Nootropics in human trials (Intro)

The word "nootropic" derives from the Greek words nous, or "mind", and trepein meaning "to bend or turn". It was first coined by Romanian psychologist and chemist, Corneliu E. Giurgea after synthesizing Piracetam.
For Giurgea a nootropic drug should have the following characteristics:
1. They should enhance learning and memory.
2. They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
3. They should protect the brain against various physical or chemical injuries (e.g. barbiturates, scopalamine).
4. They should increase the efficacy of the tonic cortical/subcortical control mechanisms.
5. They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity.

In fact, most drugs commonly labelled as nootropics do not fulfill all of these requirements. Some of the best known (e.g. Adderall, Modafinil) seem to not fulfill any, as discussed later. Instead, other characteristics like (reputed increased alertness, focus or motivation) seem to be key to their popularity.
Because of deviating definitions nootropics are more broadly defined (e.g. in wikipedia) as drugs, supplements, or other substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals. 

Some nootropics from the very common to the :

Caffeine
Caffeine is the world’s most widely used stimulant (Nawrot, et al., 2003). It is used by over 90 % of North Americans every day (Mednick et al., 2008). It is widely used because of its positive effects on mood and alertness (Lorist & Tops, 2003)and vigilance and attention (Lieberman et al., 1987). However, these effects do not seem applicable / transferable to motor learning and verbal memory and are unable to reverse effects of sleep deprivation, with a dose of 200mg in low to moderate users (< than 2 cups a day) (Mednick et al., 2008). It is also shown to be ineffective in higher cognitive tasks involving working memory (Battig et al., 1984). Overall conclusions regarding the relation of caffeine and memory have been mixed. Positive effects might stem from caffeine withdrawal in high dosage users (Mednick et al., 2008).

Nicotine
With about 1,1 billion smokers worldwide in the year 2015 (WHO 2015) nicotine takes second place as the most widely used stimulant. It was shown that the application of nicotine in non-smoking males enhances performance in continuous performance tasks and therefore is said to improve attention and working-memory (Kumari, et al., 2003), which is in line with other studies suggesting that nicotine affects short-term memory in delayed free recall tasks (Sarah & Fox, 1998)
Another study examined nicotine’s effects on alertness and performance on a covert orienting task were measured. While nicotine decreased overall reaction times in the covert orienting task, there was no change in the validity effect, the reaction time difference between validly and invalidly cued targets. However, nicotine significantly improved both EEG and self-rated measures of alertness. Nicotine seems to increases alertness in non-smokers, with no improvement in spatial attention using a covert orienting task (Griesar et al., 2002). Furthermore Nicotine seems to reduce distraction under low perceptual load by acting as a stimulus filter that prevents irrelevant stimuli entering awareness (Behler et al., 2015).

Methylphenidate/ Ritalin
Most college students I know will immediately think of Ritalin or Modafinil if they are asked to name a cognitive enhancer. Studies have found that 4.1% to 10.8% of college students in the US reported using prescription stimulants non-medically during the past year (Garnier-Dykstra, et al., 2012).
Methylphenidate (MPH - common brand name ‘Ritalin’) is used in treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. Most studies focused on the its effects on Attention, Mood, Memory and executive functions. A single dose of MPH showed a positive effect on memory. Repeated doses of MPH had a mood elevating effect but also enhanced anxiety. No statistically significant effect was found in the outcomes attention, mood and executive functions. MPH had no significant effect on sleep-deprived individuals (Repantis et al., 2010). In a 2015 review the authors found some ‘publication bias’, relating to long-term and working memory and conclude that the effect in healthy subject is probably modest overall and that healthy users resort to stimulants to enhance their energy and motivation more than their cognition (Ilieva et al., 2015). 

Modafinil
Modafinil is used in treatment of disorders such as narcolepsy, shift work sleep disorder, and excessive daytime sleepiness associated with obstructive sleep apnea. Most studies focused on its effects on attention, mood, memory, wakefulness and executive functions and motivation. A single dose showed positive effects on attention only. On sleep deprived individuals it was shown to have an impact on executive functions, on memory and wakefulness but there was an insignificant effect on mood and attention (Repantis et al., 2010). A 2012 meta-analysis found that Modafinil was likely effective but criticised the gaps in the literature. (Kelley et al., 2012) 
A recent study on chess players found significantly enhanced performance with Modafinil or Ritalin but only when the players were not under time pressure (Franke et al. 2017). 

Adderall
Mixed Amphetamine Salts also known under the brand Name Adderall became increasingly popular in recent years as an athletic performance enhancer and cognitive enhancer. Like Ritalin, it is also used to treat ADHD and narcolepsy.
Overall effects of Adderall on cognition have been reviewed as very modest, while having a huge effect on perception. It was found to enhance performance in word recall, embedded figures and Raven's Progressive Matrices, but only for lower performing individuals (Ilieva et al., 2013). Adderall might also impair creativity in high performing individuals (Farah et al., 2009).

L-theanine & Caffeine
L- theanine is primarily found in plants (e.g. in the leaves of green and black tea) and fungus. Results evidently demonstrated that L-theanine clearly has a pronounced effect on attention performance and reaction time response in normal healthy subjects susceptible to having high anxiety (Higashiyama et al., 2011).
A dose of L-theanine equivalent to eight cups of black tea improves cognitive and neurophysiological measures of selective attention, to a degree that is comparable with that of caffeine. The combination of Theanine and caffeine seem to have additive effects on attention in high doses (Kahathuduwa et al.,2016).
Studies suggest that 97 mg of L-theanine in combination with 40 mg of caffeine helps to focus attention during a demanding cognitive task (Giesbrecht 2010).

Bacopa Monnieri
Bacopa Monnieri is an herb which has been used in Ayurvedic medicine for centuries. Bacopa's primary mechanism of action is still unclear, it seems to be an anti-oxidant, a weak acetylcholinesterase inhibitor and a cerebral blood flow activator (Aguiar & Borowski , 2013).
There is some evidence to suggest that Bacopa Monnieri improves memory with little evidence of enhancement in any other cognitive domains (Pase et al., 2012).

Piracetam
Closing the circle to the beginning of this short introduction to the topic: Giurgea first coined the term "nootropic" when he synthesized Piracetam in 1964. Since it is not approved by the US FDA, it is primarily used in Europe, Asia, and South America. It is commonly prescribed for cognitive impairment and dementia in several countries of Europe. Research suggests that Piracetam might also have a positive effect on healthy individuals. Subjects were given 3×4 capsules at 400 mg per day, in a double blind study. Each subject learned series of words presented as stimuli upon a memory drum. No effects were observed after 7 days but after 14 days verbal learning had significantly increased (Dimond & Brouwers, 1976). It might also be beneficial for cognitive decline associated with age. Aging subjects did significantly better in a computerized perceptual-motor tasks when on piracetam than on a placebo. (Mindus et al. 1976). While these old studies may not be that reliable, it is still held that Piracetam's “efficacy is documented in cognitive disorders and dementia, vertigo, cortical myoclonus, dyslexia, and sickle cell anemia. While high doses are sometimes necessary, piracetam is well tolerated” (Winblad, 2005). Since Piracetam was first synthesized many structurally similar compounds have emerged. These so called Racetams have poorly understood mechanisms of action; however, piracetam and aniracetam are known to act as positive allosteric modulators of AMPA receptors and appear to modulate cholinergic systems (Gualtieri et al., 2002).

References
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* Battig , K., Martin, J. R., & Feierabend , J. M. (1984). The effects of caffeine on physiological functions and mental performance. Experentia, 1218–1223.
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* Dimond, S. J., & Brouwers, E. M. (1976). Increase in the power of human memory in normal man through the use of drugs. Psychopharmacology, 307-309.
* Farah , M., Haimm , C., Sankoorikal , G., Smith , M., & Chatterjee , A. (2009). When we enhance cognition with Adderall, do we sacrifice creativity? A preliminary study. Psychopharmacology,541-547.
* Franke, A.G.; Gränsmark, P., Agricola, A., Schühle, K., Rommel, T., Sebastian, A., Balló, H.E., Gorbulev, S., Gerdes, C., Frank, B., Ruckes, C., Tüscher, O., Lieb, K. (2017) "Methylphenidate, modafinil, and caffeine for cognitive enhancement in chess: A double-blind, randomised controlled trial" in: European Neuropsychopharmacology Vol27, Issue 3, 1, pp248-260
* Garnier-Dykstra, L. M., Caldeira, K. M., Vincent, K. B., O’Grady, K. E., & Arria, A. M. (2012).Nonmedical use of prescription stimulants during college: Four-year trends in exposure opportunity, use, motives, and sources. J Am Coll Health, 226-234.
* Giesbrecht, T., Rycroft , J. A., Rowson , M. J., & De Bruin , E. A. (2010). The combination of L-theanine and caffeine improves cognitive performance and increases subjective alertness. Nutritional Neuroscience, 283-290.
* Griesar , W. S., Zajdel , D. P., & Oken , B. (2002). Nicotine effects on alertness and spatial attention in non-smokers. Nicotine & Tobacco Research, 185-194.
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* Higashiyama, A., Htay, H. H., Ozeki, M., Juneja, L. R., & Kapoor, M. P. (2011). Effects of l-theanine on attention and reaction time response. Journal of Functional Foods, 171-178.
* Ilieva, I., Boland, J., & Farah, M. (2013). Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Neuropharmacology, 496-505.
* Ilieva IP, Hook CJ, Farah MJ. (2015) Prescription Stimulants' Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis.; J Cogn Neurosci. 2015 Jun;27(6):1069-89. 
* Kahathuduwa, C. N., Dassanayake , T. L., Amarakoon , A. M., & Weerasinghe, V. S. (2016). Acute effects of theanine, caffeine and theanine-caffeine combination on attention. Nutritional Neuroscience.
* Kelley, A.M.; Webb, C.M., Athy, J.R., Ley, S., Gaydos, S. (2012) "Cognition enhancement by modafinil: A meta-analysis" in Aviation Space and Environmental Medicine; Vol83, Issue 7, p685-690
* Kumari, V., Gray, J., H ffytche, D., Mitterschiffthaler, M., Das, M., Zachariah, E., . . . Sharma, T. (2003). Cognitive effects of nicotine in humans: an fMRI study. NeuroImage, 1002-1013.
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* WHO (2015). WHO global report on trends in tobacco smoking 2000-2025. WHO Library Cataloguing-in Publication Data .
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