Brain energy is often confused with motivation, but these are two distinct phenomena. Brain energy is the actual metabolic energy available to the neurons, in the form of adenosine triphosphate (ATP) molecules. ATP is the "energy currency" of the cell, and is produced primarily by oxidative metabolism of energy from food. High motivation increases the use of this energy, but in the absence of sufficient metabolic capacity it eventually results in stress, depression, and burnout as seen in manic depression. Most attempts at cognitive enhancement only address the motivation side of the equation.
The “smart drug” culture has generally been thinking pharmaceutically rather than biologically. Behind that pharmaceutical orientation there is sometimes the idea that the individual just isn't trying hard enough, or doesn't have quite the right genes to excel mentally.
-Ray Peat, PhD
Any simple major enhancement to human intelligence is a net evolutionary disadvantage.
-Eliezer Yudkowsky (Algernon’s Law)
I propose that this constrain is imposed by the energy cost of intelligence. The conventional textbook view of neurology suggests that much of the brain's energy is "wasted" in overcoming the constant diffusion of ions across the membranes of neurons that aren't actively in use. This is necessary to keep the neurons in a 'ready state' to fire when called upon.
Why haven't we evolved some mechanism to control this massive waste of energy?
The Association-Induction hypothesis formulated by Gilbert Ling is an alternate view of cell function, which suggests a distinct functional role of energy within the cell. I won't review it in detail here, but you can find an easy to understand and comprehensive introduction to this hypothesis in the book "Cells, Gels and the Engines of Life" by Gerald H. Pollack (amazon link). This idea has a long history with considerable experimental evidence, which is too extensive to review in this article.
The Association-Induction hypothesis states that ion exclusion in the cell is maintained by the structural ordering of water within the cytoplasm, by an interaction between the cytoskeletal proteins, water molecules, and ATP. Energy (in the form of ATP) is used to unfold proteins, presenting a regular pattern of surface charges to cell water. This orders the cell water into a 'gel like' phase which excludes specific ions, because their presence within the structure is energetically unfavorable. Other ions are selectively retained, because they are adsorbed to charged sites on protein surfaces. This structured state can be maintained with no additional energy. When a neuron fires, this organization collapses, which releases energy and performs work. The neuron uses significant energy only to restore this structured low entropy state, after the neuron fires.
This figure (borrowed from Gilbert Ling) summarizes this phenomena, showing a folded protein (on the left) and an unfolded protein creating a low entropy gel (on the right).
To summarize, maintaining the low entropy living state in a non-firing neuron requires little energy. This implies that the brain may already be very efficient, where nearly all energy is used to function, grow, and adapt rather than pump the same ions 'uphill' over and over.
Cost of Intelligence
To quote Eliezer Yudkowsky again, "the evolutionary reasons for this are so obvious as to be worth belaboring." Mammalian brains may already be nearly as efficient as their physics and structure allows, and any increase in intelligence comes with a corresponding increase in energy demand. Brain energy consumption appears correlated with intelligence across different mammals, and humans have unusually high energy requirements due to our intelligence and brain size.
Therefore if an organism is going to compete while having a greater intelligence, it must be in a situation where this extra intelligence offers a competitive advantage. Once intelligence is adequate to meet the demands of survival in a given environment, extra intelligence merely imposes unnecessary nutritional requirements.
These thermodynamic realities of intelligence lead to the following corollary to Algernon’s Law:
Any increase in intelligence implies a corresponding increase in brain energy consumption.
What is called genius is the abundance of life and health.
-Henry David Thoreau
This idea can be applied to both evaluate nootropics, and to understand and treat cognitive problems. It's unlikely that any drug will increase intelligence without adverse effects, unless it also acts to increase energy availability in the brain. From this perspective, we can categorically exclude any nootropic approaches which fail to increase oxidative metabolism in the brain.
This idea shifts the search for nootropics from neurotransmitter like drugs that improve focus and motivation, to those compounds which regulate and support oxidative metabolism such as glucose, thyroid hormones, some steroid hormones, cholesterol, oxygen, carbon dioxide, and enzyme cofactors.
Why haven't we already found that these substances increase intelligence?
Deficiencies in all of these substances do reduce intelligence. Further raising brain metabolism above normal healthy levels should be expected to be a complex problem because of the interrelation between the molecules required to support metabolism:
If you increase oxidative metabolism, the demand for all raw materials of metabolism is correspondingly increased. Any single deficiency poses a bottleneck, and may result in the opposite of the intended result.
So this suggests a 'systems biology' approach to cognitive enhancement. It's necessary to consider how metabolism is regulated, and what substrates it requires. To raise intelligence in a safe and effective way, all of these substrates must have increased availability to the neuron, in appropriate ratios.
I am always leery of drawing analogies between brains and computers but this approach to cognitive enhancement is very loosely analogous to over-clocking a CPU. Over-clocking requires raising both the clock rate, and the energy availability (voltage). In the case of the brain, the effective 'clock rate' is controlled by hormones (primarily triiodothyronine aka T3), and energy availability is provided by glucose and other nutrients.
It's not clear if merely raising brain metabolism in this way will actually result in a corresponding increase in intelligence, however I think it's unlikely that the opposite is possible (increasing intelligence without raising brain metabolism).