Here it is:
Despite rapid inhibition of RBC AChE (and a presumed increase in central cholinergic activity), neither huperzine A nor galantamine impacted neurobehavioral performance.
The lack of neurobehavioral efficacy in this study was not entirely unexpected. Our subjects consisted of healthy, non-sleep-deprived young adults. In addition, although practice effects were evident on some tasks (discussed next), in general, performance levels on all tasks were high…
Results from prior studies indicating pro-cognitive effects, taken together with our findings, indicate that in otherwise normal, healthy adults with intact central cholinergic functioning, AChE-inhibiting compounds do not exert cognition-enhancing effects. Also, the results presented here indicate that these compounds do not interfere with the normally high levels of neurobehavioral functioning seen in this cohort…
AChE activity is higher in the cerebral cortex of groups that have been trained and tested on more difficult problems than in those given easier problems. An experiment in which littermates were either trained on a difficult problem or were untrained reported that the trained rats developed significantly higher cortical AChE than their untrained littermates
So, AChE is higher, which means that acetylcholine levels should be lower here, which could be taken to mean that AChE-Is and/or supplemental choline would help in these instances, where they may not help in instances where acetylcholine levels aren’t lowered, which would make AChE-Is, and perhaps supplemental choline, CONDITIONALLY BENEFICIAL, which isn’t terribly difficult to accept I suppose.
Study below:
As for the two seemingly conflicting studies on bitartrate, we’ll call them YES (for the one that showed benefits) and NO (for the one that did not).
Study YES was published in 2015, while NO was published in 2016. YES is actually referenced in NO. The following was consistent in both studies it seems:
In line with previous studies on the acute effects of choline on behavior [46, 49–51] and to control for choline uptake unaffected by other supplements, participants were restricted from drinking alcohol the day preceding the study and participants were not allowed to have breakfast, coffee, or cigarettes before the experiment (overnight fasting, only water and caffeine-free fruit tea without sugar allowed).
But things are getting interesting here. From the methodology of NO:
Participants also performed a visuospatial motor task which was unrelated to the memory task. Results of this task are published in a different article [46].
Reference 46 is the YES study.
Apparently then a new experiment (Experiment #3 in YES) was conducted:
As the results from experiment 1 and 2 contrasted our expectations, we wondered whether the null-results were a consequence of low statistical power or low choline concentrations. Although the previously reported acute effects of choline bitartrate on visuomotor performance were highly significant and strong [46], its effects on memory could be more subtle. Hence, we designed a third experiment to replicate the results of experiment 1 and 2 but with a larger sample size, a larger stimulus set, and a higher dose of choline bitartrate supplementation. We also extended the set of tasks to assess choline’s effects on verbal working memory. Thus, the study design, procedure, and apparatus were identical to experiment 1 except that experiment 3 included an extended visuospatial working memory task, an extended declarative memory task, and an additional verbal working memory task.
From the discussion:
Choline is known to improve behavioral functions in healthy, young adults that rely on the cholinergic peripheral nervous system [46]. A perhaps more likely explanation is that the substance choline bitartrate may not affect cholinergic cell receptors in the central nervous system. Some chemicals may not be able to cross the blood-brain barrier but still affect the peripheral nerves. The blood-brain barrier actually keeps the central and peripheral neurotransmitter pools separate [66]. Alternatively, choline may not be synthesized into acetylcholine at the brain regions important for memory. This limitation would then have to be specific to choline bitartrate as the supplementation of other choline-containing substances result in rapid increases in acetylcholine levels a variety of brain regions in humans [57, 58, 60, 67, 68] and rats [22]. In line with this notion are results from a study showing that a single dose of 2g of choline bitartrate also did not produce any effects on either a visual or auditory memory task [47]. However, when combined with 25mg of caffeine performance was significantly improved on both tasks compared to a placebo group. The authors suggest that administration of choline bitartrate alone might lead to an oversaturation in choline availability unless the synthesis of acetylcholine is stimulated through increases in neuronal firing. Similarly, a combination of 100mg of caffeine and 2g of choline has been shown to significantly improve performance on a backwards digit span test compared to either caffeine or choline on its own [48]. Therefore the effectiveness of choline bitartrate on its own might be limited unless for instance combined with a substance such as caffeine which is thought to disinhibit neuronal firing through the release of adenosine. Another possible explanation is that we might have been unable to find an effect of choline bitartrate on memory performance due to individual differences in participants’ (baseline) neurochemical make-up. It is not uncommon for the relationship between the availability of a neurotransmitter and task performance to follow an inverted U-curve. Thus, additional acetylcholine synthesis might have both improved and impaired memory performance depending on a participant’s baseline position on the inverted U-curve. Lastly it might be possible that choline bitartrate has to be supplemented for a longer period of time before the memory system can benefit from its increased availability.
The note on caffeine + choline is interesting, as one rodent study found that 50mg/kg caffeine for rats (so 8mg/kg for humans) paired with 120mg/kg choline (19.2mg/kg for humans) increased peak levels by 112%, compared to only 54% without caffeine. BUT caffeine didn’t increase ACh release without choline, so it was more of potentiating effect than just an additive one:
From the human caffeine + choline study referenced in the discussion of NO, we see they used:
one of the following drug combinations. a) Choline 2 gm, b)
Choline 2 gm + Caffeine 25 mg, c) Choline 2 gm + Caffeine 50 mg, d) Choline 2 gm +
Caffeine 100 mg , e) Placebo. Pleasant Hills Apothecary provided the drugs. Choline
was administered as choline bitartarate and placebo was magnesium stearate.
They concluded:
In conclusion, choline, by itself, was not effective for improving shortterm memory at the 2 gm dose. However, combinations of choline (2 g) with low doses
of caffeine (25 mg) facilitated visual short-term memory. When the dose of caffeine was
increased 2 fold to 50 mg, this combination no longer enhanced memory but impaired it.
Even more intriguing is the finding that a four-fold increase of caffeine from 25 mg to
100 mg did nothing to memory when compared to placebo. These data suggest that
caffeine and choline combinations can facilitate short-term memory, but effectiveness is
dependent on the dosage of choline and caffeine within the combination.
https://dsc.duq.edu/cgi/viewcontent.cgi?article=1983&context=etd
So that sort of throws a wrench in things, as choline alone didn’t have any benefits, choline with 25mg caffeine had benefits, and choline with 50mg had the opposite of benefits, while choline and 100mg caffeine again had no benefits, but was not detrimental. Very strange. What would a lower dose of choline and a higher dose of caffeine do? Or a lower dose of choline and the same dose(s) of caffeine?
That said, we do have one study on CDP-Choline + caffeine, although it only compared the combination to placebo. But it still did have a placebo group, and subjects were similar young adults:
Results of the present study propose that 250 mg of citicoline, when combined with caffeine, results in significant improvements in measures of sustained attention and working memory.
TL;DR:
So there seems to be a lot of factors at play here, including but perhaps not limited to:
-Doses of caffeine and choline used (and their combination)
-Form of choline used (dl vs l bitartrate vs CDP)
-Tasks performed and what they’re testing
-Individual subject tolerance/responsiveness/variability/etc.
So there may not be a single definitive answer here TBH.
Edit: it may well be what works for one person may not work for another with choline + caffeine. Or one dose/combination may work better than another for some people, or some tasks/goals, etc. Very interesting stuff.