Nootropics are active compounds that act on the central nervous system to enhance cognitive function. There are myriad compounds with nootropic activity, each targeting different elements of the vast assortment of processes that give rise to cognitive function.
However, since the benefits of individual compounds are often mild, two or more ingredients are frequently combined into nootropic stacks to obtain better, stronger or longer effects. Nootropic stacking is common practice: an online nootropics survey showed that most users take stacks of several different chemicals daily. The best nootropic stacks are designed to take advantage of the synergy between ingredients — they can be combined to improve absorption, increase potency, potentiate benefits or decrease side-effects. When nootropics are well combined, the improvement of the whole is greater than the sum its parts.
Synergies enhance benefits with Nootropic Stacks
One of the most popular examples of ingredient synergy is probably the caffeine and L-theanine stack. By itself, caffeine has a well-known stimulatory and productivity-enhancing outcome by promoting wakefulness, concentration, motivation, and alertness. However, caffeine can sometimes cause restlessness and anxiety. When combined with L-theanine, the productivity and creativity-enhancing benefits of caffeine are upregulated, but anxiety and jitteriness are counterbalanced by L-theanine’s capacity to promote relaxation without sedation. This synergy between caffeine and L-theanine makes them a widely sought-after nootropic stack for focus and productivity.
Another example is phenylethylamine, popularly known as the ‘love potion’. Phenylethylamine increases synaptic levels of dopamine, serotonin, and norepinephrine in the brain, improving mood, attention and concentration. However, since phenylethylamine is quickly metabolized by the enzyme monoamine oxidase-B (MAO-B), these benefits are observed only at high doses. But when phenylethylamine is stacked with MAO-B inhibitors, such as hordenine, its breakdown is delayed, allowing it to remain active for a longer period of time and to be beneficial at lower doses.
Similarly, curcumin, a potent antioxidant and neuroprotective molecule found in turmeric, is unlikely to have substantial benefits on its own because of its poor bioavailability. But when curcumin is paired with piperine, a compound found in black pepper, its breakdown and elimination are delayed and its absorption and bioavailability are increased up to 20-fold. Piperine also increases the absorption and bioavailability of other nutrients, including green teas epigallocatechin gallate (EGCG).
These examples show how the interaction between two ingredients can be explored to improve their benefits in a straightforward way. But the synergistic potential of nootropics can be explored with greater complexity, particularly when the mechanisms of action of each ingredient are well understood.
Synergistic targeting of neural pathways: Choline supplements
Just as cognition emerges from the concerted activity and intricate balance of multiple elements, so should all these elements be simultaneously optimized. Targeting pathways is, therefore, more likely to be beneficial than targeting a single chemical reaction. A good example is the cholinergic system. Choline supplements are among the most popular nootropics because choline is the precursor for the neurotransmitter acetylcholine.
Acetylcholine is involved in many key functions in the brain, particularly in memory and learning, in alertness and in sustaining attention. An enhancement of cholinergic activity can be achieved by increasing the synaptic levels and the turnover of acetylcholine.
Choline supplementation with CDP-choline or alpha-GPC will increase the levels of choline in the brain, but the functional outcome will be restricted by the rate of choline uptake by neurons, where acetylcholine is synthesized. Stacking them with docosahexaenoic acid (DHA), for example, may increase their benefits because DHA, the main structural component of the neuronal cell membrane, facilitates the capacity of the high-affinity choline uptake system to transport choline into neurons, resulting in an increase in the availability of choline for acetylcholine synthesis.
Acetylcholine synthesis also requires acetyl-CoA, and, consequently, coenzyme A, which is synthesized from the essential nutrient vitamin B5. Vitamin B5 is therefore indirectly required for the synthesis of acetylcholine; adding vitamin B5 to a cholinergic stack may increase the availability of acetyl-CoA for the synthesis of acetylcholine and thereby enhance the stack’s ability in increasing acetylcholine levels.
But in order for acetylcholine to be synthesized, the enzyme that produces it — choline acetyltransferase — needs to be available. That’s where Bacopa monnieri can be helpful – it activates choline acetyltransferase, increasing the output of acetylcholine. Once acetylcholine is released into the synaptic cleft (the space between two neurons in a synapse), bacopa also helps enhance its benefits by decreasing the activity of acetylcholinesterase, the enzyme that hydrolyses acetylcholine and terminates signal transmission, allowing acetylcholine to remain active for longer. A similar outcome can be attained with Huperzine A, EGCG or L-Theanine. After acetylcholine is hydrolyzed, choline can then be taken up again through the choline uptake system (enhanced by DHA) and restart this process.
When combined, these ingredients can, therefore, enhance cholinergic action through multiple, complementary and interdependent mechanisms. But the nootropic response of this combination can be further enhanced by ingredients that promote synaptic plasticity, the changes in synaptic strength that underlie learning and memory. A possible target is cAMP, a signaling molecule that acts as a messenger within the cell. The cAMP signaling pathway has been shown to regulate synaptic plasticity by increasing the release of neurotransmitters into the synapse, not only acetylcholine, but also glutamate and GABA. This action can be enhanced by forskolin, which increases intracellular levels of cAMP through the activation of adenylate cyclase, the enzyme that produces cAMP, leading to an increased responsiveness to extracellular stimuli.
Whole system upgrade using Nootropic Stacks
There are nootropic stacks for energy, for focus, for memory, for studying, for motivation. These are great and serve a specific purpose. But a major appeal of nootropics is the potential for a sustained and long-lasting enhancement of cognitive function as a whole.
By enhancing a whole system, the right combination of ingredients is more likely to have a significant functional impact. Understanding the neuroscience of cognitive enhancement — the system, its processes and the response of nootropics on those processes — is a step forward in designing more complex and beneficial nootropic stacks. As our understanding of the brain advances, we’re more likely to find better ways to hack into these systems.