Why not Cocoa Flavanols for Autism?

  

Judging by my blog statistics, lots of people are interested in broccoli (Sulforaphane) to treat autism.  Thanks to the patents held by Johns Hopkins, you can expect to hear much more about Sulforaphane in the coming years.

Meanwhile, Columbia University and Mars, the chocolate people, have released a study showing that “flavanoids” in cocoa can do wonders for memory loss in older people.  In effect, they can restore memory in 60 years olds to where it was 20 or 30 years earlier.

If you take a step back and look at what is known by science about oxidative stress and antioxidants, all will become much clearer.

Oxidative Stress Pioneers

In an earlier post we met Paul Talalay, a German-American, who worked at Johns Hopkins.  He specializes in foods that protect you from cancer.  He is Mr Broccoli. 

It turns out that perhaps the real pioneer in this field is a 100% German, called Helmut Sies, who also studies foods that act as antioxidants and nutrients that provide protection from cancer.  We have his very detailed diagram below, that explains the relationship between many of the factors involved in oxidative stress.  I wish I had found it earlier.  I added the six outer boxes.

If you want to read clever studies about this subject, just include Helmut Sies in your search; for example “selenium Helmut Sies”.

Redox Pioneer: Professor Helmut Sies

On this graphic you will see GSH (Glutathione).  When you take NAC (N-acetylcysteine) you directly raise the level of GSH.  When eat broccoli you activate Nrf2, which is a Redox switch, just under the traffic light in the graphic.

When you eat certain flavonoids, like Cocoa, or carotenoids like lycopene (found in tomatoes), you again promote the anti-oxidative free radical scavenger effect.  Look in the blue boxes under diet.

Not on the diagram, we also have flavonolignans which are natural phenols composed of a part flavonoid and a part lignan. As pointed out in a comment in the last post by Seth Bittker, one interesting  flavonolignan is Silibinin, which has anti-oxidant and chemoprotective effects

Note the presence of (Coenzyme) Q10 in the yellow box.  This is part of the mitochondrial cocktail suggested by Dr Kelley from Johns Hopkins for regressive autism.  Q10 is depleted by statins.

Glutathione peroxidases, in the yellow box, are also very interesting.  These are selenium-containing enzymes.  GPx (x goes from 1 to 8)  catalyze the reduction of H₂O₂ and organic hydroperoxides to harmless products. This function helps to maintain membrane integrity and to reduce further oxidative damage to molecules such as lipids and lipoproteins with the associated increased risk of conditions such as atherosclerosis.  It appears GP₁ may be defective in autism and this is contributes to increased oxidative stress.  This area has been well studied due to its impact on heart disease.  You appear to be able to counter the lack of GPx with yeast-bound selenium, other forms of selenium do not work, due to a lack of bioavailability. A post will appear just on Selenium.

There are several other potent (exogenous) antioxidants that we have come across:-

• Alpha lipoic acid also known as ALA or Tioctic acid (found  in Dr Kelley’s cocktail)
•   L-Carnosine (studied by Dr Chez )
•  Vitamin C (suggested by many, including Dr Kelley)

Another day, another anti-oxidant

In human health, two well used anti-oxidant drugs are Alpha lipoic Acid (ALA,  also known as Tioctic acid) and N-acetyl cysteine (NAC).  They share many similar effects.

•       Potent antioxidant
•       Increase insulin sensitivity
•       Improve memory in those with mild cognitive          impairment
•       May lower blood pressure
•       Improve behavior in autism

NAC is widely used to treat Chronic obstructive pulmonary disease (COPD) and ALA is used to treat diabetic neuropathy. Perhaps they could be interchanged

·        NAC has a chemoprotective effect
·        ALA has been shown to induce cell cycle arrest in  human breast cancers      cells

Back to Cocoa Flavanols and Mars

This flurry of activity was driven by a well publicized study done at Columbia University Medical Center (CUMC), using a high cocoa flavanol concentration drink provided by Mars.

Dietary cocoa flavanols reverse age-related memory decline

   

In the CUMC study, 37 healthy volunteers, ages 50 to 69, were randomized to receive either a high-flavanol diet (900 mg of flavanols a day) or a low-flavanol diet (10 mg of flavanols a day) for three months. Brain imaging and memory tests were administered to each participant before and after the study. The brain imaging measured blood volume in the dentate gyrus, a measure of metabolism, and the memory test involved a 20-minute pattern-recognition exercise designed to evaluate a type of memory controlled by the dentate gyrus.
The high-flavanol group also performed significantly better on the memory test. “If a participant had the memory of a typical 60-year-old at the beginning of the study, after three months that person on average had the memory of a typical 30- or 40-year-old,” said Dr. Small. He cautioned, however, that the findings need to be replicated in a larger study—which he and his team plan to do.

This is very impressive.  But how do the other anti-oxidants compare?

Well, without funding from Mars, researchers only managed the money to test ALA and NAC on mice; but as you might expect, the result was similar.

The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice

Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.

Cocoa Flavanols are good for your heart

This is also good news, but it does seem that antioxidants are generally very good for your heart.

First cocoa.

In this study blood pressure, glucose, insulin and cholesterol were all markedly affected for the better by the cocoa as was cognitive function.

This is great;  but it is what Helmut Sies has been telling the world for many years.

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment

The Cocoa, Cognition, and Aging (CoCoA) Study

Abstract—Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing _990 mg (high flavanols), _520 mg (intermediate flavanols), or _45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P_0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P_0.05) lower in subjects assigned to high flavanols (38.10_10.94 and 104.10_28.73 seconds, respectively) and intermediate flavanols (40.20_11.35 and 115.97_28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60_17.97 and 139.23_43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P_0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50_6.75 versus 22.30_8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained _40% of composite z score variability through the study period (partial r2_0.4013; P_0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.

There are more cocoa studies:-

Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults  The effect of acute consumption of a flavonol-rich cocoa drink on cerebral vasomotor reactivity in African Americans

Mars Cocoa Science website

Cocoa Flavanols as a therapy for Autism

Based on the work of Helmut Sies and the trials funded by Mars, it is pretty obvious that 1,000mg of cocoa flavanols a day would very likely have a marked effect on someone with autism, assuming that is they were not already taking NAC, ALA, Carnosine, Broccoli, Sulforaphane or Selenium.  500 mg should also have an effect.

Choice of antioxidant

The question is what is the ultimate treatment for oxidative stress in autism?

I guess this will depend on exactly what type of autism you have (regressive or not), to what extent you have a mitochondrial dysfunction and whether you have any genetic dysfunction related to oxidative stress.

What works best in Billy, may be suboptimal in Charlie, but still much better than nothing at all.

It looks to me that NAC and ALA will likely be the most potent antioxidants.

If you live in the US, you can buy cocoa flavanols in standardized doses from Mars.  One capsule = 125mg of cocoa flavanols.   I have to add that I am far more inclined to believe Mars, than those supplement companies out there.  You can buy tablets saying they contain 50 mcg of Selenium, but what do they really contain? 

You can also buy “high flavanol” raw (non-alkalized) cocoa powder in big bags.  This lighter brown cocoa has lost far less of the flavonoids in the processing process.  In theory, a 5g teaspoon of the very best one will contain (on a good day) 415 mg of flavavols.

Mars are only supplying their CocoaVia products in North America, so if you want to try cocoa flavanols you have a few options:-

·        8.5 teaspoons of standard raw cocoa  (content will vary widely)

                or

·        1.2 teaspoons of “Chococru” upmarket raw cocoa

                or

·        4 capsules of CocoaVia from Mars  

Each of the above should give you 500mg of cocoa flavanols, which would look like a good starting point.  As with NAC, the studies show that the benefit increases the more you take, but the extra benefit drops off.

If somebody in the US tries CocoaVia, do let us know the result.

Not surprising, Mars tell us on the label that the product is not intended for children.  I do not suppose they ever thought of it being an autism therapy either.

I do like the idea of the redox switch, Nrf2, which Sulforaphane is known to activate.  I also like the idea of the enzyme GP₁ that acts as catalyst in the oxidation/reduction process.

The science is around 20 years old and nobody has yet figured it all out;  they probably will not conclusively do so in the next 20 years either.

Food for thought!

Autism Flare-Ups & Leaky Blood Brain Barrier

As I discussed in an earlier post, autism flare-ups occur regularly in the lives of many autistic children.  The cause might be a pollen allergy, food allergy or indeed an illness that does not cause a fever.

That last part might sound odd, but fever actually reduces autistic behaviours.  This has been noted and documented by many, but never conclusively explained.  Lots of parents have noticed and one even created a blog about it, but they have not explained it.

To investigate the fever effect, you first need to understand thermoregulation, the process by which the body sets and maintains its temperature and the role played by of the HPA axis (hypothalamic-pituitary-adrenal axis).  The simplified explanation is that the body initiates a fever as part of its defence mechanism to the threat that has been detected, like an infection of some kind.  Certain hormones are released so as to raise and then maintain a steady higher temperature; they include TRH, ACTH, AVP, PRL and TSH. It occurred to me that if you could identify which hormone increase was behind the reduction in autistic behaviours during fever, you would be on to something really useful.  This is something that is very poorly covered in the literature and so it is very difficult to prove anything.  My hunch is that TRH is the one and I am looking into ways to prove it.  I wrote an early post all about TRH, which I believe, for other reasons could have great therapeutic value in autism. 

The Peter Hypothesis of TRH-induced Behavioural Homeostatis in Autism

Back to flare ups …

 

Sickness involving stress/inflammation, but without fever, makes autistic behaviours worse.  Stress and inflammation have been shown in research to make the Blood Brain Barrier (BBB) more permeable.  In an earlier post we discovered that histamine itself increases the permeability of the BBB.

If you want to read up on the BBB, here is some heavy reading:-

The Blood-Brain Barrier/Neurovascular Unit in Health and Disease

The other observation that seems not to get documented in the literature is the effect of a new cause of stress/inflammation on any previously existing or dormant ones.  This is very relevant in autism since part of the brain is known to be in a near permanent state of inflammation/stress.  So if a new site of inflammation/stress elsewhere in the body will “re-ignite” other weak sites around the body (including the brain) then we have a problem.  Just as we showed that pollen and food allergies sparked autism flare ups, so can a viral infection.

Because there is no temperature, you may hardly notice the virus. Most parents think their kids are only really sick if they have a temperature.

These observations actually apply to all of us.  My son Monty, aged 10 with ASD, currently has a virus that does not cause a fever.  I know all about it, because I subsequently caught it from him.  Having caught it myself, I see why it would affect Monty’s behaviour.  It goes on far longer than a common cold, but outwardly after a day sneezing and a runny nose there is little to notice.  Since I am now focused on autism flare up and comorbidities, I am taking a lot of notice.  I can see that in my own body sites of previous inflammation do indeed flare up.  Like many people, I occasionally suffer from GERD, which you might know better as “heartburn”.  This causes inflammation to the oesophagus and when it occurs you can actually feel it, as I can while writing this.

Imagine you have a brain with chronic neuroinflammation, even if you are taking steps to put out that fire (NAC and statins) along comes a wave of inflammatory cytokines released elsewhere in the body and they act to reignite the inflammation in the brain again.

In healthy neurotypical people the brain is better protected from such inflammatory cytokines due to a more effective Blood Brain Barrier (BBB).  In autism there is plenty of evidence pointing to a more permeable BBB.

You cannot stop your child getting pollen allergies, though you might well adjust diet to avoid food allergies; but can you do anything to keep those pro-inflammatory cytokines out of the brain?

We know for a fact that certain substances weaken the BBB; we just need to find the neuro-protective ones that can strengthen the BBB.  Such substances do indeed exist.  A common issue than arises is that what works in the test tube (in vitro) does not always work in humans (in vivo) and also what works in rodents (the typical laboratory test subject) may not apply to humans.

Other diseases linked to leaky BBB - Multiple Sclerosis & Alzheimer’s

The best known disease long thought to be caused by a breakdown in the BBB is multiple sclerosis.  People with MS and those trying to help them have a big interest in what might protect the BBB.

I found it interesting that recent research shows that Alzheimer’s disease is also triggered by a failure in the BBB.  

Alzheimer's protein damages blood brain barrier

Alzheimer's disease: A breach in the blood–brain barrier

Alterations in brain blood vessels in mice precede the neural dysfunction associated with Alzheimer's disease. The finding highlights potential targets for drug development.

Alzheimer’s disease (AD) is well researched/funded since it is the leading cause of dementia.  It is characterised by both oxidative stress and neuroinflammation, as is autism.  Drugs developed for AD that target strengthening the BBB or reducing stress/inflammation in the brain would be good targets to trial in autism.

Substances neuro-protective to the BBB.

If you look in the literature you struggle to find much research on strengthening the BBB.  Much more frequent reference is made to “neuro-protective” ,which is something good but subtly different.

  

Mast cell stabilizers.

                         

Mast cell stabilizer drugs work to prevent allergy cells called mast cells from breaking open and releasing chemicals that help cause inflammation.

 

Commonly used mast cell stabilizers in medicine include  the drugs Cromoglicic acid and   Ketotifen.  These drugs are used in treating allergies and asthma. Both these drugs have been covered in earlier posts and at least Ketotifen is used in autism. Some researchers suggest that truly effective mast cell stabilizers for humans do not exist.  It is suggested that mast cell stabilizers would be highly protective of the BBB.

Lipoic Acid

It has been stated that Lipoic acid is protective of the BBB, also known as  Alpha lipoic acid and thioctacid; it is another antioxidant.  I have also mentioned it previously in this blog.

Thioctacid is prescribed by doctors to patients with diabetic polyneuropathy in Germany and most East European countries.  It not only reduces symptoms of neuropathy but it also reduces the amount of insulin patients require.  It is given both intravenously and orally.  I am told that oral administration is effective, but research showed that IV has the strongest effect.

In autism some people in the US take advantage of its metal-chelating properties.  All anti-oxidants have should have metal-chelating properties, by the way.

 

Here is a study from the world of Multiple Sclerosis, into the protective properties of Lipoic Acid.

Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity

In the following research NAC was combined with Lipoic Acid to reverse memory impairment and oxidative stress in the brain.

The antioxidants α-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8  mice

These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants

From Iran, I found a hypothesis about lipoic acid reducing inflammation in autism. 

Gold nanoparticles and lipoic acid as a novel anti-inflammatory treatment for autism, a hypothesis

Anti-oxidants as neuroprotectors

Anti-oxidants will indirectly strengthen the BBB, since they reduce the oxidants that damage the BBB.  Are all anti-oxidants equal?  There is an argument that you should match the anti-oxidant to the oxidant.  The most powerful anti-oxidant available seems to be NAC, and I am already using it.  My second choice would be L-carnitine, since there has been at least one positive clinical trial in autism.

A prospective double-blind, randomized clinical trial of levocarnitine to treat autism spectrum disorders

It works in a quite different way to NAC and it also has an effect on the mitochondria.  As you saw above, there is also a case to be made for alpha lipoic acid (ALA), as an antioxidant.  In the research combinations of antioxidants have been trialled, just not for autism.  In an ideal world, some research would be carried out comparing the effectiveness of different combinations of NAC, Carnitine and ALA.

Interestingly as with lipoic acid, L-carnitine improves insulin response in diabetics.

I found this Alzheimer’s research interesting.  It tested NAC, carnitine and SAMe.  SAMe is used in to treat many neurological conditions, including ADHD, which I view as autism-lite.  It is also used to treat seizures, a major comorbidity of autism.

Effects ofdietary supplementation with N-acetyl cysteine, acetyl-L-carnitine andS-adenosyl methionine on cognitive performance and aggression in normal miceand mice expressing human ApoE4.

In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer's Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against A beta neurotoxicity), acetyl-L-carnitine (which raises ATP levels, protects mitochondria, and buffers A beta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents.

Statins

Statins are claimed to increase the integrity of the BBB.  I am already convinced of the benefit of Atorvastatin, for other reasons.

Flavonoids:  luteolin, Quercetin, Rutin

Dr Theoharides from Tufts University in Boston where he is Professor of Pharmacology, Internal Medicine (Allergy) and Biochemistry is a proponent of flavonoids to stabilize mast cells,  He favours a mix of luteolin, Quercetin, Rutin all mixed up in olive kernel oil.  He says it works far better than Ketotifen and cromolyn.  His mixture is marketed under the name Neuroprotek.

Mast stabilizers are claimed to reduce BBB permeability, so as a consequence these flavonoids should help

I initially found it odd that such a scientist was favouring natural extracts,  so I thought I would see what other neuro-protective extracts might be out there.

Naturally occurring neuro-protectants

The internet is full of natural remedies and most have little supporting evidence.  Here are two that I found interesting.

Blueberries

These are both very tasty, available and remarkably good for you; nobody is exactly sure why.  They seem to slow down cognitive decline in older people, reduce neuroinflammation and promote cell survival.

Antioxidant and neuroprotective properties of blueberry polyphenols: a critical review

Over the last 10 years an increasing scientific interest has developed about polyphenols, which are very abundant in blueberries, as they have been seen to produce favourable effects related to neuroprotection and linked to a possible decrease of age-related cognitive and motor decline, as shown by the improvement of such functions in animal models with a supplemented diet. Such effects could not only be explained through a purely antioxidant action but also through more complex mechanisms related to inflammation, genic expression, and regulation of cell survival

Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection.

Withania Somnifera, also known as Ashwagandha

On the surface, this ages old Indian medical remedy looks interesting, not least because one study showed it could reverse Alzheimer’s Disease.  It is claimed to do many things, including protecting the BBB.

Withania somnifera reverses Alzheimer's disease pathology

Indeed it is an ingredient used in some supplements used for autism and if you Google it, you will parents recommending it.

Not being a regular to such types of “medicine” I did some research and found that you should buy the actual root rather than the ground up bits available in capsules.  The logic being that they put the leftovers in the capsules and that the capsules may give an overly concentrated dose, as compared to the tea version. 

With root you make a kind of herbal tea.  It is actually very easy and quite inexpensive; indeed the root seems easier to find than the capsules.  In keeping with my self-experimentation approach, I brewed up a batch of Withania somnifera tea and gave it a try.  Well there genuinely is an effect; you do feel different, although I would not call it “better”.  The problem is, as I learnt a couple of hours later, that it can, and does, irritate the gastrointestinal tract.  Maybe my brew was too strong or maybe I am just sensitive to it.  On WEBMD they list the following side effects:-

ASHWAGANDHA Side Effects & Safety

Ashwagandha is POSSIBLY SAFE when taken by mouth short-term. The long-term safety of ashwagandha is not known. Large doses of ashwagandha might cause stomach upset, diarrhoea, and vomiting.

It’s not known whether it’s safe to apply ashwagandha directly to the skin.

Special Precautions & Warnings:

Pregnancy and breast-feeding: Do not use ashwagandha if you are pregnant. It is rated LIKELY UNSAFE during pregnancy. There is some evidence that ashwagandha might cause miscarriages. Not enough is known about the use of ashwagandha during breast-feeding. Stay on the safe side and avoid use.

Stomach ulcers: Ashwagandha can irritate the gastrointestinal (GI) tract. Don’t use ashwagandha if you have a stomach ulcer.

“Auto-immune diseases” such as multiple sclerosis (MS), lupus (systemic lupus erythematosus, SLE), rheumatoid arthritis (RA), or other conditions: Ashwagandha might cause the immune system to become more active, and this could increase the symptoms of auto-immune diseases. If you have one of these conditions, it’s best to avoid using ashwagandha.

Surgery: Ashwagandha may slow down the central nervous system. Healthcare providers worry that anaesthesia and other medications during and after surgery might increase this effect. Stop taking ashwagandha at least 2 weeks before a scheduled surgery.

Since Ashwagandha can make the immune system more active, it would seem unsuitable for autism, which we have established in this blog is linked to an already overactive immune system.

Conclusion

Finding a remedy to permeability of the blood brain barrier (BBB), was never going to be simple, if it was, then multiple sclerosis and Alzheimer’s disease would have already  become curable.  But, knowing what weakens the BBB does help explain why autism flare-ups occur, and in turns this helps us to minimize them.

I think I will stick with the blueberries and steer clear of the Ashwagandha, at least until I have to worry about Alzheimer’s.  The L-carnitine is getting a trial as a supplemental anti-oxidant and mitochondria protector, as will Dr Theoharides’ somewhat expensive Neuroprotek.  Alpha lipoic acid is now in third position in my anti-oxidant league table and will be studied further.   NAC remains in pole position as antioxidant proven to reduce autistic behaviours.  The very inexpensive Ketotifen may have capabilities above and beyond those accepted by Theoharides, as suggested by the fact that it has the remarkable ability to prevent the onset of asthma in the at risk group.

I wrote an earlier post on flavonoids.  These are good parts of fruits that you usually miss out on in juices, since they are concentrated in the skins.  Indeed though olive oil contains beneficial flavonoids, many remain in the stone/kernel in the centre,  It was of interest to me that Theoharides uses olive kernel oil rather than regular olive oil to bind his Neuroprotek together.  All berries seem to be particularly good for you, including cranberries, blackberries, blueberries, billberries and raspberries. I think these flavonoids are likely more about promoting your general health than any autism breakthrough.