This article has been published for reference purposes (originally published in 2016) and does not represent beliefs or ethos of the current Peak Nootropics editorial team.

Choline is essential to the body as the main precursor to the nootropic neurotransmitter, acetylcholine. There are certain processes such as High Affinity Choline Uptake (HACU) that primarily affect choline transport and the required synthesis of acetylcholine within the neurons.

It is important to understand High Affinity Choline Uptake and the mechanisms involved. High Affinity Choline Uptake is the rate limiting step at which choline gets converted into acetylcholine. In essence, it is the system in which choline is converted into acetylcholine. Like any system within the body, it can be manipulated and certain nootropics have a primary effect on this system.

High affinity choline uptake may be assisted in part by a low affinity system when demands for acetylcholine are high. The low affinity system will assist carrying extra choline throughout the body to cells even if the task does not relate to acetylcholine synthesis. Compared to the high affinity system, the low affinity system is much more inefficient for acetylcholine synthesis. The low affinity system may further deplete both brain and blood levels of choline.

Choline also has other functions within the body

Keeping choline levels sufficient for the high affinity choline uptake system may ensure the highest conversion of acetylcholine synthesis. This may possibly explain why some people experience negative effects when taking racetam nootropics without choline supplementation.

Supplementing with choline or acetylcholine precursors may be necessary for some nootropics users to experience benefits and to get the full range of the high affinity system. If the high affinity system is not activated to a full extent it is likely that choline and therefore, free acetylcholine within the brain is low. This of course, is all pure speculation however the theory of choline supplementation with nootropics is largely supported amongst nootropic enthusiasts.


Blood concentrations of choline are generally lower than brain concentrations however the level of each is directly related. Increasing blood concentrations of choline may stimulate the release of acetylcholine from vesicles in the brain. Having low blood levels of choline may cause the brain to not release enough acetylcholine from these vesicles.

The uptake of choline and release of acetylcholine in a neuron; note the stored acetylcholine in vesicles

Unlike the low affinity choline uptake system, the one with high affinity is sodium channel and energy dependant. It is believed that the high affinity system is the main system for which acetylcholine is synthesized. High affinity choline uptake and blood concentrations of choline are directly related. When levels of blood choline are low, an increased demand for acetylcholine is needed and therefore less is released. This may influence the overall efficiency of the HACU system.


Two racetam nootropics work primarily to affect the high affinity choline uptake system. Coluracetam and pramiracetam both influence the system by increasing the rate of HACU. These two are both known to be highly cholinergic and potent cognitive enhancers. It is possible that other nootropics work on this system however these two stand out by being to most influential on the system and it is believed to be the primary method of action.

Pramiracetam and coluracetam have both been shown to be very powerful cholinergic nootropics. They put typical ACh positive allosteric modulators like piracetam in the dust. The strong effects are likely to be primarily from their effects of High Affinity Choline Uptake.
The method of action of coluracetam and pramiracetam may prevent certain mood side effects seen with other cholinergic such as piracetam. Depressive symptoms can be observed in some people taking piracetam and related racetams. While the research is few and far between, pramiracetam and coluracetam have been suggested to have some mild anti-depressant qualities.

Seeing as coluracetam and pramiracetam primarily work to improve high affinity choline uptake, supplementation with adequate amounts of choline may be needed. Blood levels of choline and therefore, brain concentrations should be adequate for the high affinity choline uptake system to work properly. Without free acetylcholine within the brain, the high affinity system may not be able to do its job properly.


The high affinity choline uptake system has no doubt proven in science to be the primary action in which choline is delivered to neurons for synthesis into acetylcholine. There are several factors that seem to affect the system. Firstly, blood/brain concentrations of choline and free acetylcholine should be a in the amounts which allows the brain to release acetylcholine. Without these concentrations, the brain will likely “hold on” to acetylcholine within the nesicles therefore reducing the rate of high affinity choline uptake.

The two racetams, coluracetam and pramiracetam work as strong cholinergic nootropics affecting the HACU system. They may offer a reduction in mood side effects when compared to other cholinergic nootropics and racetams. Having an adequate supply of choline within the body may be necessary for these nootropics to offer full benefits as well as to reduce the amount of side effects.