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Ketones as Nootropics

Ketones as Nootropics

Marco de Almeida @

Ketones as nootropics might be something you haven’t heard before. As a refresher, cognitive enhancers (or nootropics or smart drugs) are extremely niche prescription or off-the-counter drugs or supplements that enhance cognition, e.g., memory, learning, alertness, etc. They are very well known in the competitive world of athletes, entrepreneurs, business people, and overwhelmed students.

On the other hand, not every cognitive enhancer needs to be exogenous (taken from outside the body in the form of a supplement like this one). Some can be synthesized endogenously (inside the body). Ketones might be one of those. Let’s find out.
Food was once scarce for our distant ancestors. Better functioning brains and bodies during fasting state gave early humans advantages in overall survival chances. Also, according to one article in Ageing Research Reviews, the importance of memorizing the terrain, the location of food, water, or danger spots and conveying this information to the tribe, in those circumstances, meant the difference between life and death [1]. Today looks quite different. We have delicious meals at the click of a button delivered to our doorstep. In most of the world, food is abundant. That means no more running, hunting, and starving—good for us! Or is it really so good?!
 

Even if you are not into ketogenic dieting, there is a high chance you have come across the term ketone at least once this year. There is growing interest over ketones as nootropics, and it’s not showing any signs of slowing down. Let’s see if it is justified and how does it affect our brains in particular.

“Hard Times Create Strong Men. Strong Men Create Good Times. Good Times Create Weak Men. And, Weak Men Create Hard Times.”
―G. Michael Hopf

What Are Nootropics?

“The only difference between the master and the novice is that the master has failed more times than the novice has tried.”
―Stephen McCranie

First things first, what are nootropics? Corneliu Giurgea, a Romanian neuroscientist, coined the term nootropic (pronounced new-tropic) in 1972. He believed that smart drugs should be invented and made widely available for the purpose of enhancing the general population’s brain health and increasing human intelligence. According to Dr Giurgea’s findings, nootropics enhance cognition, memory, alertness, concentration, creativity, and attention. They became known as cognitive enhancers, substances that amplify the way the brain’s many cognitive functions operate and how we process information. Simply put, cognitive enhancers (or nootropics or smart drugs) are prescription or off-the-counter drugs or supplements that enhance cognition. Some nootropics contribute to brain health while others can be quite dangerous. Since Marco’s Grounds only works with safe and natural compounds in their purest forms, for most of our discussions we will restrain ourselves to natural nootropics that increase cognition safely.

Where the Magic Happens

“I don’t measure a man’s success by how high he climbs, but how high he bounces when he hits the bottom.”
―George S. Patton

Our brain likes glucose, that’s a long-known fact first published by Erbsloh et al. in 1958. With only around 2% of the total body weight, the brain’s energy demands are remarkably high. It requires a whopping 20% of glucose-derived energy, according to a study published in Trends in Neurosciences [2, 3].
 
What happens if the glucose runs out? It’s simple. Our body reaches for our fat supplies and breaks them into ketones, which are then used by our brains as a source of energy. What makes the switch from glycolysis to ketogenesis state? Mostly, intermittent fasting, high-performance exercise, or low-carbohydrate intake are going to deplete glucose reserves kept in the form of glycogen, stored primarily in the liver and muscular tissue. As described in an article published in Biochemistry, this leads to fat being processed into free fatty acids as an alternative source of energy.
 

They will travel through the blood and reach the liver and be further metabolized to three ketones: acetone, acetoacetate, and β-hydroxybutyrate [4]. The latter two can enter neurons, where our mitochondrial power plants convert them into the ultimate energy currency, i.e., adenosine triphosphate (ATP).


Ketones-High-Octane Brain Fuel?

“We cannot solve problems with the kind of thinking we employed when we came up with them.”
―Albert Einstein

Ketones as nootropics provide neuronal protection, improved energy efficiency, and synaptic interactions, offering overall long-term cognitive health and function.
 

Increased Cognition and Reduced Aging

Studies in Neurology and Journal of Exercise Rehabilitation revealed that β-hydroxybutyrate stimulates the production of brain-derived neurotrophic factor (BDNF). BDNF supports the health and survival of existing neurons in the brain and helps the growth and differentiation of new ones (neurogenesis). The up-regulation of BDNF improves mitochondrial oxidative capacity and ultimately enhances neuroprotection [5, 6]. What will actually make the brain work better are communication points between neurons called synapses—think as synapses as bottlenecks limiting information transfer rate. BDNF helps there, too; it modulates both short- and long-lasting synaptic interactions, which are critical for cognition and memory, as documented in a study published in Cellular and Molecular Neurobiology [7]. This, in return, promotes long-term cognitive health and function. It wires up our brain. BDNF production declines as we age, so it is essential to keep our minds young just as the rest of our bodies.
 
On top of that, if the ketogenic diet is combined with exercise, we get a win-win situation: a faster glycogen depletion and quicker entry into ketosis, plus the exercise-induced increase in serum BDNF which is positively correlated with an increase in muscle strength as published in Obesity [8]. Oh, and not just that: say goodbye to stress and anxiety too! Research published in Neuroscience suggests that regular and prolonged exercise can relieve hippocampal-dependent memory loss caused by chronic stress [9]. Brains in a ketogenic metabolism state or supplemented with ketones show signs of reduced anxiety, as researchers found in a study published in Frontiers in Molecular Neuroscience [10].
 

A study published in Medicine & Science in Sports & Exercise where exogenous ketones (not synthesized in the body but taken in the form of a supplement) were used, revealed that cognitive performance in stressful situations was better than placebo after ketone ester ingestion [11]. Both endogenous and exogenous ketones improve the brain function when compared to glucose, exogenous ketones are just more convenient to take and require much less willpower. Communication between brain regions is destabilized by glucose and stabilized by ketones as nootropics, irrespective of whether ketosis is achieved with a ketogenic diet or exogenous ketone ester. Brain network destabilization may reflect early signs associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain as described by research found in Proceedings of the National Academy of Sciences of the United States of America [12].


Increased Energy Efficiency and Reduced Cellular Damage

Excess free radicals have been associated with functional decline in aging brains. Ketogenic metabolism is more efficient than glycolytic metabolism. Ketone bodies can be the most efficient energy source in almost every tissue and have more ATP production per mole of energy substrate than pyruvate (the end product of glucose breakdown called glycolysis), according to a study published in Molecular Neurobiology [13]. Ketogenic diet inhibits oxidative damage and augments mitochondrial mass and mitochondrial bioenergetics in the brain. Have a look at The Mitochondria Factor shall you want a brief primer into mitochondrial significance. It also up-regulates biosynthesis of a major antioxidant in our brain and body known as glutathione, enhances mitochondrial antioxidant status, and protects mitochondrial DNA against oxidative damage, based on studies in Neurochemical Research and Journal of Neurochemistry [14, 15].
 

Overall, ketosis modifies neural networks in the brain towards increased functionality and resistance to stress, injury, and disease, as underlined in a review in Nature Reviews Neuroscience [16]. So, ketogenic diets and exercise strengthen both the muscles and brain cells. Both caloric restriction and exercise result in stronger activations of neuronal networks in the brain, especially neurons in the temporal and frontal lobes, whereas these same neuronal circuits are relatively deactivated in individuals who are sedentary and overfed according to an article in Ageing Research Reviews [1]. For instance, those regions of the brain are involved in motor function, problem-solving, spontaneity, memory, language, impulse control, emotion processing, as well as social and sexual behavior, to cite a few. It stands to reason that stronger, denser neuronal connections around those brain regions would also improve those areas of life.

How Can You Maximize Ketones as Nootropics?

“Learn as if you will live forever, live like you will die tomorrow.”
―Mahatma Gandhi

In the end, it seems like we don’t have to choose between the mind or body, we can improve them simultaneously or at least that’s what ketones say.

Consuming a universal cognitive-enhancing complex like Maximum Mind while being in a fasted state or consuming exogenous ketones as nootropics in the form of a supplement is extremely likely to yield even more profound cognitive benefits. Consult Maximum Mind standalone results here.

Literature

  1. Mattson, M.P., Evolutionary aspects of human exercise–born to run purposefully. Ageing Res Rev, 2012. 11(3): p. 347-52.
  2. Mergenthaler, P., et al., Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends in neurosciences, 2013. 36(10): p. 587-597.
  3. Erbsloh, F., A. Bernsmeier, and H. Hillesheim, [The glucose consumption of the brain & its dependence on the liver]. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr, 1958. 196(6): p. 611-26.
  4. Dhillon, K.K. and S. Gupta, Biochemistry, Ketogenesis, in StatPearls. 2020, StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC.: Treasure Island (FL).
  5. Kim, S.W., K. Marosi, and M. Mattson, Ketone beta-hydroxybutyrate up-regulates BDNF expression through NF-κB as an adaptive response against ROS, which may improve neuronal bioenergetics and enhance neuroprotection (P3.090). Neurology, 2017. 88(16 Supplement): p. P3.090.
  6. Park, C.H. and Y.S. Kwak, Analysis of energy restriction and physical activity on brain function: the role of ketone body and brain-derived neurotrophic factor. J Exerc Rehabil, 2017. 13(4): p. 378-380.
  7. Kowianski, P., et al., BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity. Cellular and Molecular Neurobiology, 2018. 38(3): p. 579-593.
  8. Catalán, V., G. Frühbeck, and J. Gómez-Ambrosi, Chapter 8 – Inflammatory and Oxidative Stress Markers in Skeletal Muscle of Obese Subjects, in Obesity, A.M. del Moral and C.M. Aguilera García, Editors. 2018, Academic Press. p. 163-189.
  9. Kim, D.M. and Y.H. Leem, Chronic stress-induced memory deficits are reversed by regular exercise via AMPK-mediated BDNF induction. Neuroscience, 2016. 324: p. 271-85.
  10. Ari, C., et al., Exogenous Ketone Supplements Reduce Anxiety-Related Behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats. Frontiers in molecular neuroscience, 2016. 9: p. 137-137.
  11. Evans, M. and B. Egan, Intermittent Running and Cognitive Performance after Ketone Ester Ingestion. Med Sci Sports Exerc, 2018. 50(11): p. 2330-2338.
  12. Mujica-Parodi, L.R., et al., Diet modulates brain network stability, a biomarker for brain aging, in young adults. Proceedings of the National Academy of Sciences of the United States of America, 2020. 117(11): p. 6170-6177.
  13. Rehni, A.K. and K.R. Dave, Impact of Hypoglycemia on Brain Metabolism During Diabetes. Mol Neurobiol, 2018. 55(12): p. 9075-9088.
  14. Hasan-Olive, M.M., et al., A Ketogenic Diet Improves Mitochondrial Biogenesis and Bioenergetics via the PGC1α-SIRT3-UCP2 Axis. Neurochem Res, 2019. 44(1): p. 22-37.
  15. Jarrett, S.G., et al., The ketogenic diet increases mitochondrial glutathione levels. J Neurochem, 2008. 106(3): p. 1044-51.
  16. Mattson, M.P., et al., Intermittent metabolic switching, neuroplasticity and brain health. Nature reviews. Neuroscience, 2018. 19(2): p. 63-80.
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