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Benefits and Harms of ‘Smart Drugs’ (Nootropics) in Healthy Individuals

• Review Article
• Published: 02 April 2022
• Volume 82 , pages 633–647, ( 2022 )

Cite this article

• Fabrizio Schifano 1 ,
• Valeria Catalani 1 ,
• Safia Sharif 1 ,
• Flavia Napoletano 2 ,
• John Martin Corkery 1 ,
• Davide Arillotta 1 ,
• Suzanne Fergus 1 ,
• Alessandro Vento 3 , 4 , 5 &
• Amira Guirguis 1 , 6  

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A Correction to this article was published on 27 April 2022

This article has been updated

‘Smart drugs’ (also known as ‘nootropics’ and ‘cognitive enhancers’ [CEs]) are being used by healthy subjects (i.e. students and workers) typically to improve memory, attention, learning, executive functions and vigilance, hence the reference to a ‘pharmaceutical cognitive doping behaviour’. While the efficacy of known CEs in individuals with memory or learning deficits is well known, their effect on non-impaired brains is still to be fully assessed. This paper aims to provide an overview on the prevalence of use; putative neuroenhancement benefits and possible harms relating to the intake of the most popular CEs (e.g. amphetamine-type stimulants, methylphenidate, donepezil, selegiline, modafinil, piracetam, benzodiazepine inverse agonists, and unifiram analogues) in healthy individuals. CEs are generally perceived by the users as effective, with related enthusiastic anecdotal reports; however, their efficacy in healthy individuals is uncertain and any reported improvement temporary. Conversely, since most CEs are stimulants, the related modulation of central noradrenaline, glutamate, and dopamine levels may lead to cardiovascular, neurological and psychopathological complications. Furthermore, use of CEs can be associated with paradoxical short- and long-term cognitive decline; decreased potential for plastic learning; and addictive behaviour. Finally, the non-medical use of any potent psychotropic raises serious ethical and legal issues, with nootropics having the potential to become a major public health concern. Further studies investigating CE-associated social, psychological, and biological outcomes are urgently needed to allow firm conclusions to be drawn on the appropriateness of CE use in healthy individuals.

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Substances used and prevalence rates of pharmacological cognitive enhancement among healthy subjects

Is methylphenidate beneficial and safe in pharmacological cognitive enhancement.

Pharmacological Neuroenhancement: Substances and Epidemiology

Change history, 27 april 2022.

A Correction to this paper has been published: https://doi.org/10.1007/s40265-022-01716-0

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Schifano, F., Catalani, V., Sharif, S. et al. Benefits and Harms of ‘Smart Drugs’ (Nootropics) in Healthy Individuals. Drugs 82 , 633–647 (2022). https://doi.org/10.1007/s40265-022-01701-7

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Forty years after the first reports on stimuli-responsive phase transitions in synthetic hydrogels, the first medicines based on responsive components are approaching the market. Sensitiveness to internal or external signals of the body can be achieved by means of materials (mostly polymers, but also lipids and metals) that modify their properties as a function of the intensity of the signal and that enable the transduction into changes in the delivery system that affect its ability to host/release a therapeutic substance. Integration of responsive materials into implantable depots, targetable nanocarriers and even insertable medical devices can endow them with activation-modulated and feedback-regulated control of drug release. This review offers a critical overview of therapeutically-interesting stimuli to trigger drug release and the evolution of responsive materials suitable as functional excipients, illustrated with recent examples of formulations in clinical trials or already commercially available, which can provide a perspective on the current state of the art on smart drug delivery systems.

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Nootropics as Cognitive Enhancers: Types, Dosage and Side Effects of Smart Drugs

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• 1 Department of Agroenvironmental Chemistry and Plant Nutrition, Czech University of Life Sciences Prague, Kamýcká 129, 165 00 Prague, Czech Republic.
• PMID: 36014874
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• DOI: 10.3390/nu14163367

Nootropics, also known as "smart drugs" are a diverse group of medicinal substances whose action improves human thinking, learning, and memory, especially in cases where these functions are impaired. This review provides an up-to-date overview of the potential effectiveness and importance of nootropics. Based on their nature and their effects, this heterogeneous group of drugs has been divided into four subgroups: classical nootropic compounds, substances increasing brain metabolism, cholinergic, and plants and their extracts with nootropic effects. Each subgroup of nootropics contains several main representatives, and for each one, its uses, indications, experimental treatments, dosage, and possible side effects and contraindications are discussed. For the nootropic plant extracts, there is also a brief description of each plant representative, its occurrence, history, and chemical composition of the medicinal part. Lastly, specific recommendations regarding the use of nootropics by both ill and healthy individuals are summarized.

Keywords: Panax ginseng; Paullinia cupana; antioxidant activity; ayurvedic; brain injury; learning; memory; nootropics; piracetam; smart drugs.

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• Drug-Related Side Effects and Adverse Reactions*
• Nootropic Agents* / therapeutic use
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• Published: 02 March 2016

Smart drugs: A dose of intelligence

• Amber Dance 1  

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As mind sports becomes the new frontier for doping concerns, research is exploring whether users really get any value from 'smart drugs'.

In August 2015, 80 professional video gamers from around the world gathered for the ESL One Cologne competition in Germany. With US$250,000 in prize money up for grabs, pressure was high, and competition organizer ESL wanted to ensure fair play. At some point during the two-day event, a random selection of players received a tap on the shoulder and were escorted to a discreet back room where a physician awaited.

For the first time in its 16-year history, ESL was taking saliva samples on its lookout for dope. Smart drugs were allegedly circulating, helping players to get in the zone. “Just like in normal sports, it's not OK to win because you took a pill,” says Anna Rozwandowicz, ESL's director of communications and the first head of its anti-doping initiative. That weekend, all the tests came back clean.

E-athletes aren't the only ones allegedly popping pills to try to enhance their mental faculties. Use of the drugs seems to be common, although finding firm data is not easy. In 2014, a survey of British and Irish students reported that more than 3% currently used prescription medications as cognitive enhancers 1 . A 2013 survey of surgeons found that nearly 20% had used medication for cognitive enhancement at least once 2 . And an informal survey ( go.nature.com/xmlrn2 ) from 2008 reported that a similar proportion of Nature readers had used medications off-label to improve memory or concentration.

Many smart drugs are prescription medications either purchased illegally or used off-label. Top choices include Adderall (amphetamine) and Ritalin (methylphenidate) — treatments for attention-deficit hyperactivity disorder (ADHD) — and modafinil, which is a medication for sleep disorders such as narcolepsy. In people with ADHD or sleep disorders, these drugs can raise brain function so that it matches that of healthy people. But it is not clear whether the same medications can push a neurologically healthy, well-rested individual onto a higher cognitive plane. There is also the question of side effects. Despite these uncertainties, the apparently widespread use of neuroenhancers has prompted an ethical debate about whether their use is fair in school exams or mental games.

Like a boss

They don't really live up to the name smart pills

It is hard to say just how much these medications help an average person. Amphetamines improve focus and can make dull tasks seem interesting. So they might change a student's perspective from, 'Ugh, chemistry', to 'Ooh! Carbon bonds!' — even though that student is not any brighter. “They don't really live up to the name smart pills,” says Martha Farah, a cognitive neuroscientist at the University of Pennsylvania in Philadelphia. “Nothing that would turn you from a B to an A student or suddenly give you winning business ideas.”

It's still not clear precisely how these drugs produce their effects. Adderall and Ritalin are the best understood. Their main effects seem to relate to the neurotransmitters noradrenaline and dopamine, each of which mediates several effects, including attention and reward. Normally, a neuron releases these neurotransmitters as a message, telling other neurons to fire or stay quiet. Once the signal has been received, the first neuron re-absorbs the neurotransmitters. These medications block that re-uptake, so that the signals persist. Amphetamines also have other actions, such as preventing the breakdown of neurotransmitters.

Understanding of the cognitive-enhancement mechanism of modafinil is more sketchy. The drug affects “pretty much every major neurotransmitter in the brain”, says Ruairidh Battleday, a neuroscientist at the University of California, Berkeley. These include dopamine and noradrenaline, so part of its effect is probably similar to that of Adderall and Ritalin.

Extra neurotransmitters help parts of the brain to communicate better, particularly the prefrontal cortex, which neuroscientist Kimberly Urban calls the brain's “boss”. When noradrenaline and dopamine are present in the right amounts, the boss is an effective manager, explains Urban, who works at the Children's Hospital of Philadelphia. Too few neurotransmitters, and the boss is sluggish; too many, and it gets overwhelmed. The goal of treatments for ADHD and narcolepsy is to get the boss to the peak of function. Healthy users hope that they can raise their boss's peak.

People seeking a chemical boost do have legal options. “By far the most commonly used neurocognitive enhancers are nicotine and caffeine,” says Peter Morgan, a psychiatrist at Yale University School of Medicine in New Haven, Connecticut. Instead of blocking reuptake, caffeine stimulates the release of extra noradrenaline and dopamine; its effects aren't as strong or as long-lasting as those provided by the other drugs. Nicotine mimics the neurotransmitter acetylcholine, which affects learning and memory. And no one bans people from pumping up their brains by smoking or drinking coffee during competitions or before an exam.

Unclear benefits

Researchers are attempting to quantify the effects of prescription neuroenhancers in healthy people. In one study, Stefano Sensi, a neurologist at G. d'Annunzio University of Chieti–Pescara in Italy, and his team asked 26 university students to take an intelligence test. They then gave each volunteer either a dose of modafinil or a placebo before re-administering the test 3 . For the test, called Raven's matrices, participants were required to complete the ninth pattern in a 3 × 3 geometric puzzle. They were scored on the number of grids that they answered correctly. Solving the puzzle requires quick and flexible thinking — called fluid intelligence.

Results were mixed and depended on the difficulty of the matrices. Modafinil made no difference on the easiest or the hardest puzzles. The drug did increase scores for the grids of medium difficulty, mostly for those who scored low in the pre-drug test; it made little difference to participants who nailed the matrices on their first try.

Sensi's work was among 24 papers included in a 2015 review of modafinil in healthy people 4 . The studies used a variety of cognitive tests, and the review found that, on average, modafinil did seem to help — particularly with decision-making, planning and fluid intelligence. The more complex the task, the more that modafinil helped. “On the basis of the evidence,” says Battleday, “modafinil is improving people's performance.” But the results were not uniformly positive. Not every test showed benefits and, in a couple, the drug seems to have stunted creativity.

The review authors also noted that many cognitive tests had been designed to assess impairment, not enhancement. For example, people with a brain injury or dementia may struggle with a clock-drawing test, but someone with normal cognition will usually get it right — leaving no room for smart drugs to assist. Psychologists have few options to adequately measure cognition in healthy people, says review co-author Anna-Katharine Brem, a neuropsychologist at the University of Oxford, UK.

As with any mind-altering drug (caffeine and nicotine included) addiction or dependence are concerns. People who take drugs for ADHD do not seem to get hooked, says James McGough, a child and adolescent psychiatrist at the University of California, Los Angeles. However, he does not know if the same drugs might prove addictive in healthy people. After all, Adderall is an amphetamine, which has established addictive properties. Ritalin and modafinil seem to be less addictive, says Urban, but that does not mean that regular use is without risk. Morgan points out that regular use of coffee and cigarettes causes consumers' brains to adapt so that they need the stimulant just to function at their normal cognitive level. He suspects, the same might occur with smart drugs, even if users lack the compulsive craving that characterizes addiction.

As for long-term effects, nobody knows. Urban and colleagues' experiments in rats indicate that Ritalin could be bad for developing brains 5 . The researchers treated both adults and juveniles with one milligram per kilogram body weight, which is within the normal range for human treatment. In the grown-up rats, the drug increased nerve firing in their prefrontal cortex. But in the 15-day-old rats, equivalent to a preteen human, firing went down. If Urban stopped the drug, the effects went away. But when she tripled the dosage — equivalent to a high, but not unheard of, human prescription — the firing rates stayed low even 70 days after the treatment stopped.

The neurotransmitters that the medications are known to target, noradrenaline and dopamine, are crucial regulators of brain maturation during puberty, Urban explains. Although the drugs don't seem to cause problems in teenagers with ADHD, they might throw off development of a healthy brain. She speculates that the poor firing patterns observed in the rats might translate to problems with working memory and flexible thinking in people. For example, someone might have a hard time finding a new route to work if their usual path is blocked. Indeed, she says, healthy children who take too much Ritalin can exhibit “extreme perseverance”— for example, being unable to pause a video game when it's time for dinner, persisting with one topic of conversation without being able to switch gears, or feeling emotions such as anger for a longer time than a situation warrants.

Smart moral compass

Smart drugs are still primitive, Sensi says. They temporarily alter multiple neurotransmitters, so they aren't very specific. A better approach, he suggests, could be to develop drugs that would promote nerve-cell growth or the rewiring of the brain, inducing changes that would permanently enhance thinking.

However, the current medications are still potent enough to raise ethical questions. One such concern revolves around social equality. Not everyone has equal access to smart drugs, and there is a danger that only the privileged will be able to get ahead with amped-up cognitive powers. The result would be yet another force widening the gap between the haves and the have-nots, says Nita Farahany, a bioethicist at Duke University in Durham, North Carolina. Or, there might be a sort of arms race, with people taking ever more advanced smart drugs just to keep up. At her own institution, Farahany says, students were so worried about brain-boosters that the university amended its honour code in 2011 to state that “the unauthorized use of prescription medication to enhance academic performance” was a form of cheating.

For now, at least, even the scientists who study smart drugs aren't relying on them. Most of those interviewed for this article said that they stick to coffee, tea or energy drinks. Morgan, for his part, suggested that the same cognitive benefits can be achieved by simply taking a refreshing nap.

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Establishing Natural Nootropics: Recent Molecular Enhancement Influenced by Natural Nootropic

Noor azuin suliman.

1 Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia

Che Norma Mat Taib

Mohamad aris mohd moklas, mohd ilham adenan.

2 Atta-ur-Rahman Institute for Natural Product Discovery, Aras 9 Bangunan FF3, UiTM Puncak Alam, Bandar Baru Puncak Alam, 42300 Selangor Darul Ehsan, Malaysia

Mohamad Taufik Hidayat Baharuldin

Rusliza basir.

Nootropics or smart drugs are well-known compounds or supplements that enhance the cognitive performance. They work by increasing the mental function such as memory, creativity, motivation, and attention. Recent researches were focused on establishing a new potential nootropic derived from synthetic and natural products. The influence of nootropic in the brain has been studied widely. The nootropic affects the brain performances through number of mechanisms or pathways, for example, dopaminergic pathway. Previous researches have reported the influence of nootropics on treating memory disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Those disorders are observed to impair the same pathways of the nootropics. Thus, recent established nootropics are designed sensitively and effectively towards the pathways. Natural nootropics such as Ginkgo biloba have been widely studied to support the beneficial effects of the compounds. Present review is concentrated on the main pathways, namely, dopaminergic and cholinergic system, and the involvement of amyloid precursor protein and secondary messenger in improving the cognitive performance.

1. Introduction

The “nootropic” or simplified as a “smart drug,” “brain booster,” or “memory enhancing drug,” is a common term that will tag along with the compound responsible for the enhancement of mental performance. By definition, nootropic is a compound that increases mental functions including memory, motivation, concentration, and attention [ 1 ]. There are two different nootropics: synthetic, a lab created compound such as Piracetam, and notable natural and herbal nootropics, such as Ginkgo biloba and Panax quinquefolius (American Ginseng).

Natural nootropics are proven in boosting the brain function while at the same time making the brain healthier. Nootropics act as a vasodilator against the small arteries and veins in the brain [ 2 ]. Introduction of natural nootropics in the system will increase the blood circulation to the brain and at the same time provide the important nutrient and increase energy and oxygen flow to the brain [ 3 ]. Despite the 3% weight of total body weight, the brain receives around 15% of the body's total blood supply and oxygen. In fact, the brain can only generate energy from burning the glucose [ 4 ], proving that neuron depends on the continuous supply of oxygen and nutrients.

In contrast to most of other cells in the body, neuron cannot be reproduced and is irreplaceable. The neuron cells are persistently expending the converted energy to maintain the repair of the cell compartments. The energy generated from the glucose is crucial for maintenance, electrical, and neurotransmitter purposes [ 5 ]. The effect of natural nootropics is also shown to reduce the inflammation occurrence in the brain [ 6 ]. The administration of nootropics will protect the brain from toxins and minimising the effects of brain aging. Effects of natural nootropics in improving the brain function are also contributed through the stimulation of the new neuron cell. As incentive from the new neuronal cell, the activity of the brain is increased, enhancing the thinking and memory abilities, thus increasing neuroplasticity [ 7 ].

Commercialised natural nootropics in the market are reacting at different mechanisms, thus affecting different parameters. Natural nootropics alter the concentration of existing neurotransmitters. Natural nootropics have been disclosed to stimulate the release of dopamine, uptake of choline, cholinergic transmission, function of α -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor, turnover of phosphatidylinositol, and activity of phosphatase A2 [ 8 ]. Some of the natural nootropics act as a positive allosteric modulator for acetylcholine or glutamate receptor [ 9 ]. The release of neurotransmitter [ 10 ] and the increase activity of neurotransmitter [ 11 ] induced by natural nootropics facilitate the long-term potential (LTP) and improve synaptic transmission.

2. Suggested Molecular and Cellular Mechanisms

Establishment of new natural nootropic must consider the cellular and molecular mechanism of cognitive processes. A neuron has a known structural and functional plasticity or termed as synaptic plasticity, responsible for synaptic remodelling or known as cellular learning. Modulation in the molecular level in the neuron will alter the cognitive properties [ 12 ]. Through this review, there are few suggested mechanisms mediating the effects of nootropics in cognitive performance.

2.1. Glutaminergic Signalling

Glutamatergic transmission is an example of synaptic plasticity associated with LTP. Glutamate is an essential neurotransmitter involved in cognitive processes [ 13 ]. There are two different types of glutamate receptors: ionotropic (AMPA, kainite and NMDA receptors) and metabotropic receptors, distributed on the pre- and postsynaptic sites of the neuron. These receptors are responsible for neuronal network that allows the cognitive performance [ 14 ]. The release of glutamate will activate N-methyl-D-aspartate (NMDA) and AMPA receptors. AMPA receptor is responsible for synaptic transmission, while NMDA receptor is responsible for classic learning and memory [ 15 ]. The brain will respond by opening the Na + /K + ion channel and depolarising the cell membrane [ 16 ]. However, hyperactivity of glutamate receptors can cause oxidative stress to occur responding to the cognitive dysfunction [ 17 ].

Glutamate, which acts by activating NMDA receptor, is a main excitatory neurotransmitter related in cognition function [ 15 ]. The NMDA receptor is an ionotropic channel and distributes abundantly in the hippocampus, cortex, and thalamus [ 18 ] that assists the movement of Ca 2+ , Na + , and K + ions [ 19 ]. Activation of the NMDA receptor is reported to initiate the LTP observed in the hippocampus. LTP is part of the synaptic plasticity responsible for the physiological changes of cognitive functions [ 20 ]. LTP is remarkably studied in the hippocampus associated with learning and memory [ 21 ]. The increased Ca 2+ permeability and blockage of voltage-dependent Mg 2+ contribute to the synaptic plasticity and the formation of memory [ 19 ]. Increased Ca 2+ also affects the gene and protein expression for LTP and, subsequently, may lead to neurotoxicity due to overexcitation of glutamate observed in Alzheimer's disease [ 16 ]. Blockage of NMDA receptor displays the cognitive impairment in animal models. The models are mimicking the association between the receptor to dementia [ 22 ] and schizophrenia [ 23 ] diseases. Downregulated glutamate is observed in Alzheimer's disease [ 24 ] accompanied by the reduction of NMDA receptor in the hippocampus [ 25 ].

AMPA receptor, another type of ionotropic channel, is known to mediate the fast and immediate postsynaptic response to glutamate release and thus may contribute to synaptic plasticity [ 26 ]. The receptor can be found throughout the brain, especially in the thalamus, hypothalamus, cerebral cortex, hippocampus, basal ganglia, and cerebellum [ 18 ], being also permeable for Na + and K + [ 27 ]. Increased density of AMPA receptor in the hippocampus was shown to enhance the memory consolidation [ 28 ]. The use of AMPA modulator causes the deactivation and desensitisation of the receptor in the hippocampus thus subsequently facilitating the cognitive performances, including short-term memory [ 29 ].

2.2. Cholinergic System

In regulating the cognitive functions, the central cholinergic system is suggested to be an essential neurotransmitter associated with, namely, acetylcholine (ACh) [ 30 ]. The neuronal nicotinic ACh receptor is established located on the presynaptic terminal and applies an action on hippocampal synaptic transmission via stimulating the release of glutamate [ 31 ]. The activation of nicotinic ACh receptor is stimulated by activation of protein kinase C (PKC). These events subsequently maintain the phosphorylation of the receptor [ 32 ] and sustain the upregulation of glutamate release. Afterward, the high expression of glutamate initiates the long-lasting acceleration of hippocampal synaptic transmission [ 33 ]. Taking piracetam as an example, nootropics are suggested to involve the biochemical modifications in the aged brain [ 34 ]. Treatment of nootropics shows pronounced effects in the impaired brain functions induced by number of noxious stimuli, for example, hypoxia, aging, and injury [ 35 ].

Cognitive dysfunction is related to diminish cholinergic function, treated by stimulation of central cholinergic activity expressing the improvement of cognitive performances [ 36 ]. The loss of neuronal cholinergic observed in the hippocampal area is responsible for the major characteristic of Alzheimer's disease. In treating Alzheimer's disease-type senile dementia, central cholinergic system is suggested to be improved. Administration of established nootropics is established to increase the level of ACh and upregulation of receptor binding for cholinergic in the frontal cortex and hippocampus [ 37 ]. Downregulation of noradrenergic function is studied to diminish the behavioural impairment due to degeneration of cholinergic system [ 38 ]. The nootropics activities are observed through the downregulated ACh esterase activity. The reduction subsequently leads to upregulation of ACh expression in the brain. Thus, good agents of nootropics are able to decrease norepinephrine (NE) and elevate the 5-hydroxytryptamine (5-HT) expression observed in the central cortex, hippocampus, and hypothalamus [ 39 ].

2.3. Amyloid Precursor Protein

Dysfunction of the cholinergic system in Alzheimer's disease is also accompanied by the involvement of amyloid protein, specifically amyloid β -protein, and neurofibrillary tangles [ 40 ]. Modulation of processing of cellular component is also influenced by the neuronal transmission and synaptic plasticity. Amyloid precursor protein (APP) is one example of cellular component affected. APP is detected in the membrane of synaptic preparation and leading to the involvement of a fragment of APP in synaptic formation and maintenance [ 41 ]. The consequences of the influence of APP seem to contribute to the memory formation [ 42 ]. Introduction of natural nootropics increases the learning and memory performance, which causes upregulation of APP expression [ 43 ]. Knockout APP in mice was observed to impair the behavioural activity and alter the structure and length of the neuron [ 44 ]. In introducing natural nootropic, modulation of APP processing must be approached since it mediates the formation of specific neurotropic APP fragments, which is important for memory functions.

Patients diagnosed with Alzheimer's disease are expressed with the deposition of insoluble or oxidised amyloid- β derived from APP present in the brain [ 45 ]. β -amyloid peptide is another fragment derived from the APP, contributing to the impairment of short-term working memory [ 46 ]. Oversynthesis of β -amyloid from APP may be influenced by the increased neuronal activity thus subsequently causing the depression of synaptic transmission [ 47 ]. The patient's brain also contains an activated caspase-3. Caspase-3 is a cysteine protease that facilitates the apoptosis induced by the mitochondrion [ 48 ]. Marx [ 49 ] has listed a possible reason of the onset of Alzheimer's disease, namely, due to deposition of amyloid- β , apoptosis, and presence of oxidative stress. The amyloid- β -induced apoptosis leads to the neuronal degeneration [ 50 ]. High expression of amyloid- β in the neuron stimulates neuronal apoptosis death due to induction of caspase-3 activities [ 51 ]. Production of amyloid- β fibril is an indicator for development of Alzheimer's disease. The amyloid- β fibril is responsible for permeability of lipid membrane [ 52 ] and stimulation of Ca 2+ conductance [ 53 ].

2.4. Secondary Messenger

Schwartz [ 54 ] has claimed the involvement of secondary messenger implicated in the cognitive purpose. The evolution of the intracellular signalling cascade involves various enzymes and selective protein-protein interactions in response to the cognitive performance. LTP, as mentioned before, is related to the activation of NMDA receptor and leads to influx of Ca 2+ . It is originating the series of events causing the activation of pre- and postsynaptic mechanisms [ 55 ]. Ca 2+ is observed to activate PKC in the dentate gyrus [ 56 ], a molecule that is involved in learning and memory processes [ 57 ]. The administration of PKC activator [ 58 ] and nootropic drugs were observed to improve the memory performances, suggesting the involvement of similar pathway, the PKC pathway [ 59 ].

Upon PKC activation, it localises to specific subcellular sites and confers different physiological function [ 60 ]. The failure for this translocation to occur is found in normal ageing and number of neuronal pathologies [ 61 ]. Considering the role of PKC in learning and memory mechanisms, PKC improves synaptic plasticity in the brain. In addition, diminished calcium/calmodulin-dependent protein kinase II (CaMKII) and PKC activity contribute to downregulation of NMDA receptor, thus reducing the release of glutamate [ 62 ].

2.5. Miscellaneous

Insulin receptor becomes another target for investigating the effect of nootropic in cognitive purposes. Insulin plays a role in the neuropathological views, including involvement in neurotropic and neuromodulatory functions [ 63 ]. In the central nervous system (CNS), insulin is synthesised and released from neuron as a response to depolarisation [ 64 ]. As observed from a number of studies, insulin receptors are also responsible for learning and memory [ 65 ]. High expression of insulin receptors is found in the hippocampus, including in the dentate gyrus and CA1 pyramidal cells [ 66 ]. Neuron insulin or insulin receptor in the hippocampus can modulate the synaptic activity mediated by NMDA, which subsequently suppress the AMPA and GABA A receptors. It alters the synthesis and the activity of a number of neurotransmitters [ 67 ]. Activation of neuronal insulin will stimulate the signalling pathway of cognitive function, including activation of mitogen-activated protein kinase (MAPK), PKC, and phosphatidylinositol-3-kinase (PI3K) [ 67 ]. Diabetic rats were observed to experience cognitive impairment and LTP [ 68 ].

Other than insulin receptor, angiotensin receptor also facilitates the signal transduction in the CNS. Angiotensin, a peptide hormone, is part of the renin-angiotensin system that stimulates the release of aldosterone from the adrenal cortex. Angiotensin II (Ang II), one of the subtypes of angiotensin, regulates the blood pressure via a number of actions. The most significant actions are vasoconstriction, renal actions, and increased aldosterone biosynthesis [ 69 ]. Ang II also interacts with other neurotransmitters, causing the release of noradrenaline and the synthesis of serotonin [ 70 ]. Ang II facilitates the cognitive and behavioural processes through its specific receptors and metabolites expressed in animal models [ 71 ]. Upon cognitive impairment of Alzheimer's disease patient, the Ang II in the brain inhibits the release of acetylcholine through inhibition on angiotensin type 1 receptor (AT1) [ 72 ]. Acetylcholine is known as a critical neurotransmitter responsible for memory.

Review by van der Staay et al. [ 73 ] has established a definition of cognition enhancer. Overall, a cognition enhancer is a pharmacological compound that enhances the mnemonic and cognitive function that can cross the blood-brain barrier. The cognition function is influenced by the cognition enhancer including the learning, consolidation and retrieval, and memory. As a contrast, it does not have psychopharmacological activity such as sedation and has minimal or no adverse effects with low toxicity level. Listed below are examples of natural nootropic that were proved to improve cognitive and memory properties.

3. Examples of Nootropic

3.1. pyrrolidinone derivatives.

Pyrrolidinone is a class of 5-membered lactams with a four-carbon heterocyclic ring structure with biological interest [ 74 ] found in many pharmaceuticals and natural products. The synthesis of nootropic from pyrrolidinone derivatives has common features including enhancing the learning process, diminishing the impaired cognition, and protecting against brain damage. Number of pyrrolidine derivatives are commercially available, including piracetam, oxiracetam, aniracetam, and promiracetam [ 75 ]. Administration of aniracetam or piracetam affects the muscarinic receptor binding in the different brain regions [ 76 ]. Study by Pilch and Müller [ 77 ] had established the upregulation of m-cholinoceptor in the brain responding to the aging brain.

Piracetam or 2-oxo-1-pyrrolidineacetamide, a cyclic derivative of gamma-aminobutyric acid (GABA) [ 78 ], is widely used in treating senile dementia and Alzheimer's disease [ 79 ]. Studies showed the role of piracetam in enhancing the memory and learning [ 80 ] and act synergistically with choline leading to greater enhancement of cognition. Winnicka et al.'s study [ 78 ] showed the effect of piracetam on regulating the release of glutamate observed in the cortex and hippocampus, suggesting involvement of NMDA receptor induced by piracetam. Despite having a low affinity for glutamate receptors, piracetam initiates a number of effects on the receptors, for example, on AMPA receptor. Treatment of piracetam causes activation of AMPA receptor thus stimulating the influx of Ca 2+ in the brain and increasing the density of AMPA receptors in the synaptic membrane of the cortex. Piracetam also causes the release of glutamate stimulated by potassium in the hippocampal nerves [ 81 ]. Recent reports suggest the neuroenhancing effect of piracetam is via stimulation of acetylcholinergic and glutamatergic systems, plus elevation of membrane permeability [ 82 ].

Introduction of aniracetam is usually related to the involvement of AMPA receptor [ 83 ], cholinergic system [ 84 ], and metabotropic receptor [ 85 ], as part of cognition function. Aniracetam, including pyrrolidinone derivative compounds, is established to diminish the cognitive impairment [ 86 ]. Systemic administration of aniracetam improves the cognitive performance observed behaviours, suggesting the involvement of AMPA in the dentate gyrus [ 87 ]. The effects of cognitive enhancer of aniracetam are postulated due to the slow rate of deactivation [ 88 ] and desensitisation of AMPA receptors [ 89 ] observed using hippocampal slide. Other studies had suggested the involvement of activated hippocampal PKC and sustained ratio of membrane and cytosolic PKC γ [ 90 ]. The enhancement of PKC γ is subsequently induced by the phosphorylation of glutamate receptor subunits, thus modifying the channel kinetics of AMPA receptor [ 91 ]. The study showed that the intrahippocampal aniracetam mediates the formation of behavioural LTP, thus representing the synaptic mechanism induced by the treatment [ 83 ].

Another example of pyrrolidinone derivative is nefiracetam (N-(2,6-dimethyl-phenyl)-2(2-oxo-1-pyrrolidinyl)), a piracetam-like nootropic agent. Studies show that the compound improves the impaired cognitive due to drugs [ 92 ], morphine [ 93 ], or ageing [ 94 ]. Intake of nefiracetam is postulating the cholinergic system, as ACh receptor enhances the release of neurotransmitter [ 31 ]. Nefiracetam is studied to influence the phosphorylation of nicotinic ACh receptor by activating the PKC, thus helping the release of neurotransmitter from the presynaptic terminal [ 32 ]. Synaptic transmission influenced by nefiracetam is not mediated through the blocking of GABAergic transmission and enhanced postsynaptic ionotropic glutamate receptor. Interestingly, nefiracetam is improving the synaptic strength by aiming at the nicotinic ACh receptor [ 33 ] possibly by Na + without affecting the permeability of Ca 2+ [ 32 ]. Another study suggests that the inhibition of PKA is responsible for the effect of nefiracetam on Ca 2+ channel [ 32 ]. In contrast to piracetam and oxiracetam, nefiracetam enhances the N- and L-type Ca 2+ channels but not T-type [ 95 ].

DM235 or sunifiram is a recent compound structurally related to piracetam and is known to prevent cognitive deficits. The compound is observed to improve the impaired cognitive functions by inhibiting the induction of amnesia [ 96 ]. As discussed previously, pyrrolidinone derivatives prevent the amnesia induced by the impaired cholinergic system [ 97 ] and ameliorate the cognitive deficits [ 98 ]. Similar to other pyrrolidinone derivatives, sunifiram increases the release of neurotransmitter from the presynaptic terminal [ 99 ]. Amnesia can be induced by altering the neurotransmitter system through GABA. Activation of GABA receptor impairs the cognitive function including the learning and memory processes [ 100 ]. In contrast to other pyrrolidinone derivatives, sunifiram is more potent while having a similar characteristics with piracetam. Sunifiram is observed to ameliorate the memory function and has less adverse effects [ 81 ]. A recent study reports the improvement of hippocampal LTP induced by sunifiram is mediated by the glycine-binding site of NMDA receptor [ 101 ], an attractive binding site for Alzheimer's disease drugs [ 102 ]. Thus, the reaction of sunifiram on the same binding site is suggested to ameliorate the impaired cognitive function of Alzheimer's disease patients [ 101 ]. Stimulation of the binding is also associated with the increased autophosphorylated CaMKII and PKC α thus suggesting the enhanced memory and hippocampal LTP [ 103 ].

3.2. Bacopa monnieri

Bacopa monnieri or Brahmi is derived from the family of Scrophulariaceae, found throughout the Indian subcontinent in a wet, damp, and marshy area [ 104 ]. It has purple flowers with numerous branches and small oblong leaves ( Figure 1 ). This plant is known to be used for number of nervous system disorders, including insomnia, anxiety, and epilepsy. According to Ayurvedic medical practitioners, Bacopa monnieri is categorised as a medhya rasayana, a compound that stimulates and enhances the memory and intellect. These properties were studied preclinically and clinically [ 105 ]. The property of memory, facilitating action of this plant, is contributed by the chemical constituents of bacoside A, assigned as 3-(a- l -arabinopyranosyl)-O- β - d -glucopyranoside-10, 20-dihydroxy-16-keto-dammar-24-ene [ 106 ], and bacoside B [ 107 ]. The treatment of a mixture of bacosides A and B is mediating the three types of learning function, procedural, declarative, and spontaneous, and improves the episodic memory observed in animal models [ 108 ]. Beside enhancing cognition and memory functions, Bacopa monnieri are also known for their anxiolytic effects and in managing the convulsive sicknesses [ 109 ].

Bacopa monnieri . The plant has purple flowers with oblong leaves found throughout the Indian subcontinent. This plant is classified under the family of Scrophulariaceae. On the right is the chemical structure for bacosides [ 107 ].

Singh and colleagues [ 110 ] had suggested the membrane dephosphorylation triggered by bacosides concurrently leads to elevation in protein and RNA turnover observed in certain brain regions. The nootropics effect of Bacopa monnieri is mediated by enhancement of protein kinase activity and production of protein in the hippocampus [ 39 ]. Study done by Anand and colleagues [ 111 ] demonstrated the characteristics of natural antioxidant and DNA damage preventing agent of the Bacopa monnieri . Other effects of Bacopa monnieri are including hepatoprotective agent against morphine toxicity [ 112 ], calcium antagonist [ 113 ], anticancer agent [ 114 ], and antiaddictive agent [ 115 ]. Despite that, the combination of bacosides A and B also was studied to express antistress property [ 116 ], protecting the brain from smoking induced membrane damage [ 117 ], and protective function against d -galactosamine induced liver injury [ 118 ].

3.3. Nicotine

Nicotine is a potent parasympathomimetic alkaloid derived from the family of plants of Solanaceae ( Figure 2 ). The psychoactive nicotine is found in the leaves of Nicotiana rustica , the tobacco plant Nicotiana tabacum , Duboisia hopwoodii , and Asclepias syriaca [ 119 ]. Despite its addiction liability and undesired adverse effects [ 120 ], nicotine is found to improve learning and memory properties and enhance the memory impairment due to lesion of the septohippocampal pathways or aging. Downregulated expression of nicotinic receptor is observed in Alzheimer's disease patients [ 121 ].

Nicotiana mutabilis . The plant is classified under the family of Solanaceae and contains nicotine as psychoactive compound (a). Compound A, syn-5-isobutoxy-2-phenyl-3-(3-pyridyl)-isoxazolidine (b), and compound B, syn-2,5-diphenyl-3-(3-pyridyl)-isoxazolidine (c), are example of synthesised nootropics derived from nicotine for learning and memory purposes [ 122 ].

Due to the prohibition of the use of nicotine, novel nicotine analogue is synthesised and evaluated, namely, syn-5-isobutoxy-2-phenyl-3-(3-pyridyl)-isoxazolidine (compound A) and syn-2,5-diphenyl-3-(3-pyridyl)-isoxazolidine (compound B) [ 122 ]. Nicotine and its synthesised analogs are established to react on different pathways, expressing improvement in memory [ 123 ]. Compounds A and B are postulated to stimulate the release of acetylcholine through the activation of presynaptic nicotine acetylcholine receptors. These receptors are responsible for modulating the release of neurotransmitter [ 124 ].

3.4. Ginkgo biloba

Ginkgo biloba or maidenhair tree is the only species derived from family of Ginkgophyta and the order of Ginkgoales. It is called a “living fossil” since the morphology and features of the plant are changed for over 100 million years [ 125 ]. The plant is well-known for its medical used as well as being a source of food [ 126 ]. Despite the lack of reports, Ginkgo biloba is claimed to have neuroprotective effects observed in human and animal models [ 127 ]. A recent report has suggested the effect of Ginkgo biloba in treating Alzheimer's disease patient or other cognitive disoders. Ginkgo biloba also has been listed under group of antidementia drugs [ 128 ]. It acts as antioxidant and antiapoptotic properties and also induces inhibition effects against caspase-3 activation and amyloid- β -aggregation toward Alzheimer's disease.

The extract of the leaves diminishes the amyloid- β fibrillogenesis, reduces the apoptosis induced by mitochondria, and downregulates the caspase-3 activity [ 51 ]. This plant also is proposed to have antiamyloidogenic property whereby the plant extract prevents the production of amyloid fibrils [ 51 ]. The compound found in Ginkgo biloba , terpenoid, namely, bilobalide and ginkgolide, is observed to be involved in the caspase-3 activation [ 51 ]. Nakanishi [ 125 ] has proposed the memory enhancing effect of ginkgolides. The ginkgolides are compounds in the plant that terminate the effects of amyloid peptide on LTP ( Figure 3 ).

Ginkgo biloba . The plant is classified under the family of Ginkgoaceae, the only species in the division of Ginkgophyta. With 40 m in height, this tree is characterised by the fan-shaped leaves composed of more than two distinct lobes (a). Ginkgolide A, R 1 =H; R 2 =H; R 3 =OH, Ginkgolide B, R 1 =OH; R 2 =H; R 3 =OH, Ginkgolide C, R 1 =OH; R 2 =OH; R 3 =OH, Ginkgolide J, R 1 =H; R 2 =OH; R 3 =OH, Ginkgolide M, R 1 =OH; R 2 =OH; R 3 =H (b) [ 129 ].

3.5. Panax ginseng

Panax ginseng (Asian ginseng) is described as the “king herb" and has an important position in the traditional Chinese medicine [ 130 ]. A lot of reports are discussing the role of P. ginseng especially in improving the cognition function of Alzheimer's disease patients. Antioxidant property in P. ginseng is claimed to suppress Alzheimer's disease-like pathology [ 131 ]. The intake of P. ginseng in healthy individuals is observed to increase the memory performances [ 132 ].

The active constituents of the Panax spp. are ginsenoside saponins, which are divided into Panaxadiol, Panaxatriol, and oleanolic acid groups. The Panaxadiol and Panaxatriol groups are studied to increase the release of neurotransmitters in the brain [ 133 ]. Other ginsenosides affect the secretion of corticosterone and uptake of NE, dopamine, serotonin, and GABA [ 134 ]. It is suggested that the high ratio of Panaxatriol to Panaxadiol is responsible for the enhancement of memory and cognitive properties [ 135 ]. P. quinquefolius (American ginseng) has a lower ratio of Panaxatriol to Panaxadiol as compared to P. ginseng (Asian ginseng) ( Figure 4 ) [ 136 ].

Panax ginseng . Ginseng belongs to the genus Panax of the family Araliaceae, found in the cooler climates. The name of the plant is derived from the Chinese term meaning “person” and “plant root” due to the feature of the root that resembles the legs of a person (a). Ginsenosides, the principal bioactive compounds of P. ginseng . A, Panaxadiol; B, Panaxatriol; C, oleanolic acid (b) [ 137 ].

3.6. Rhodiola rosea

Rhodiola rosea ( R. rosea ), known as golden root and Arctic root, is reported to improve cognitive function [ 138 ], enhance memory and learning [ 139 ], and protect the brain [ 140 ]. Belonging to the family of Crassulaceae, this plant is observed to increase the level of 5-HT and NE in the cerebral, prefrontal, and frontal cortex [ 139 ]. At the same time, the intake of R. rosea causes the upregulation of DA and ACh in the limbic system pathways, responsible for emotional calming [ 141 ], as R. rosea is acting as antioxidant agent. The study showed that the introduction of R. rosea may protect the nervous system against oxidative damage, thus lowering the risk of Alzheimer's disease onset. The treatment of the plant also enhances the learning and memory impairment in Alzheimer's disease [ 142 ]. Sharing the same property with Bacopa monnieri and Panax ginseng , R. rosea is considered to be an “adaptogen” that enhances endurance, resistance, and protest against stressful situation [ 143 ]. Salidroside, an active component of R. rosea , is claimed to have neuroprotective and antioxidative effects ( Figure 5 ) [ 140 ].

Rhodiola rosea . It belongs to the family of Crassulaceae. R. rosea is growing on the sea cliffs and on the mountains. The plant is dioecious, with yellow to greenish yellow flowers (a). Salidroside is claimed as an active constituent responsible for neuroprotective and antioxidant properties (b) [ 140 ].

4. Conclusion

The understanding of the mechanisms influenced by the administration of natural nootropics has been expanded tremendously in this past decade. Establishing natural nootropic is challenging as optimum dose has to pass blood brain barrier so that it can stimulate responding mechanism. In the same time, the nootropic is helping the body systems such as blood circulation as well as energy booster. There are a number of mechanisms influenced by the administration of nootropics, such as glutaminergic signalling and amyloid precursor protein, also responsible for neuro-related diseases such as dementia and Alzheimer's disease. Thus, the understanding of the mechanism stimulated by nootropic is expected to increase the cognitive performances of the cognitive impairment patients.

Competing Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Nootropics, or ‘Smart Drugs,’ Are Gaining Popularity. But Should You Take Them?

T he idea that a pill can supersize human intelligence is decidedly science fiction. But plenty of real-world researchers and drug-makers are working to develop nootropics: pills, supplements and other substances designed to improve various aspects of cognition.

A rough translation for the word “nootropic” comes from the Greek for “to bend or shape the mind.” And already, there are dozens of over-the-counter (OTC) products—many of which are sold widely online or in stores—that claim to boost creativity, memory, decision-making or other high-level brain functions. Some of the most popular supplements are a mixture of food-derived vitamins, lipids, phytochemicals and antioxidants that studies have linked to healthy brain function. One popular pick on Amazon, for example, is an encapsulated cocktail of omega-3s, B vitamins and plant-derived compounds that its maker claims can improve memory, concentration and focus.

But do “smart pills” really work?

Many of these supplements include exotic-sounding ingredients. Ginseng root and an herb called bacopa are two that have shown some promising memory and attention benefits, says Dr. Guillaume Fond, a psychiatrist with France’s Aix-Marseille University Medical School who has studied smart drugs and cognitive enhancement. “However, data are still lacking to definitely confirm their efficacy,” he adds.

Many of the food-derived ingredients that are often included in nootropics— omega-3s in particular , but also flavonoids —do seem to improve brain health and function. But while eating fatty fish, berries and other healthy foods that are high in these nutrients appears to be good for your brain, the evidence backing the cognitive benefits of OTC supplements that contain these and other nutrients is weak.

A 2015 review of various nutrients and dietary supplements found no convincing evidence of improvements in cognitive performance. While there are “plausible mechanisms” linking these and other food-sourced nutrients to better brain function, “supplements cannot replicate the complexity of natural food and provide all its potential benefits,” says Dr. David Hogan, author of that review and a professor of medicine at the University of Calgary in Canada.

Even if you eat foods that contain these nutrients, Hogan says their beneficial effects are in many ways cumulative—meaning the brain perks don’t emerge unless you’ve been eating them for long periods of time. Swallowing more of these brain-enhancing compounds at or after middle-age “may be beyond the critical period” when they’re able to confer cognitive enhancements, he says.

None of this rules out the potential for some OTC nootropics to improve memory, focus or other aspects of cognition. There just isn’t much compelling evidence to support these claims.

Certain pharmaceuticals could also qualify as nootropics. For at least the past 20 years, a lot of people—students, especially—have turned to attention deficit hyperactivity disorder (ADHD) drugs like Ritalin and Adderall for their supposed concentration-strengthening effects. While there’s some evidence that these stimulants can improve focus in people without ADHD, they have also been linked, in both people with and without an ADHD diagnosis, to insomnia, hallucinations, seizures, heart trouble and sudden death, according to a 2012 review of the research in the journal Brain and Behavior . They’re also addictive.

More recently, the drug modafinil (brand name: Provigil) has become the brain-booster of choice for a growing number of Americans. According to the FDA , modafinil is intended to bolster “wakefulness” in people with narcolepsy, obstructive sleep apnea or shift work disorder. But when people without those conditions take it, it has been linked with improvements in alertness, energy, focus and decision-making. A 2017 study found evidence that modafinil may enhance some aspects of brain connectivity, which could explain these benefits.

Modafinil has some vocal fans, including the “biohacker” and Bulletproof founder Dave Asprey. And at least some of the existing research on modafinil hasn’t turned up serious long-term health risks.

But there are some potential side effects, including headaches, anxiety and insomnia. Part of the way modafinil works is by shifting the brain’s levels of norepinephrine, dopamine, serotonin and other neurotransmitters; it’s not clear what effects these shifts may have on a person’s health in the long run, and some research on young people who use modafinil has found changes in brain plasticity that are associated with poorer cognitive function.

There are some other promising prescription drugs that may have performance-related effects on the brain. But at this point, all of them seem to involve a roll of the dice. You may experience a short-term brain boost, but you could also end up harming your brain (or some other aspect of your health) in the long run. “To date, there is no safe drug that may increase cognition in healthy adults,” Fond says of ADHD drugs, modafinil and other prescription nootropics.

That’s not to say all smart drugs are risky or ineffective.

“One of my favorites is 1, 3, 7-trimethylxanthine,” says Dr. Mark Moyad, director of preventive and alternative medicine at the University of Michigan. He says this chemical boosts many aspects of cognition by improving alertness. It’s also associated with some memory benefits. “Of course,” Moyad says, “1, 3, 7-trimethylxanthine goes by another name—caffeine.”

While caffeine was once considered risky, most experts today agree that caffeine (at least in coffee and green tea) is more beneficial than harmful when it’s consumed in moderation.

But if you’re really looking to boost your brain function in a way that is absolutely, 100% proven to be safe and effective, Moyad says the answer is clear: get some exercise. “I think exercise has the ability to beat any pill for people trying to improve their cognition or memory who are otherwise healthy,” he says.

There’s strong evidence that regular exercise improves memory and fends off age-related cognitive decline. Working out also improves your heart health and lowers your risk for death and disease, Moyad says.

Exercise isn’t as effortless as taking a pill. But it’s likely the safest way to strengthen your brain—at least for now.

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Smart drugs. – Mgr. Hrozek Hrozek

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Mgr. Hrozek Hrozek

Master's thesis, smart drugs., thesis defence.

• Supervisor: doc. PharmDr. Jan Gajdziok, Ph.D.
• Reader: doc. PharmDr. Ruta Masteiková, CSc.

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Master programme / field: Pharmacy / Pharmacy

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• Hyaluronan based drug carrier systems Kristina Nešporová
• Bacterial components as nanocarriers for drug delivery and their usage in animal and human health care Martin Řiháček
• Vybrané deriváty pyridinu imobilizované na koloidních nanosystémech určených pro asymetrickou katalýzu a pro transport léčiv Dattatry Shivajirao Bhosale
• Synthesis of peptide and their application for cell penetration and drug delivery Vedran Milosavljević
• Vliv struktury polymerních nosičů léčiv na jejich Daniela Kubátová
• Použití polymerních materiálů pro lékové formy na bázi osmotické pumpy Tereza Sklenářová