Ketone body esters as acute 'mood lifters'?

[Alchemica]

Recently got into the fasting. I like the mood stability and uplift.

Firstly has anyone used the commercial 'BHB exogenous ketone' salts and got an acute nice noteworthy mood reaction? There are commercial βHB salt products - quite pricey - but I want to know if anyone has heard of the cheap ketone esters, particularly super cheap (and fragrant!) ethyl acetoacetate, being used safely orally?

 

I'm not going to slack off using will power to fast for my added uplift but I'm curious... it could be quite nice as an acute quite enjoyable mood lifter. Is it the βHB, or is acetoacetate a nice mood lifter? Ketones, particularly BHB, upregulate GABAergic tone but are they 'enjoyable' acutely orally administered?

 

"...researchers don’t know the exact cause of these [euphoric] feelings. Acetoacetate, acetone and BHB, or any of their metabolites, may all be involved, as well as the effects of low blood sugar, which can cause euphoria and giddiness."

 

People  felt remarkably well, and experienced a mild intoxication:

 

 

not dissimilar to the effects of ethanol.

 

Bloom speculated that acetoacetate had caused the inexplicable jubilation. [1]

 

Aside from acute prosocial anxiolytic effects which I deem as an important therapeutic area to address in many conditions, I'm also primarily looking for sustainable better health in my life, as are many people with epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia etc. My intermittent fasting is proving interesting, mood stabilising and uplifting in conjunction with other measures, pushed that quite a bit but it's personally not sustainable to run an extreme 'deprivation diet'. Just skipping breakfast and healthy meals at the other times with my exercise is probably my best bet. There are a few suggestions on ways to stay in a fasting state during IF [1].

 

Caved in and thought I had to try the most economical βHB salts, to get a gauge on it's effects. Probably get around to doing some trials with that this week. It is suggested elevations of β-hydroxybutyrate may partly mediate the beneficial effect of IF in CNS conditions. "Brain BHB concentration increased from a nonfasted level of 0.05 +/- 0.05 to 0.60 +/- 0.26 mM (after second day of fasting), increasing further to 0.98 +/- 0.16 mM (after the third day of fasting)" [2]

 

While βHB salts or other supplements "aren’t a great fat loss tool – they’re simply ways of increasing your blood ketones" and increase energy in, I'm more generally looking for the therapeutic benefits of ketones on the brain for the moment. Both would be nice - I'm getting really good kJ intake reductions and maintaining my exercise so hoping.

 

Unfortunately, with exogenous ketone administration, blood βHB reached low levels (<1 mM) and a high amount of salts, consumed βHB, was required to achieve ketosis. That said, this is still roughly equivalent to three days of fasting. That said, gastrointestinal symptoms were reported in a large number of participants. βHB has antidepressant and antianxiety-like effects and results in modulation of multiple systems, including GABA, Glu, adenosine, neurotrophic etc and even in the presence of glucose exerts beneficial CNS effects, also exerting epigenetic effects (β-hydroxybutyrate is a HDAC inhibitor).

 

Dietary ketone salts are often racemic mixtures of the two optical isoforms of βHB, despite the metabolism and actions of L-βHB being poorly understood

 

~12 or ~24 g orally administered ketone salts  elevated D-βHB concentrations (D-βHB Cmax 1.0 mM) which returned to baseline within 3–4 h. [3]  [Another study found 0.5 g/kg bw at 2 h elevated D-βHB, with a mean value of 0.598 ± 0.300 mM [4], 0.38 g/kg bw caused only a rise to 0.3-0.4 mM βHB in trained athletes [5]. The ketone salts contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h.  L-βHB is still neuroprotective but not much is known about it's CNS effects

 

More cheaply, one can increase  βHB in the brain 90 minutes after ingesting coconut/MCT oil, which improved paragraph recall in adults with impaired memory. Preliminary studies also show ketones can improve working memory in both young and old subjects

 

[1] http://siimland.com/what-breaks-a-fast-while-intermittent-fasting/
[2] https://www.ncbi.nlm.nih.gov/pubmed/11043913
[3] https://dx.doi.org/10.3389%2Ffphys.2017.00848
[4] https://www.ncbi.nlm.nih.gov/pubmed/29850235
[5] https://www.ncbi.nlm.nih.gov/pubmed/29966721

 

"Conversion of ketone bodies (KBs) to ketone esters (KEs) eliminates KB acidity, making the KEs suitable vehicles for the delivery of KBs to the blood circulation via the gastrointestinal route. Ingestion of KE can directly increase plasma KBs to levels within the range achieved during fasting. The degree of KB elevation attained is readily controlled by the dose size

 

Studies have demonstrated that orally or intravenously administered 1,3-butanediol or glycerol esters of βHB are safe and well tolerated in animals and that the orally administered 1,3-butanediol monoester is also safe and well tolerated in humans" [2]

 

While 1,3-butanediol esters are ideal as they are readily metabolised in a manner similar to ethanol without the deleterious effect of ethanol metabolism, with subsequent conversion to βHB and, eventually (at the peripheral tissue level), to AcAc, I'm curious if ethyl acetoacetate might be healingly enjoyable orally administered?

 

While using diet is superior for weight loss than supplementation, there are a few people talking of acute βHB effects @12g of the salts: "...there was an unmistakable uplift in mental clarity, mood and energy. This continued for a number of hours. The energy & focus was clean"

It seems βHB is nicely anxiolytic in studies but maybe not intoxicating, the anxiolysis correlated with increased level of βHB .

Human pilot studies and case studies suggest that ketogenic diet and ketogenic supplement-induced ketosis is a potential therapeutic approach in the treatment of epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia.

Ketone bodies may exert their effects through modulation of GABAergic, glutamatergic, and adenosinergic system

It has also been demonstrated that administration of exogenous ketone supplements (normal food + ketone supplements and/or medium chain triglyceride/MCT), such as ketone ester (KE), ketone salt (KS) or their combination with MCT oil (e.g., KSMCT) induce rapid and sustained nutritional ketosis

https://www.frontiersin.org/.../10.../fnbeh.2018.00029/full
 

"Administration with no need for energy restriction might also be a promising intervention to improve the neuronal activity and ameliorate the degeneration of CNS" [6]

 

Just curious, couldn't spot it done anywhere...

 

From risk assessment of Ethyl Acetoacetate

 

Acetoacetate is an endogenous product of accelerated fat metabolism.

Absorption of ethyl acetoacetate via the oral route is demonstrated in animals

 

It may be anticipated that ethyl acetoacetate is partially cleaved already in the gastrointestinal tract due to acidic pH values or by bacterial activity. In a first metabolic step the absorbed portion of ethyl acetoacetate will be hydrolysed into 3-oxobutanoic acid and ethanol by the unspecific esterases of the blood. The acid moiety is an endogenous product within the lipid metabolism and is further metabolized predominantly to carbon dioxide and water; ethanol will be metabolized on known pathways.

 

In animals, acute toxicity by the oral, dermal, and inhalative routes is low as judged by tests with rats. The substance demonstrated no or only mild skin irritation and mild eye irritation in tests with rabbits. Valid human or animal data on sensitization are not available.

 

Following repeated oral exposure of ethyl acetoacetate in rats, no treatment-related adverse effects (including haematology, clinical chemistry, gross necropsy and histopathology) were reported up to 1,000 mg/kg bw/d.

 

Note: Levels above 10 mmol/L of ketone bodies are associated with ketoacidosis.

 

 

Edited July 11, 2018 by Alchemica

[Alchemica]

Tomorrow, spike those ketones in the name of a healthy brain experiment and see what I think of it as a "neurotherapeutic" and "promising anxiolytic strategy" [1], see if there are hints of enjoyable prosociality which would be nice. "Use of βHB as an efficient neurotherapeutic relies on increasing blood βHB levels so as to encourage entry of βHB to the brain." [2]

 

The main problem with using βHB as a therapeutic lies in being able to deliver sufficient βHB to the brain, due to the limited uptake of βHB across the blood brain barrier and the difficulty in sustaining high enough levels of βHB in the blood - uptake can be increased by instigation of dietary changes, such as a high fat diet or regular ingestion of medium chain fatty acids.

 

Any keto nuts suggest better (other than ketone esters) than BHB+MCTs? I want to feel it as acutely as possible... Thinking to go from intermittent fasting/low carb to using short term BHB + MCTs as my diet for a bit.

 

Ketone bodies upregulate neurotrophins, reduce neuroinflammation and hyperexcitability, causing potent neuroprotection. They also drive growth and myelination, enhance synaptic plasticity, cognition and neuronal stress resistance, improving learning and memory. Exogenous ketones also improve oxygen utilisation, especially in the central nervous system

 

There are concerns regarding the level of Ca and K provided by supplementing BHB salts, which can rise to toxic levels if excessive doses are administered, so adherence to dose recommendations is required [3]

 

In the body, "Exogenous ketone supplementation causes blood glucose to decrease significantly, likely due to the acute increase in insulin sensitivity. Therefore, exogenous ketones may present a potential therapy for type-2 diabetics via regulation of blood glucose.".

 

"BHB + MCT raises blood BHB levels much higher than BHB or MCT in isolation, with a peak just over 1.30mmol/L. Even more important is that blood BHB levels do not seem to readily fall back to the normal levels of 0.2mmol/L. Even after 8 hours blood BHB levels are 0.5mmol/L, which is over double the normal level, and they look to be only very gradually falling. Blood BHB levels look like they will be elevated for the best part of a day, but the most significant rise being between 1 and 4 hours after ingestion." [4]

 

Consumption of MCTs produces a mild ketosis which has been estimated to contribute up to 8–9% to brain energy metabolism and it is well tolerated.

 

In comparison, "In human tests, 30ml of MCT oil was able to raise blood BHB levels to about 0.55 mmol/L. This is just over half the effect that BHB salt supplementation had. MCT oil supplementation spiked blood BHB levels at just under an hour, and drops to normal levels after 3 hours. Interestingly, BHB levels continue to fall below normal levels of 0.20mmol/L to 0.12mmol/L. The low blood BHB levels show no real indication of normalising after 8 hours."

 

While the low ketone levels generated by MCT supplementation have been demonstrated to partially reverse the memory deficits of Alzheimer’s dementia, exogenous ketones have the potential for greater memory-improving effects, with maximum effect likely occurring at a beta-hydroxybutyrate blood level of 4 mmol/L or higher, the level at which ketone transport into the brain is maximised.

 

Human pilot studies and case studies suggest that ketogenic diet and ketogenic supplement-induced ketosis is a potential therapeutic approach in the treatment of epilepsy, Alzheimer's disease, autism spectrum disorder, and schizophrenia

Ketone bodies may exert their effects through modulation of GABAergic, glutamatergic, and adenosinergic system. Administration with no need for energy restriction might also be a promising intervention to improve the neuronal activity and ameliorate the degeneration of CNS.

 

Noted antidepressive and anxiolytic effects
It an efficient mitochondrial fuel, improving energy metabolism
Enhances GABAA receptor function, upregulates GABAergic activity [may increase GABA concentration], enhances inhibitory glycine receptors
Decreases brain glutamate, alters the response of NMDA receptors, L-type Ca2+ channels, reduces neuronal firing rates, mediated in part by Katp channel activity and GABAB signaling
It interacts with an inflammasome in immune cells to reduce production of inflammatory cytokines and reduce inflammation.
inhibitor of histone deacetylases resulting in upregulation of genes involved in protection against oxidative
stress and regulation of metabolism
Supplementation with βHB has been shown to extend the lifespan of C. elegans by 20%

 

[1] https://www.frontiersin.org/articles/…/fnmol.2016.00137/full
[2] https://www.ncbi.nlm.nih.gov/pubmed/27826689
[3] https://blog.undoctored.com/beware-exogenous-ketones/
[4] https://ketosource.co.uk/exogenous-ketones-how-they-work/

 

By afternoon, I'm normally crashing in mood, grumpy and tired, not that the morning is much better. I got a paradoxical lift changing my diet for once, but then the typical diet shift anergia kicked in.

 

 From a couple of days of IF, gave the BHB salts a whirl. Solid dose, 12g BHB and some MCTs.  Really, the ketone elevations offered by even large doses of the salts aren't that huge but "can help your body transition into ketosis with less misery and hunger pangs." potentially. The combo of MCTs and BHB is said to be better for BHB elevations.

 

Beta hydroxybutyric acid is antidepressive and anxiolytic. It enhances inhibitory glycine receptors at concentrations observed in humans clinically. In addition, beta-hydroxybutyric acid enhances GABAA receptor function at these concentrations. Subanesthetic concentrations may contribute to lethargy and impairment of consciousness [1] and has abilities to alter physical properties of cell membranes [2]

 

[1] https://www.ncbi.nlm.nih.gov/pubmed/17717222
[2] https://www.ncbi.nlm.nih.gov/pubmed/23339286

 

By 45min, there's a very mild energetic lift, wouldn't say much more than MCTs alone. Some restoring energy, stability of mood again and a little potential anxiolysis. Functionally nice as a mild meal tonic. Enough to get another bout of exercise in, which seemed to attune me to it more.

 

It was pleasant exercise. Just a calm, centred functional bit of exercise. Didn't feel so neurotic.

Got for another bit of exercise - just level headed.

 

All in all, maybe the BHB salts are useful but not likely to be problematic.

 

It may be therapeutically useful to for the times I crave alcohol (I've now been abstinent quite awhile),

 

"In ethanol dependence, it is suggested the following occurs "energy deficiency (“starvation”) of the brain → stimulation of production of ketone bodies → partial transition of the brain from exclusive using of glucose as the energy substrate to partial use of ketone bodies as such substrate. Under such conditions, the brain begins to be dependent, to a significant extent, on the level of these bodies in the blood, i.e., on the degree of ketonemia. With any decrease in this index, the biological requirement to replenish the amount of these compounds develops. Since rapid synthesis of ketone bodies can be readily initiated by introduction of ethanol into the organism, this organism tries to realize the corresponding behavioral reaction, i.e., to consume alcohol." [1]

 

MCTs themselves compensate for the brain energy deficits in direct proportion to the level of plasma ketones achieved. MCT-fed rats exhibited reduced anxiety-like behaviors and enhanced social behaviour [2] Data on the neuroprotective capacity of MCT-derived medium chain fatty acids (MCFA) suggest 8-carbon and 10-carbon MCFA may have cognition-enhancing properties which are not related to ketone production [3]

 

[1] https://link.springer.com/article/10.1007/s11062-016-9596-4
[2] https://www.ncbi.nlm.nih.gov/pubmed/29908242
[3] https://www.ncbi.nlm.nih.gov/pubmed/27517611

Edited July 12, 2018 by Alchemica