphor induces cold and warm sensations with increases in skin and muscle blood flow in human.
    https://www.ncbi.nlm.nih.gov/pubmed/25451841

    Possibly applying it from the lower back all the way to the back of the head along the path of the spinal cord? To be continued.

    ReplyDelete
  17. Hi Peter
    I do want to start trying to adress my oxidative stress, yet I don't know which treatment is opimal. Can you explain me the difference between NAC and L-Cystein ? Will L-Cystein have the same effects as NAC?
    Thank you :)

    ReplyDelete
    Replies
    1. In theory L-cysteine should be even better than N-acetyl-L-cysteine, but they both do the same thing. The problem is that by the time you use any of these supplements they have degraded. The most potent form of NAC seems to be NAC Sustain, likely because of the way it is formed into solid tablets.

      https://link.springer.com/article/10.1134/S1990747809020081

      Delete
  18. Peter, you are only drinking 150ml per day of a juiced beet and see benefit? I used to give this regularly to my son and will now add back in. easy to do, he likes it. Also - adding Borscht to the menu :)

    ReplyDelete
    Replies
    1. Tanya, me and my son both drink about 150 ml of beetroot juice plus some apple juice each day. I certainly notice the effect on myself. I would not say I see a dramatic effect on my son, but I doubt anyone has noticed its effect on me. It certainly is healthy. My son also likes spinach and other vegetables rich in nitrates.

      Delete
  19. Peter and all,
    My 4 year old grandson has very good auditory and visual memory. Still when we ask questions like what did you eat for lunch? Where did we go yesterday? Who came to our house this morning? he gives wrong answers. Is it a memory problem or something else?

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    1. Salempeacock, I think it is more complicated. Many children with classic autism seem very observant, in that they know exactly where their favourite book or other item is, even when the attending adult cannot find it. The problem is that at least some of this children are not "mentally present" or "ïn a fog", so they just do not respond to basic questions or just give any response, not caring whether it is correct. For us this all changed after 2 weeks of bumetanide, for one American doctor who reads this blog is was low dose clonazepam. So for these people it was a disturbed excitatory/inhibitory balance that was the problem. For your grandson it may be something else or his E/I imbalance might be of a different origin.

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