Piracetam. The phrase nootropic was initially used to describe the actions of piracetam, chemically known as 2-oxo-1-pyrrolidine acetamide, which is a cyclical derivative of gamma-aminobutyric acid (GABA) ( Vernon & Sorkin, 1991). It is one of the oldest and most extensively investigated members of the Racetam family. At present, piracetam is a prototype nootropic drug utilized in many parts of the world for the treatment of aging impairments in cognition, brain injuries, and dementia ( Keil et al., 2006; Vernon & Sorkin, 1991). Piracetam is available under a variety of brand names worldwide, with Nootropil and Lucetam being the most common. Despite its widespread use, the exact mechanism of action remains unclear ( Keil et al., 2006).

The most influential hypothesized mechanism of action for piracetam is that it increases nervous system function by increasing synaptosomal and mitochondrial membrane fluidity, usually in damaged and aging brains ( Keil et al., 2006). This idea is also supported by further inspections conducted on samples of brain matter from young and aged rats, mice, and the human brain, as it was found that piracetam particularly enhances membrane fluidity by partitioning into the phospholipid bilayer in aged brain matter (rats, mice, and humans), while displaying no changes at all in the membranes of young brain matter ( Müller et al., 1997). This change in membrane fluidity in aged brain matter could be responsible for the enhancement in cognition as the decreased signal transduction (transmitter release, receptor density, and function) that occurs as a result of less membrane fluidity is offset by piracetam ( Keil et al., 2006; Müller et al., 1997). According to this study, piracetam should only be used in aged brains, as the young and healthy population will likely gain little from taking piracetam. ( Keil et al., 2006).

Another outcome of reduced membrane fluidity among aged tissues is reduced glucose uptake. Piracetam is used to treat this condition as it causes an increase in glucose uptake, glucose use, and manufacturing of adenosine triphosphate (ATP). As mentioned above, the advantages of piracetam are generally observed only in aged brains to treat oxygen deficiency, glucose deprivation, and neurodegeneration. It is notable that all of these conditions are also associated with mitochondrial dysfunction, and piracetam has been used to treat these conditions to a great extent ( Keil et al., 2006; Müller et al., 1997). Moreover, piracetam administration improved verbal learning ability in dyslexic children and healthy student volunteers ( Wilsher et al., 1979). Among animals, piracetam aids in learning and memory by increasing the inter-hemispheric transfer of information in the brain. In addition, among healthy individuals, piracetam improved the recollection of the studied material, expanded verbal capacity, and elevated mental functioning. Some side effects associated with piracetam include insomnia, nausea, and mild dizziness ( Vernon & Sorkin, 1991).

Aniracetam. Aniracetam, also known as “N-anisoyl-2-pyrrolidinone,” is a pyrrolidinone derivative. It is marketed under common brand names, such as Draganon, Sarpul, and Referan. Glutamate, a vital excitatory neurotransmitter, and its receptors are believed to play key roles in learning and memory ( Lee & Benfield, 1994). Glutamate receptors are further classified as ionotropic and metabotropic. The three ionotropic glutamate receptors are N-methyl-D-aspartate (NMDA), Kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ( Lee & Benfield, 1994). Aniracetam’s mode of action has not been clearly established, and it does not produce any receptor-mediated effects upon interaction with NMDA or Kainate receptors. However, it acts as a positive modulator of AMPA because it decreases the rate of desensitization and decreases the rate of ion channel closure ( Lee & Benfield, 1994).

Aniracetam also acts as a positive regulator of metabotropic receptors because it potentiates metabotropic glutamate receptors at lower doses, leading to neuroprotection. Conflicting results regarding the interaction between aniracetam and metabotropic receptors have been reported ( Lee & Benfield, 1994). Some believe that the effect of aniracetam on synaptic potential is negligible after induction of long-term potentiation (LTP), and some suspect that the effect of aniracetam on synaptic potential is very different from LTP ( Lee & Benfield, 1994). Furthermore, aniracetam administration leads to increased acetylcholine levels in the rat hippocampus, which promotes cholinergic transmission ( Lee & Benfield, 1994).

After the administration of aniracetam, most of the drug binds to plasma proteins or undergoes extensive first-pass metabolism, resulting in lower bioavailability. Aniracetam is metabolized to three major metabolites: N-anisoyl-GABA, anisic acid, and 2-pyrrolidinone ( Lee & Benfield, 1994). In animal models, aniracetam lowers the amount of damage caused by trauma and cholinergic antagonists, which normally leads to diminished brain functions such as memory and learning. Among rats, memory magnifying effects have been shown on tasks such as passive avoidance and choice reactions ( Lee & Benfield, 1994). In healthy individuals, oral and intravenous administration of aniracetam minimized the effects of hypoxic hypoxidosis measured on an electroencephalogram. Additionally, the oral consumption of aniracetam lowered the cognitive damage caused by the subcutaneous administration of scopolamine. Finally, aniracetam has also been shown to be effective in patients with impaired intellectual function caused by cerebrovascular diseases ( Lee & Benfield, 1994). Some of the most common side effects of aniracetam include nausea, anxiety, and insomnia ( Lee & Benfield, 1994).

The neurotransmitter Dopamine (DA) has been implicated to play a major role in complex cognitive processes like working memory and cognitive control. The DA pathways (mainly mesolimbic and mesocortical) that emerge from the ventral tegmental area (VTA) of the midbrain project to the prefrontal cortex (PFC), anterior cingulate cortex, and other basal forebrain areas ( Cools & D’Esposito, 2011). DA in the anterior forebrain (especially the PFC) has been directly linked to working memory and various cognitive functions essential for thought processing, reasoning, and language processing. DA in the posterior brain region plays a significant role in long-term memory and in regulating human cognition ( Cools & D’Esposito, 2011).

Mixed amphetamine salts. Psychostimulants, such as mixed amphetamine salts (MAS), are marketed under the brand name Adderall. Adderall use among the healthy population is on the rise because of its cognitive enhancement properties. Upon ingestion, drug absorption occurs through the intestinal tract, and part of the drug is deactivated by the liver during this process. The drug then crosses the blood-brain barrier and produces a desired effect upon entering the brain ( Dubljević, 2013).

Amphetamine inhibits the reuptake of DA and NE by increasing their levels in the synapse. This mechanism of reuptake inhibition works because amphetamine blocks the dopamine transporter, which decreases the uptake of DA back into the presynaptic neurons for further reuse. Amphetamine also inhibits monoamine oxidase (MAO) enzymes, which are responsible for the breakdown and inactivation of monoamines (mainly DA and NE), and reverses the action of the DA transporter, which leads to the release of DA and NE ( Dubljević, 2013). Therefore, MAS results in increased synaptic availability of DA/NE and supplemental release of these neurotransmitters. Additionally, the adverse effects of amphetamines on MAO can lead to dysfunction in the MAO system, and such a breakdown has been correlated with many psychiatric disorders, such as depression and schizophrenia ( Dubljević, 2013).

DA also plays an important role in attention. ( Cools & D’Esposito, 2011). Adderall intake by healthy individuals can result in sustained drug concentrations. Adderall is also used to treat people with ADHD. Adderall has positive cognitive effects such as heightened vigilance and reduced fatigue. This means that people can use MAS to work for longer durations and more effectively ( Dubljević, 2013). However, Adderall use among healthy volunteers has many side effects such as drug abuse, addiction, insomnia, and nervousness. One of the most acute side effects of MAS is elevated blood pressure (BP), which can cause significant cardiovascular problems. Upon inhalation, this drug can induce euphoria and many other unfavorable psychiatric events ( Dubljević, 2013).

L-Deprenyl (Selegiline). L-Deprenyl is a substituted phenethylamine, which is available under common brand names such as Jumex and Eldepryl ( Knoll, 1992). L-Deprenyl binds to active enzyme sites and is a highly specific and reversible monoamine oxidase B (MAO-B) inhibitor in the nigrostriatal pathway. Monoamine oxidase is an enzyme found in many cells that catalyzes the oxidation and metabolism of monoamines ( Head et al., 1996). The breakdown of DA, which occurs under normal circumstances, is inhibited when L-deprenyl is administered. This inhibition of DA metabolism leads to increased DA levels. It is most commonly used alongside L-dopa for the treatment of Parkinson’s disease ( Head et al., 1996). Additionally, L-deprenyl can be used to improve cognitive impairment in dementia. Patients diagnosed with Alzheimer’s who are administered selegiline also show improvements in sustained attention and working memory ( Head et al., 1996).

Moreover, selegiline studies carried out in dogs have revealed that it acts as a neuroprotective agent against toxins that induce neurodegeneration, and it also helps to lower the symptoms of senile dementia ( Mills & Ledger, 2001). The neuroprotective mechanism has not been found, but it was hypothesized that L-deprenyl preserves brain function by blocking the production of toxic compounds due to injury (i.e., free radicals and endotoxins), which in turn stabilizes the uptake of catecholamines or induces synthesis of neurotrophins (i.e., BDNF and nerve growth factors) ( Zhu et al., 2000). Furthermore, doses of L-deprenyl in rats enhanced cognitive performance and increased neuroplasticity after traumatic brain injury (TBI) induced into them. The inhibition of MAO-B caused by the administration of L-deprenyl was associated with increased DA levels, which promoted cognitive recovery and increased synaptic plasticity in the damaged hippocampus. Selegiline is used as a prescription drug in many countries. Some of the side effects of this drug include dry mouth, insomnia, and elevated blood pressure ( Zhu et al., 2000).

Methylphenidate. Methylphenidate, another common nootropic, is marketed under common brand names, such as Ritalin and Concerta. This drug is primarily a norepinephrine (NE) and dopamine reuptake inhibitor, as it blocks transporters and therefore increases the accessibility of catecholamines at synapses. Such high amounts of DA in the synaptic cleft have been associated with outcomes such as increased attention and concentration in individuals ( Linssen et al., 2012). Methylphenidate is often prescribed to children with attention deficit hyperactivity disorder (ADHD), as it decreases symptoms and boosts their cognitive function. Owing to its ability to improve cognitive abilities, healthy people have also been using methylphenidate to increase their cognitive capabilities. In addition, many studies have shown that DA plays a role in spatial working memory ( Linssen et al., 2012).

Many studies have investigated the outcomes of methylphenidate in the field of cognition involving dopaminergic action. Additionally, the use of methylphenidate among healthy individuals has been shown to increase performance on tasks involving attention, especially divided-attention tasks ( Linssen et al., 2012). Its use among healthy volunteers has also been shown to elevate attention to the relocation of novel stimuli in the environment. Moreover, studies have shown that methylphenidate administration tends to improve outcomes in both spatial and non-spatial memory tasks. In one such study involving the Sternberg memory scanning task, participants had to answer whether the letters in a given memory set were present at the beginning of the task, and participants administered methylphenidate displayed increased performance on this task ( Linssen et al., 2012). Furthermore, methylphenidate has also been implicated in improving scores on tasks involving the delayed recall of a word list. In addition, dopamine reuptake inhibition due to methylphenidate increases the consolidation of declarative memory. One of the major drawbacks of methylphenidate is that it can be easily abused and causes many side effects, such as insomnia, irritability, and weight loss due to loss of appetite. ( Linssen et al., 2012).

Acetylcholine was the first neurotransmitter to be discovered and plays an important role in memory and many other cognitive functions, as well as muscle contractions. Acetylcholinesterase (AChE) is a cholinesterase enzyme found in the nervous system that is responsible for the breakdown of acetylcholine into choline and acetate. Choline is then transported back into the neuronal terminal and reused to produce acetylcholine, so the process can begin again ( Colucci et al., 2012). Acetylcholinesterase inhibitors (AChEIs) inhibit the breakdown of ACh and increase its availability at synapses. AChEIs have been shown to possess neuroenhancement properties, as they are commonly recommended for patients suffering from slight to modest amounts of Alzheimer’s disease. AChEIs have also been shown to be effective in slowing the progression of dementia ( Colucci et al., 2012).

Huperzine A. Huperzine A (HupA) is a naturally occurring, highly selective, reversible AChE inhibitor. It is an alkaloid extracted from the Chinese herb, Huperzia Serrata. This herb has a long history of use in traditional Chinese medicine, and has been used to treat fever, inflammation, and muscle strains. Several pharmacokinetic studies have revealed that upon oral administration, HupA is absorbed quickly and soon becomes widespread in the body ( Wang et al., 2009). Compared with other AChEIs, HupA has superior blood-brain barrier penetration capability, greater bioavailability for oral administration, and longer periods of AChE inhibition. HupA is also more potent and has a higher specificity and tolerability than other AChEIs. In addition to AChE inhibition, HupA exerts many other effects on physiological targets, such as regulation of beta-amyloid peptide processing, minimization of oxidative stress, neuroprotection against apoptosis, and secretion of nerve growth factors and their signaling ( Wang et al., 2009).

Research carried out in China has demonstrated encouraging results regarding the use of HupA in the treatment of multi-infarct dementia and for patients suffering from short-term and long-term memory loss due to cerebral arteriosclerosis ( McDougall et al., 2005).

In 1994, HupA was first prescribed in China for patients with AD, as it has been found to enhance memory deficits in AD, senescent amnesia, and vascular dementia ( Wang et al., 2009). Most of the research on the effectiveness of HupA and its effects on cognition in humans has been conducted in China ( McDougall et al., 2005). More recently, it has gained attention in the US and many Western countries because reports from China have demonstrated its safety and efficacy in clinical trials ( McDougall et al., 2005; Wang et al., 2009). Several studies have shown that HupA can improve cognitive potential, performance in daily activities, behavioral disturbances, and functional performance among AD patients with AD. Preliminary studies conducted among healthy students revealed that the use of HupA among adolescents improved their performance in the areas of accumulation, recognition, association, and tactual memory, resulting in an overall increase in learning and memory function ( Sun et al., 1999). However, continued treatment with HupA can result in depression and GI disturbances ( Wang et al., 2009).

Donepezil. Donepezil is marketed under the brand name Aricept. This drug is a reversible acetylcholinesterase inhibitor. It is often prescribed by medical practitioners to treat dementia and AD. The positive results of donepezil are believed to occur through elevated arousal ( Husain & Mehta, 2011). When donepezil is used by healthy young people, it enhances episodic memory but improves verbal memory when taken by a healthy elderly population. Furthermore, in sleep-deprived individuals, donepezil stunted the decline in short-term memory and visual attention, further supporting the idea that donepezil helps increase arousal ( Husain & Mehta, 2011).

In one study, donepezil and placebo were administered to pilots to test their flight performance. At the end of the study, it was found that the performance of the pilots increased slightly compared with the placebo. The researchers concluded that donepezil improved the capacity to preserve practical skills ( Repantis et al., 2010). On delayed recognition tasks where participants had to remember semantically processed terms, outcomes were better for participants who took donepezil than for those who were given placebo. In addition, while the performance of these participants improved for delayed recall of tasks, the enhancement was also sustained for longer durations compared to the placebo. The performance of the participants in the placebo group was unaffected ( Repantis et al., 2010).

Mild cognitive impairment (MCI) can be interpreted as a memory problem that does not fall within the diagnostic standards for dementia. MCI can be the first indicator of delayed dementia, particularly AD. Patients with MCI that were prescribed donepezil showed little improvement. Donepezil also has gastrointestinal side effects ( Birks & Flicker, 2006). Studies conducted on healthy young adults with donepezil showed no improvement in their performance; in fact, a mild decline in attention and decline in verbal tasks were observed in some of these individuals. However, these studies did not provide sufficient evidence to support or refute the neurological-enhancing abilities of donepezil ( Repantis et al., 2010).

L-Theanine. L-Theanine (N-ethyl-L-glutamine) is an amino acid analog of glutamine and glutamate and is one of the major psychoactive molecules found in green tea. In the early 1950s, it was first isolated in green tea leaves, “ Camellias sinensis,” and in the mushroom, “ Xerocomus badius” ( Nathan et al., 2006). Oral administration of L-theanine leads to absorption via Na ⁺- coupled co-transporters in the brush border membrane of the intestinal tract. Once absorbed, enzymatic hydrolysis largely occurs in the kidneys, and the breakdown of L-theanine results in glutamic acid and ethylamine ( Nathan et al., 2006).

Administration of L-theanine increases striatal dopamine release, and these effects are mediated by Ca ²⁺ via the activation of NMDA receptors. Furthermore, L-theanine increases the levels of tryptone (a precursor of serotonin) and leads to elevated levels of serotonin in the hippocampus, striatum, and hypothalamus ( Nathan et al., 2006). N-Ethyl-L-glutamine exerts its effects on the norepinephrine system through a second messenger system that inhibits noradrenaline-stimulated cAMP formation. L-theanine also tended to increase GABA levels in the brain. The convulsive effects of caffeine were inhibited by L-theanine administration, suggesting a possible GABA-related anticonvulsive action ( Nathan et al., 2006).

L-theanine is relatively safe and has been shown to alleviate the negative effects of caffeine, including anxiety, increased blood pressure, and reduced sleep quality ( Kimura et al., 2007). It has been used as both an attention enhancer and a relaxing agent in numerous studies ( Haskell et al., 2008). Moreover, L-theanine regulates the resting state of brain activity and considerably increases activity in alpha brain waves. This demonstrates that it acts directly on the CNS and does not lead to drowsiness ( Nobre et al., 2008). Animal studies have shown that rats exposed to L-theanine display an elevation in avoidance behavior, which eventually leads to an improvement in memorizing power. Therefore, administration of L-theanine has positive effects on cognition through enhanced memory and learning. Furthermore, ingestion of L-theanine has been shown to increase the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus ( Nathan et al., 2006). Some of the benefits of L-theanine include improved focus, lack of tolerance, and mild anxiety relief. One of the most common side effects of L-theanine is that it can cause headaches ( Nathan et al., 2006).

Caffeine. Caffeine is one of the most consumed psychoactive drugs in the world and is naturally found in coffee beans, tea, cassina, cola nuts, and cocoa beans. Caffeine has many physiological and behavioral effects ( Smit & Rogers, 2000). One of the most heavily supported mechanisms by which caffeine works is that it acts as a competitive antagonist at adenosine receptor sites (specifically at the A ₁ and A _2A receptor sites). Adenosine normally suppresses CNS activity; therefore, caffeine consumption causes an increase in CNS activity. Some of the more noteworthy short-term effects of caffeine include increases in wakefulness, alertness (due to an increase in dopamine release), blood pressure, urine output, and respiration rate. Caffeine is a vasodilator that increases the rate of metabolic activity ( Smit & Rogers, 2000). Even at low doses, caffeine shows selective acute cognitive effects such as increased vigilance, quicker verbal reasoning, enhanced speed of encoding new information, and rapid performance in semantic memory tasks ( Hewlett & Smith, 2006).

Regular caffeine use has been associated with positive outcomes, such as decreased risk of Alzheimer’s dementia, cognitive decline, cardiovascular diseases, type 2 diabetes, and stroke ( Eskelinen & Kivipelto, 2010; Lopez-Garcia et al., 2009). Conversely, long-term caffeine use has also been associated with many negative side effects, such as anxiety, insomnia, restlessness, and tachycardia. Additionally, regular caffeine use can lead to physical dependence and noticeable withdrawal symptoms ( Childs & De Wit, 2006; Eskelinen & Kivipelto, 2010).

Ashwagandha. Ashwagandha is a herb from India that has been used as an anxiolytic anxiety reducer (anxiolytic) for over 3,000 years. This herb is a member of the Solanaceae family and is botanically known as Withania somnifera Dunal, although its common name is Indian Ginseng or Winter Cherry ( Chandrasekhar et al., 2012). The meaning of the word “Ashwagandha” is “smell of the horse,” owing to the fact that the root of this herb smells like horse manure. It also has this name because a person eating extracts of this herb begins to experience the energy and power of a horse ( Chandrasekhar et al., 2012). Its mechanism of action is not entirely clear, but it is believed to have gamma-aminobutyric acid (GABA) mimetic activity, which explains its anxiolytic effect ( Kulkarni et al., 2008).

Ashwagandha is believed to enhance the properties of attention, but there is no conclusive evidence. Ashwagandha also purports to increase memory capacity and overall brain function. One of the major constituents of Ashwagandha is Withaferin A, a strong anti-inflammatory agent that has been associated with antioxidant effects in the brain. This herb plays a major role in Ayurvedic medicine and shows many diverse pharmacological properties, including antitumor, anti-inflammatory, anti-stress, anxiolytic, and antidepressant effects ( Pingali et al., 2014). Ashwagandha is also known to possess many rejuvenating features that play a remarkable role in aversion to neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). These features also play a role in the prevention of central nervous system (CNS) disorders, such as cerebral ischemia, tardive dyskinesia, and management of drug addiction ( Pingali et al., 2014). One reason for using Ashwagandha to treat drug addiction is that it does not cause withdrawal symptoms when discontinued ( Chandrasekhar et al., 2012). Ashwagandha has also been shown to be effective in improving subclinical hypothyroidism, although one of the side effects of this herb is that it can worsen hyperthyroidism ( Sharma et al., 2018).