INTRODUCTION
The truth is, although there are a myriad of proposed mechanisms as far as how ketogenic diets work (review articles have been rapidly accumulating in many different medical publications) no one can really say one way or the other, and to suggest otherwise points to an utter lack of thoroughness in reading of the literature on the topic, a bias in the interpretation of said literature, or both.
I recently had the
opportunity to attend a physician-only-lecture at a hospital about the use of
ketogenic diets for the treatment of epilepsy in children. If you at least casually follow the discourse
on this dietary approach on the interwebz, especially with regard to the
interest of effecting cures, you’d probably think that not only should all children
with epilepsy be placed on a ketogenic diet, but that failing to do so amounts
to nothing less than egregious malpractice; another failure of the medical
profession to employ the best treatments available because of the inherent
evils of pharmaceutical companies and of patent medicine.
The truth is, although there are a myriad of proposed mechanisms as far as how ketogenic diets work (review articles have been rapidly accumulating in many different medical publications) no one can really say one way or the other, and to suggest otherwise points to an utter lack of thoroughness in reading of the literature on the topic, a bias in the interpretation of said literature, or both.
I say this in part by way of
criticism and disgust, and in part because I know how complex neuropsychobiology and
neuropharmacology (and related disciplines) are and have always been owing mainly,
in my estimation, to the lack of experimental methods sophisticated enough to
draw definitive conclusions; in particular, the inability to convert
correlational data derived from such experimentation to proof of cause and
effect. What is clear, however, is that there is an energy deficiency in various neurological disorders including epilepsy; that is to say, a deficiency of glucose and oxygen, the primary
substrates by which cells of the nervous system generate energy, which is evidenced by a respiratory quotient[*]
that stabilizes at 1.0 therein.
Therefore, the most parsimonious explanation for why ketogenic diets work, when they do, is that the ketone bodies so generated are supplying neurons (and glial cells) with energy, which would normally be provided by glucose, thereby preventing these cells from literally succumbing to the demands placed on them, by all the stressors they have to deal with on a moment to moment basis. Why then do children with epilepsy develop energy deficiency problems? Or stated another way, why do they lose the ability to generate energy by way of the oxidative metabolism of glucose, in which carbon dioxide, rather than lactic acid, is produced? This is a question too complex and speculative to have a discussion on for this audience and for the space I’ve allotted myself here. Just know for now that this mismatch, between energy reserves and energy demands, represents the essence of the problem.
Therefore, the most parsimonious explanation for why ketogenic diets work, when they do, is that the ketone bodies so generated are supplying neurons (and glial cells) with energy, which would normally be provided by glucose, thereby preventing these cells from literally succumbing to the demands placed on them, by all the stressors they have to deal with on a moment to moment basis. Why then do children with epilepsy develop energy deficiency problems? Or stated another way, why do they lose the ability to generate energy by way of the oxidative metabolism of glucose, in which carbon dioxide, rather than lactic acid, is produced? This is a question too complex and speculative to have a discussion on for this audience and for the space I’ve allotted myself here. Just know for now that this mismatch, between energy reserves and energy demands, represents the essence of the problem.
I’m fully aware of the fact
that my post thus far, five paragraphs in, lacks a thesis of any kind
whatsoever. Annoying, I know. I also know readers in particular appreciate a
neat list of recommendations based on a solid foundation of evidence that
should have been presented in the body of the article.
But rather than do that,
because of the speculative nature of the subject matter, I want to finish up this
post by doing two things. The first is
to describe, in the simplest way possible, the way in which the brain should work, especially with regard to energy
and stress. The second is to have a general discussion of a few, in my estimation, means to preserve and optimize this system, based on the preceding theoretical
discussion.
By endeavoring to focus on mechanisms (which is the best we could
do at this point if we wish to avoid overstating any point) you should see why
the focus on particular foods (e.g. the sweet potato) or painting ourselves
into a corner by restricting our diets to only those foods that have been
deemed “evolutionarily-approved” (whatever that exactly means), is not only utterly
silly, but also arbitrary and fatally flawed.
ENERGY DEMANDS VS. ENERGY RESERVES
Energy problems should be expected to manifest in the brain
first and most notably because the brain, per unit weight, is the most
voracious consumer of energy, namely glucose, of all the organs in the body. (The
brain represents merely 2 percent of the body’s total weight yet accounts for
15 percent of the body’s total energy expenditure.) So when a deficiency of energy does occur, the brain and associated structures, which coordinate processes
as diverse as memory, learning, mood, and behavior, are impacted quite notably.
One reason as to why the
ketogenic diet may ‘work’ is that ketone bodies have a sedative effect in the
brain, like the neurotransmitters gamma-aminobutyric acid (GABA) and
gamma-hydroxybutyric acid (GHB), thereby protectively reducing the energy
demands so as to prevent cells from literally overworking themselves to the
point of malfunction and death.
What first got me thinking
about the similarities between GABA, GHB, and ketone bodies was an internship I
had at one of the major poison control centers in the U.S., where it was
drilled into the interns by the medical director that valproic acid (brand name Depakene), a drug used for
seizures and structurally similar to
both GABA and ketone bodies, would when taken in excess cause ammonia to
accumulate to toxic levels in the blood (for which carnitine would be given as
an antidote.) Suffice it to say here, the fact that the toxic accumulation of
ammonia is a side effect of valproic acid reinforces the idea that the ketone
bodies and valproic acid are acting in the ways that GABA normally would in the
brain.
In the brain, under normal
circumstances GABA derives from glucose by way of the highly prevalent brain
amino acid glutamate. In the absence or
improper use of glucose, valproic acid, or ketone bodies – those compounds that
are structurally similar to GABA – are probably ‘filling in’ for the glucose-derived
GABA that, for whatever reason, is missing.[†]
The synthesis of GABA is intimately tied to the oxidative metabolism of
glucose, which entails the use of enzymes found exclusively in the brain.
In all, valproic acid mimics
the effects of GABA, and the ketone bodies are probably acting in a similar yet
more basic way, owing to their structural similarity.[‡]
The not-so-rigid dichotomy between the excitatory and the inhibitory systems in
the brain is thusly shifted to favor the latter system, whereby the flow of
electrical signals through various brain pathways defensively becomes depressed. Lowering the energy charge in the cell (i.e.
depleting ATP) has a similar effect, activating the enzymes that synthesize
GABA from glucose and depleting brain dopamine (evidenced by elevated
dopamine turnover rates when GABA is introduced exogenously in relatively large
amounts). These enzymes are dependent on
vitamin B6, a deficiency of which predisposes to seizures in children and
adults.
In healthy and young people,
this system should kick in in the face of prolonged or excessive stress, which rapidly depletes energy stores in the
brain. Healthy and young people should also be more
resilient to ‘running out’ of energy, owing partly to the efficiency by which
the glucocorticoid system operates in their bodies since the glucocorticoids,
in excess, interfere with the storage of glucose in brain cells.[§] The turnover of GABA is many times higher
than that of other neurotransmitters, such as acetylcholine and dopamine,
suggesting that the brain has many homeostatic mechanisms in place to maintain
GABA concentrations within a certain physiological range under a wide range of
external conditions.
SUMMARY/CONCLUSIONS
1. To me, like the
use of synthetic glucocorticoid products, ketogenic diets, as of now, is nothing
more than a last-ditch effort when all other means fail. Merely a symptomatic solution, there are
probably long-term consequences associated with having this system chronically
active and in overdrive. I’ve heard
mentioned offhand by a Paleo blogger that high fat diets relieve anxiety in
rats by way of GABA, apparently without reading the study that was linked to
support this claim. Some of the
beneficial effects of these diets can be attributed to the surge in glucose
brought about by the stress hormones, temporarily relieving the energy stress
caused by the deficiency of glucose, so as to prevent the irreversible
degradation of brain structural material that would otherwise supply that
energy, as well as GABA. At the same
time, owing to their purported sedative and inhibitory effects in the brain,
the ketone bodies themselves are neuroprotective. However, the ketone bodies incidentally block the oxidative metabolism of glucose.
2. Vitamin B6 is a cofactor
(tightly bound) of two enzymes: one involved in the synthesis of
glucose-derived glutamate and one that makes GABA from glutamate. A deficiency of vitamin B6 decreases its
concentrations in the cells that make GABA, favoring the inactive state of the
two vitamin B6-dependent enzymes involved in making GABA. In point of fact, a diet deficient in vitamin
B6 in children and adults can lead to seizures that respond dramatically to
treatments that include the vitamin.[**]
3. The amino acids
taurine and glycine have similar receptor interaction patterns as GABA. As such, taurine and glycine induce 'inhibitory' effects in the regions of the brain where they are active. Animal studies show that chronically low
intake of these amino acids, or their precursors, could lead to irreversible degenerative
changes in the brain, eyes, and spinal cord.
4. The rationale
behind the use of pharmaceutical anti-depressants (i.e. stimulants) stems
largely from experiments in which correlations are made between levels of
certain neurotransmitters in the brain (or their metabolites in the blood and
urine) and the ability of animals to which stressors are imposed, to cope and
to avoid developing conditioned helplessness, where the
animals simply give up and fail to perform effective avoidance responses to
subsequent stressors.
Whether
these measured neurotransmitters are, in fact, the cause of depression – a condition
that is already poorly defined – is uncertain, as, if you recall, the wherewithal
currently available to study these relationships lack the requisite
sophistication.
However, as
I’ve stated before, animals permitted to develop effective means to cope with
stressors have lower levels of anxiety, which, in turn, make then more
effective at coping with stressors.
GABA, and probably the ketone bodies and valproic acid, helps individuals
cope more effectively with various stressors, in part by reducing anxiety, without
adding to the energy stress like the anti-depressants, which now
bear the black box warning, the most serious of all warnings, alerting
clinicians and patients of an increased risk of suicidal thoughts and behaviors
in children and young adults. Cortisol
levels are also lower in animals with effective coping mechanisms. To put things in more concrete terms, the ability
to turn fears and worries into plans and actions soften all of the energy
problems described above and help to preserve brain functioning.
5. The
rapidity with which learning is acquired I think reflects how efficiently the
systems in the brain and the body ‘work’ to maintain energy availability and the
delicate balance among dopamine, serotonin, cortisol, noradrenalin and GABA.
The
distinction, however, between learning and simple arousal and stimulation should
be made and recognized, especially when interpreting experiments designed to
study the ins and outs of learning.
Suffice it to say here, reducing anxiety and employing effective coping techniques
facilitates the acquisition of the biochemical and physical changes in the
brain that are thought to signify learning.
Learning implies adaptability to changes in the environment, the
capacity for which, according to Han Selye and others, determines our
susceptibility to disease, aging, and death.
6. Maintaining
steady blood glucose levels helps to prevent the drastic changes in glucose
availability to the brain, of which merely transient interruptions can cause
harm. I’ve found through my own
experimentation that small, mixed meals spaced out equally throughout the day are superior to large, intermittent meals.
Dear reader,
From
hereon out, I’ll be writing for Matt Stone’s site, 180degreehealth, somewhat regularly as a
site author, so some of my future articles will be posted there, not here. I’ll be sure to let you know each time
one of my posts go live over there.
Happy
Thanksgiving,
Andrew
[*] A respiratory quotient of 1.0
indicates pure glucose use in relation to protein and fat.
[†] Glucose can be converted to GABA,
but ketone bodies and fatty acids can’t.
[‡] Because I was asked once already
(email), and because its’ probably on the minds of readers now, I’ll mention
here so as to dodge answering the same question that as a supplement, GABA is
probably useless, as GABA, being highly charged, is unlikely to cross into the
brain from the blood, and very little GABA is found outside the central nervous
system.
[§] The primary glucocorticoid secreted
by the adrenal cortices is hydrocortisone, or cortisol.
[**] Since there are many other vitamin
B6-dependent enzymes in the brain, we can’t say for sure that the improvements
seen upon the addition of vitamin B6 are due to effects on the GABA system
only.
