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Showing posts with label Ketones. Show all posts
Showing posts with label Ketones. Show all posts

Wednesday 8 November 2023

Glycine-NAC for longevity, but for Autism? and Ketogenic “Autistic” Fish


Fish taking a ketone ester

Lonesome fish

  

Baylor College of Medicine in the US have a patent on the combination of glycine and the anti-oxidant NAC to promote healthy aging, which they licensed to Nestle. You can easily make it yourself - just buy both separately. 

GlyNAC supplementation reverses mitochondrial dysfunction, oxidative stress and aging hallmarks to boost strength and promote health in aging humans

One of the intriguing questions from this trial is why so many improvements occur toward promoting health. We believe that this is due to the combined effort of three separate components – glycine, cysteine (from NAC) and glutathione, and not just due to glutathione itself. Glycine and cysteine are both very important for cellular health on their own, and GlyNAC provides both. 

We believe that the improvements in this trial and in our previous studies are the result of the combined effects of glycine and NAC and glutathione, and we refer to this combination as the "Power of 3" said Sekhar.

You need cysteine and glycine to make the body's key antioxidant, glutathione (GSH).  Older people and people with autism are likely to lack GSH.

If you add the precursors via supplementation, you will hopefully increase the production of GSH.



  

GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage

Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis by evaluating the effect of supplementing GlyNAC vs. placebo in C57BL/6J mice on (a) length of life; and (b) age-associated GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage in the heart, liver and kidneys. Results showed that mice receiving GlyNAC supplementation (1) lived 24% longer than control mice; (2) improved/corrected impaired GSH synthesis, GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage. These studies provide proof-of-concept that GlyNAC supplementation can increase lifespan and improve multiple age-associated defects. GlyNAC could be a novel and simple nutritional supplement to improve lifespan and healthspan, and warrants additional investigation.

 

Glycine and N‐acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial


GlyNAC supplementation for 24‐weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin‐resistance and endothelial dysfunction, and genomic‐damage, and improved strength, gait‐speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.

 


 

 

Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review

Glycine is most important and simple, nonessential amino acid in humans, animals, and many mammals. Generally, glycine is synthesized from choline, serine, hydroxyproline, and threonine through interorgan metabolism in which kidneys and liver are the primarily involved. Generally in common feeding conditions, glycine is not sufficiently synthesized in humans, animals, and birds. Glycine acts as precursor for several key metabolites of low molecular weight such as creatine, glutathione, haem, purines, and porphyrins. Glycine is very effective in improving the health and supports the growth and well-being of humans and animals. There are overwhelming reports supporting the role of supplementary glycine in prevention of many diseases and disorders including cancer. Dietary supplementation of proper dose of glycine is effectual in treating metabolic disorders in patients with cardiovascular diseases, several inflammatory diseases, obesity, cancers, and diabetes. Glycine also has the property to enhance the quality of sleep and neurological functions. In this review we will focus on the metabolism of glycine in humans and animals and the recent findings and advances about the beneficial effects and protection of glycine in different disease states. 

As glycine is a very successful immunomodulator that suppresses the inflammation, its action on arthritis is investigated in vivo through PG-PS model of arthritis. PG-PS is a very crucial structural component of Gram-positive bacterial cell walls and it causes rheumatoid like arthritis in rats. In rats injected with PG-PS which suffer from infiltration of inflammatory cells, synovial hyperplasia, edema, and ankle swelling, these effects of PG-PS model of arthritis can be reduced by glycine supplementation [66].

 

Glycine has a wide spectrum of defending characteristics against different injuries and diseases. Similar to many other nutritionally nonessential amino acids, glycine plays a very crucial role in controlling epigenetics. Glycine has much important physiological function in humans and animals. Glycine is precursor for a variety of important metabolites such as glutathione, porphyrins, purines, haem, and creatine. Glycine acts as neurotransmitter in central nervous system and it has many roles such as antioxidant, anti-inflammatory, cryoprotective, and immunomodulatory in peripheral and nervous tissues. Oral supplementation of glycine with proper dose is very successful in decreasing several metabolic disorders in individuals with cardiovascular disease, various inflammatory diseases, cancers, diabetes, and obesity. More research investigations are needed to explore the role of glycine in diseases where proinflammatory cytokines, reperfusion or ischemia, and free radicals are involved. Mechanisms of glycine protection are to be completely explained and necessary precautions should be taken for safe intake and dose. Glycine holds an enormous potential in enhancing health, growth, and well-being of both humans and animals.

  

Ketogenic Fish – rebuilding social affinity 

Regular readers will have noted that some people with autism, but normal IQ, are deeply troubled by their lack of social affinity and seek out ways to improve it.

Perhaps we can learn something on that subject from Masato Yoshizawa, an evolutionary developmental biologist and neurobiologist at the University of Hawaii. Yes, that’s right, an evolutionary developmental biologist – they exist! Back in 2018 he published a paper called “The evolution of a series of behavioral traits is associated with autism-risk genes in cavefish”.

“Many people first doubted that the fish have an autism-like state; I also doubted it at first,” said Yoshizawa. But as he soon found out, even patterns of gene regulation resembled autistic patients.

His recent paper uses his cavefish to look at how the ketogenic diet affects behaviour. 

In the experiment, cavefish where fed the same ketogenic milk provided to human patients, albeit with a few modifications for fish consumption, and their behavior was monitored. As a comparison, a type of A. mexicanus fish that lives in rivers and not caves were also tested.


The surface fish do not display the same autism like behaviors as their cave dwelling relatives. In the presence of other surface fish, individuals will begin to follow each other and swim together, something rarely seen in cavefish, Yoshizawa said. The surface fish also do not do the repetitive behavior of swimming in circles.

 

Using these fish as a comparison, Yoshizawa and his students watched and waited. Amazingly, after a month of the ketogenic diet, the cavefish began to act like the more social surface fish. They would follow each other in groups and ceased going round in circles. There were some other behaviors, such as attention to a specific task and sleeping, that were unaffected, but overall the results were promising and according to Yoshizawa, suggest dopamine could be key to how the diet affects behavior.

 

According to Yoshizawa, there are two plausible ideas as to how the ketones produced by a ketogenic diet are acting on behavior. The first involves the mitochondria, which use either carbs or fat to produce energy in our cells, and the other involves epigenetics, which simple refers to any non-genetic influence which turns genes on and off.

 

Ketones are known to create detectable increases in gene expression in cells. Pulling apart exactly how things like, diet, environment, genes and neurotransmitters are linked is incredibly difficult but could reveal which pathways are best to target for autism treatments or could identify a specific ketone which works more efficiently than others.

 

 

Cavefish provide clues to the keto diet's effect on autism-like behavior 

 

Metabolic shift toward ketosis in asocial cavefish increases social-like affinity

 

Background

Social affinity and collective behavior are nearly ubiquitous in the animal kingdom, but many lineages feature evolutionarily asocial species. These solitary species may have evolved to conserve energy in food-sparse environments. However, the mechanism by which metabolic shifts regulate social affinity is not well investigated.

Results

In this study, we used the Mexican tetra (Astyanax mexicanus), which features riverine sighted surface (surface fish) and cave-dwelling populations (cavefish), to address the impact of metabolic shifts on asociality and other cave-associated behaviors in cavefish, including repetitive turning, sleeplessness, swimming longer distances, and enhanced foraging behavior. After 1 month of ketosis-inducing ketogenic diet feeding, asocial cavefish exhibited significantly higher social affinity, whereas social affinity regressed in cavefish fed the standard diet. The ketogenic diet also reduced repetitive turning and swimming in cavefish. No major behavioral shifts were found regarding sleeplessness and foraging behavior, suggesting that other evolved behaviors are not largely regulated by ketosis. We further examined the effects of the ketogenic diet via supplementation with exogenous ketone bodies, revealing that ketone bodies are pivotal molecules positively associated with social affinity.

Conclusions

Our study indicated that fish that evolved to be asocial remain capable of exhibiting social affinity under ketosis, possibly linking the seasonal food availability and sociality.

 

Are these behavioral and growth changes induced by ketosis? The KD contains high amounts of fat, sufficient levels of proteins, and a minimum amount of carbohydrates. This question motivated us to test the molecular basis of the effects of KD feeding by supplementing major ketosis metabolites, ketone bodies, to the standard diet.

 

In humans, KD feeding induces ketosis, in which the liver releases beta-hydroxybutyrate (BHB) and acetoacetate via beta-oxidation of fat [63].

 

Instead of supplying a massive amount of fat using the KD, BHB might be responsible for the majority of effects observed after KD feeding. With this idea, the ketone ester (D-b-hydroxybutyrate-R 1,3-Butanediol Monoester; delta-G® [64]) was provided as a supplement to both surface fish and cavefish for 5 weeks. The ketone ester (KE) was expected to undergo complete hydrolysis by the gut esterases, resulting in two BHB molecules (and acetoacetate) [64]. It does not contain any salt ions, unlike the sodium or potassium salt forms of BHB, nor does it has the racemic L-form, where only the D-form is considered to be biologically active [65]. Since we were unsure whether gut esterases were available in juvenile-adolescent fish at 3 months old, we used 6–7-month-old fish that have a mature gut system but are in the young adult stage. The results indicated that the KE supplementation significantly reduced the serum GKI (Additional file 2: Fig. S8), while promoting nearby interactions in cavefish (Fig. 7A, B). Swimming distance was slightly reduced in cavefish (Fig. 7C). Turning bias was not reduced by KE supplementation in cavefish (Fig. 7D). There was no detectable difference between CD and KE supplemental diets in sleep duration or VAB (Additional file 2: Fig. S9A and B, respectively).

  

We also tested the supplemental feeding of the BHB salt form (sodium salt form of racemic BHB: 50% L-form and 50% D-form). We used 11–12-month-old fish in this study since the younger fish seemed to suffer from the high-salt-containing diet. The 4-week feeding result was essentially the same as the KE-supplemented diet feeding: the BHB salt supplemental diet significantly reduced GKI in the serum of surface and cavefish (Additional file 2: Fig. S10), while promoting nearby interactions in cavefish but reduced the duration of nearby interactions in surface fish (Additional file 2: Fig. S11A, B). No major change in response to the BHB feeding was detected in swimming distance (Additional file 2: Fig. S11C), turning bias (Additional file 2: Fig. S11D), sleep (Additional file 2: Fig. S12A), and VAB (Additional file 2: Fig. S12B) in cavefish, while the BHB salt reduced growth (standard length and weight) in surface fish (Additional file 2: Fig. S12C, D). In contrast, cavefish did not show any detectable negative effects on growth under the BHB salt supplemental feeding (Additional file 2: Fig. S12C, D).

 

In summary, BHB (KE and BHB salt) treatment encompassed the effect of the KD treatment—promoting social interactions. BHB, particularly KE, had a no-detectable negative effect on growth. These facts suggest that ketone bodies can be responsible factors for the positive effects on social behaviors of KD feeding. BHB treatment also indicated that older-age cavefish (6–7 months or 11–12 months old) were still capable of responding to ketone bodies, not only younger age groups (3–4 months old).

 

You can treat an old-fish new tricks!

Indeed, some of our adult readers are treating themselves with ketone esters.

Both ketone esters and ketone salts were trialed in the fish. In humans ketone esters are the clear winner because they provide a much longer lasting effect.

There is no reason why they have to be so expensive, the bulk chemical is not expensive.

  

Conclusion

For longevity and, more importantly, healthy life expectancy it has long been clear that high doses of anti-oxidants are beneficial.

The question is how best to get this effect.

The most potent way is via intravenous infusion of something like ALA (alpha lipoic acid). In some countries intravenous ALA is a mainstream therapy for people with diabetes, not surprisingly thanks to the ALA some of these people also overcome their other health conditions, like heart disease, and increase their healthy lifespan.

Most people will not have this option and probably do not want intravenous therapy anyway.

Oral supplementation with NAC is cheap, effective and available.

Is adding glycine going to have any incremental effect?  Quite possibly it will. If you are lacking glycine, this will hold back your production of GSH (glutathione). Glycine itself might well provide a health benefit.

Dr Sekhar, over at Baylor College in Houston, refers to the “power of three” (NAC, glycine and glutathione/GSH). The immediate, short-lived, beneficial effect is directly from the anti-oxidant effect of NAC itself.

If, like me, you have chosen to take NAC you are experiencing the “power of two” (NAC and Glutathione/GSH).  Glycine is really cheap and so why not take the extra step and add it? You may increase Glutathione/GSH and glycine has its own direct antioxidant and anti-inflammatory properties.

When it comes to young people with autism who take NAC, is the benefit from the immediate antioxidant effect of NAC, or is it from the increase in GSH?  Here I think we know the answer.  The behavioral effect of NAC is quite short-lived and it matches the short half-life of NAC.  Is there a secondary effect from NAC releasing cysteine that gradually increases GSH (glutathione)? Quite possibly, but in autism you really do need to give NAC 3-4 times a day, so the direct effect of NAC itself looks to be key.

Is Glycine NAC going to be better than NAC for young people with autism? Glycine has its own interesting properties and glycine is cheap. It even can help some of those with sleep problems (3g one hour before bed time).

There are plenty of anecdotal reports on the internet of Aspies finding glycine supplementation helpful - some find it makes them more social.

There is a potential problem for bumetanide-responders. In these people if GABA is operating "in reverse", due to high intracellular chloride, the same may be true of glycine. You would then expect a negative reaction

GABA and glycine in the developing brain

GABA and glycine are major inhibitory neurotransmitters in the CNS and act on receptors coupled to chloride channels. During early developmental periods, both GABA and glycine depolarize membrane potentials due to the relatively high intracellular Cl concentration. Therefore, they can act as excitatory neurotransmitters. GABA and glycine are involved in spontaneous neural network activities in the immature CNS such as giant depolarizing potentials (GDPs) in neonatal hippocampal neurons, which are generated by the synchronous activity of GABAergic interneurons and glutamatergic principal neurons. GDPs and GDP-like activities in the developing brains are thought to be important for the activity-dependent functiogenesis through Ca 2+ and/or other intracellular signaling pathways activated by depolarization or stimulation of metabotropic receptors. However, if GABA and glycine do not shift from excitatory to inhibitory neurotransmitters at the birth and in maturation, it may result in neural disorders including autism spectrum disorders.

 

And those ketone esters (KE)?

Well they are really expensive, when packaged up for humans, but they should be helpful to a sub-group within autism.

Will ketone esters (KE) make our reader Stefan feel more social? Quite possibly, but they are likely too expensive to take every day. Glycine is cheap and worth a try for social affinity, based on the anecdotes from other Aspies.

Some readers are already big fans of ketone esters.  They do not need any further proof from those cavefish in Hawaii.











Tuesday 17 October 2023

Takeaways from Thinking Autism 2023


I did present at the Thinking Autism 2023 conference in London recently.  I was last there in 2019 and there were many familiar faces.

Emotions were very much on show - joy, desperation, bewilderment, hope, fear, frustration and more.

The United Kingdom is amongst the worst countries in the world if you want to treat autism.  Even the idea of treating autism can get you into trouble. For severe autism it is much better to say treating ID (intellectual disability) – what sane person could object to that?

My takeaways are very specific to me, but here they are anyway.

 

So many doctors!

This year I was approached by many doctors who have children with ASD.  Among them were GPs, pediatricians, a neurologist, and a psychiatrist.

When you understand the basis of autism it is not surprising that so many doctors have kids with autism, particularly doctors married to a doctor.

 

Fertility treatment increasing the risk of autism

I did mention in my book the link between difficulty conceiving and having children with autism. Mothers who have had miscarriages are at risk of having a child with autism and children produced via IVF therapy have an elevated chance of autism.

One of the speakers at the conference, who uses diet as a therapy, told us that 30-40% of her patients where conceived by IVF therapy.  Wow – I thought. They are mainly children with milder autism, only 10% of her patients have severe autism.

 

From struggling to get on IVIG to how to come off it

Many parents struggle to get onto IVIG therapy for their child.  It is very expensive and, being an intravenous therapy, it is not so easy to administer to a child with severe autism.

Having finally got on IVIG therapy and responded well to it, how do ever wean the child off it, without losing all those gains?

This was a side issue arising from the conference and is an issue to some other readers of this blog.

What is very interesting is the potential to give IVIG therapy just once to very young children who developed normally but then suffer a regression into “autism.”  It seems to work for some. You might get it in Russia, but don’t bother asking in the UK.

 

My son is 14, I have tried everything else now I am ready for pills

Some people do respond well enough to dietary modification and OTC supplements, but more severe autism likely needs pharmaceuticals. For one mother at the conference she had come to this conclusion.  It is never too late to start to treat severe autism. Good luck to her!

 

Never give up

Never give up was the last point on my talk.

One mother at the conference was a very good example. She had finally had her twins examined at the UK’s top children’s hospital, Great Ormond Street Hospital (GOSH).  They have had MRIs, lumbar punctures to get spinal fluid samples and they have had genetic testing.  That is a triumph in the UK health system.

As she told us, she had to play the cancer card. She told her doctors “why do you go to such great lengths to save my life from cancer and yet do nothing for my twin boys with severe autism?”

Now one has a diagnosis of cerebral folate deficiency and one has a mutation is DISC1, a schizophrenia gene already covered, with therapy ideas, in my blog.  High dopamine in spinal fluid was only to be expected - it is a feature of schizophrenia. Light is at the end of the tunnel.  This mother was also very helpful to other mothers present.

 

School reporting on parent treating autism

I was disappointed to hear that a school had reported one mother for treating her child’s autism.

 

Ketones really do benefit some!

I did write a lot about the multiple possible benefits of ketones/BHB in autism.

The week before the conference one mother wrote to tell me that both she and her child with autism respond well to HVMN Ketone-IQ.

I knew our doctor reader Agnieska was a big fan of the BHB ester product Ketoforce, which seems to have disappeared during Covid.

At the conference a Spanish psychiatrist was listing the therapies in my blog that have helped his son and they included NAC, Bumetanide and BHB.

There are several new ketone products based on diol ketone esters, like HVMN Ketone-IQ.

Our reader Daniel mentioned very recently that he is using a product called DeltaG, a proprietary blend of diol ketone esters. HVMN Ketone-IQ is a pure diol ketone ester, while DeltaG is a proprietary blend of diol ketone esters.

The active ingredient in Ketone-IQ is R-1,3 Butanediol, also referred to as R-1,3-Butylene glycol, which maintains FDA GRAS status as a flavor molecule.

 

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=173.220

 

1,3-Butylene glycol (1,3-butanediol) may be safely used in food in accordance with the following prescribed conditions:

(a) The substance meets the following specifications:

(1) 1,3-Butylene glycol content: Not less than 99 percent.

(2) Specific gravity at 20/20 deg.C: 1.004 to 1.006.

(3) Distillation range: 200deg.-215 deg.C.

(b) It is used in the minimum amount required to perform its intended effect.

(c) It is used as a solvent for natural and synthetic flavoring substances except where standards of identity issued under section 401 of the act preclude such use.

 

This raw ingredient is very cheap.

Once it is packaged up as a supplement, it becomes very expensive.

As Agnieszka mentioned on the conference sidelines, you do have to look at the ingredients. In HVMN Ketone-IQ there is potassium benzoate as the preservative.  Potassium benzoate is a DAO inhibitor. DAO, or diamine oxidase, is an enzyme that breaks down histamine, a compound that can cause a variety of symptoms in histamine-sensitive people, such as headache, flushing, hives, and diarrhea.

 

“If my son can take the bus aged 20, I’d be happy”

One doctor mother showed me a video of her untreated young son with severe autism.  I told her how I have treated my son since 2012 and what the result has been. He passed his high school exams (GCSEs) in maths, science, geography, and English.  Now he has learnt how to travel independently from home by bus.  Time for those pills.






Friday 24 April 2020

The Ketone D-BHB as a Medical Food for Heart, Kidney and Brain Disease (Alzheimer’s, some Autism …)



 Nestle’s research centre in Lausanne, Switzerland
I did write extensively about the potential to treat some autism using the ketone BHB (beta hydroxybutyrate). This can be achieved either by following a strict ketogenic diet or just by eating medical foods that contain/produce BHB.
Some readers are now big consumers of BHB supplements and anyone taking BHB should be interested in today’s paper, that I assume was paid for by Nestlé.
Nestlé make everything from baby milk formula to George Clooney’s Nespresso.  You may not be aware that they also have a business selling medical food; they have been looking at ketones to treat Alzheimer’s for some time.  This is quite similar to Mars developing Cocoa flavanols to improve heart and brain health.
Most ketone supplements are sold to help you lose weight or boost athletic performance.  The military also uses ketones in survival rations. 
We saw that you can increase the level of ketones in your body by supplementing: -
·        MCT oil (medium chain triglyceride oil, which usually contains about 60% caprylic C8 acid and 40% capric C10 acid).  This is a product already sold by Nestlé
·        Neat caprylic acid, C8
·        BHB salts (potassium, sodium, calcium etc)
·        BHB esters (also called ketone esters KE)
These products range from expensive to very expensive.
People requiring ketones as an alternative fuel to glucose, like those with Alzheimer’s need quite large amounts of the supplements.  In Alzheimer’s a glucose transporter at the blood brain barrier is restricting the flow of glucose in blood and so the brain is starved of “fuel”.  Mitochondria in the brain can be powered by both ketones and glucose, so if not enough glucose cannot get through, you have the option to increase the amount of ketones.
Babies fed with mother’s milk are on a high ketone diet.  You can safely combine both glucose and ketones as a fuel for your body.
The news from today’s paper has already been translated to a usable therapy. 
There is growing interest in the metabolism of ketones owing to their reported benefits in neurological and more recently in cardiovascular and renal diseases. As an alternative to a very high fat ketogenic diet, ketones precursors for oral intake are being developed to achieve ketosis without the need for dietary carbohydrate restriction. Here we report that an oral D-beta-hydroxybutyrate (D-BHB) supplement is rapidly absorbed and metabolized in humans and increases blood ketones to millimolar levels. At the same dose, D-BHB is significantly more ketogenic and provides fewer calories than a racemic mixture of BHB or medium chain triglyceride. In a whole body ketone positron emission tomography pilot study, we observed that after D-BHB consumption, the ketone tracer 11C-acetoacetate is rapidly metabolized, mostly by the heart and the kidneys. Beyond brain energy rescue, this opens additional opportunities for therapeutic exploration of D-BHB supplements as a “super fuel” in cardiac and chronic kidney diseases.
One of the main benefits of ketones is their ability to act as an alternative energy source to glucose or fatty acids for production of ATP by mitochondria. Caloric restriction and intermittent fasting also produce transient mild-moderate ketosis (6, 7).
While a high dose of MCT can provide a moderate increase in blood ketones (+0.5–1.0 mM), gastrointestinal intolerance and high caloric load limit their use. Second, ketone esters (KE) made of a BHB ester linked to butanediol provide one molecule of D-BHB after digestion, with the butanediol being further metabolized by the liver to D-BHB (9). KE increase blood ketones above 1 mM but are also limited at high dose by their gastric tolerability and severe bitterness (10).
Third, perhaps the most physiologic way to raise blood ketones is via the oral intake of D-BHB itself. Exogenous D-BHB is directly absorbed into the circulation, with some of it being converted to AcAc by the liver, and both ketones being distributed throughout the body. Until recently, only racemic mixtures of dextro (D) and levo (L) BHB (D+L-BHB) were available and oral human studies with them have been reported (9, 1114). As L-BHB is not metabolized significantly into energy intermediates and is slowly excreted in the urine (9, 15), D+L-BHB would be anticipated to be less ketogenic than pure D-BHB. 
Levo, Dextro and Racemic
When certain chemicals are manufactured, they usually contain an equal mixture of the left-handed and right-handed version, this is called a racemic mixture. These versions are called enantiomers.
One enantiomer is an optical stereoisomer of another enantiomer. The two molecules are mirror images of each other, which are not superimposable - much like your left and right hand.
In the case of the chemical BHB, only the right-handed version has an effect on your body.  If you take the salt potassium BHB, half of the product has no effect other than raise your level of potassium.
Zyrtec is an antihistamine made of Cetirizine, but it is a racemic mixture.  If you want pure L-Cetirizine, you would buy Xyzal not Zyrtec.
Arbaclofen/ R-baclofen is the right-handed version of baclofen
Rezular/R-verapamil is the right-handed version of verapamil.
Back to the study:
The study compared three therapies: -

D-BHB

14.1 g of pure salts of the D enantiomer of D-BHB were used. The D-BHB supplement tested was formulated as a mixture of three salts: sodium D-beta-hydroxybutyrate, magnesium (D-beta-hydroxybutyrate and calcium (D-beta-hydroxybutyrate). Each oral serving provided 12 g D-beta-hydroxybutyric acid, 0.78 g sodium, 0.42 g magnesium, and 0.88 g calcium, citrus flavouring and sweetener (Stevia), dissolved in 150 mL of drinking water.

D+L-BHB

14.5 g of an equimolar mixture of commercial D and L beta-hydroxybutyrate salt was used (KetoCaNa, KetoSports, USA). Each serving provided a mixture of 12 g D+L-Beta-hydroxybutyric acid, 1.3 g sodium, 1.2 g calcium, orange flavoring and stevia, dissolved in 150 mL of drinking water.

MCT oil

Fifteen grams of medium chain triglyceride (MCT) (60% caprylic C8 acid and 40% capric C10 acid) emulsified in 70 mL of a 5% aqueous milk protein solution.


This chart shows the concentration of ketones in your blood plasma after taking either of the three therapies.

This chart shows the concentration of just the ketone D-BHB in your blood plasma after taking either of the three therapies.
 This chart shows the concentration of the ketone ACAc in your blood plasma after taking either of the three therapies.
  

This chart shows where the ketones are going; the chart shows the distribution of the ketone “tracer” acetoacetate (AcAc) by organ after D-BHB oral intake.  The effect is greatest on the heart and kidney, but some does reach the brain.

From the dynamic brain scan, CMRAcAc and KAcAc could be determined for all main regions of the brain and compared to baseline values previously determined in healthy young adults. Overall and compared to baseline, each region demonstrated an increase in CMRAcAc and KAcAc of ~4.7 and 2.3-fold, respectively, about 1 h after taking D-BHB. This indicated that AcAc is effectively taken by the brain and by other organs particularly the heart and the kidney.
Ketone production from an exogenous dietary source has been traditionally achieved by MCT. This requires a bolus intake to saturate the liver with MCFA, producing excess acetyl-CoA which is then transformed to AcAc and BHB, which are released into systemic circulation. The Cmax achieved with MCT is usually between 300 and 600 μM, with higher values being difficult to reach due to GI side effects and liver saturation. Here we show that D-BHB, a natural and biologically active ketone isomer, raises blood ketone Cmax above 1 mM without noticeable side effects. In comparison, an equivalent dose of D+L-BHB or MCT only achieved half this ketone level, with similar Tmax at 1 h. Thus, compared to D+L-BHB, D-BHB significantly reduces the salt intake needed to achieve the same plasma ketone response.
Results from a previous study (9) comparing KE to D+L-BHB showed that at the same dose of D-BHB equivalent, the increase blood ketone iAUC had the same magnitude, suggesting that exogenous D-BHB and KE produce similar ketosis.
Note that KE means Ketone Ester and the study (9) is this one: -

On the Metabolism of Exogenous Ketones in Humans

Ketone esters are available, but horribly expensive and taste really bad.

Conclusion
In previous posts the numerous possible beneficial modes of action of BHB were outlined. The summary post is here: -

Ketone Therapy in Autism (Summary of Parts 1-6)

In practise some people with autism seem to benefit a lot, some moderately and some not at all.
Monty, aged 16 with ASD, fits in the “moderately benefits” category.  The combination of about 20ml of caprylic acid (C8) plus a scoop of Potassium BHB powder does produce more speech.
It is not a cheap or very convenient therapy, compared the others I use.
I would agree with Nestlé that the limiting factor with BHB salts is the “salt”.  As they comment in their paper 
“compared to D+L-BHB, D-BHB significantly reduces the salt intake needed to achieve the same plasma ketone response”
Giving someone with heart disease "sodium anything" is not a good idea. A potassium salt would be safer, but even then, your heart is the limiting factor on potassium use.  Calcium salts are unwise in people with autism, because it appears to be able to upset calcium ion signalling, which would also be a potential risk in heart disease.
As I mentioned to one parent who is a big time user of BHB salts, if you switch to D-BHB you can either produce twice the ketones of regular potassium BHB, with the existing potassium load, or reduce your dosage by half and keep the same effect and save some money.
I think potassium D-BHB is good choice.  If you are taking bumetanide you may no longer need a potassium supplement (K-BHB becomes your potassium supplement).
I think people with autism and genuine mitochondrial disease are highly likely to benefit from D-BHB.  These are people who show symptoms in their entire body, i.e. lack of exercise endurance. For these people, eating (or producing via diet) large amounts of ketones will increase the production of ATP in their brains and so improve cognitive function.  D-BHB undergoes a different process to glucose, as it “converted” to ATP by the process called OXPHOS
(Oxidative phosphorylation). Some people with autism lack the enzyme complexes needed to complete OXPHOS, these people who should try D-BHB.
BHB has other beneficial effects, some relating to inflammation that seem to explain its benefit in other types of autism.  The effects were investigated here.
In the brains of people with Alzheimer’s there is decreased expression of glucose transporter 1 (GLUT 1) at the blood brain barrier. This starves the brain of glucose, which is fuel for the brain. D-BHB is an alternative fuel for mitochondria that is not dependent on GLUT 1.  People with early onset Alzheimer's would seem the best ones for this therapy, that would include many people with Down Syndrome.