INTRODUCTION:

Memory is the capacity of an individual to encode, store and retrieve information and events for either short term or long term. There are three stages of memory –Sensory memory, short term memory and long-term memory. Sensory memory allows individuals to retain impressions of sensory information after the original stimulus has ceased. Short term memory is also known as working memory. It lasts about for 20 seconds. Long term memories are all the memories we hold for longer period of time. Further, long term memory is divided into two types – Implicit and Explicit memory. Implicit memory (Procedural) is related to skills and habits whereas Explicit (Declarative) memory is related to information. Declarative memory is of two types – Semantic memory (memory related to general knowledge and facts about the world) and Episodic memory (memory related to biographical details of our individual lives)¹.

Cognitive function is how a person’s mind processes information and how they think about their own mental functioning. Perception, attention, memory, motor abilities, language, visual and spatial processing, and executive functions are all parts of the brain that are involved in cognition. The loss of these skills is known as cognitive dysfunction. This may have an impact on a person’s ability to think, remember².

Cognitive impairments are among the most prevalent and debilitating neurological conditions globally. According to the World Health Organization (WHO), more than 55 million people worldwide live with dementia, with Alzheimer’s disease (AD) accounting for 60-70% of cases. Mild Cognitive Impairment (MCI), often a precursor to dementia, affects about 15-20% of individuals over age 65. Additionally, cognitive issues are common in psychiatric disorders like schizophrenia and depression³.

Several factors, including natural (ageing, physical and mental stress), environmental (excess levels of carbon monoxide, carbon dioxide, methyl mercury in the atmosphere, and aluminium in foods), and iatrogenic (electroconvulsive shock therapy and use of certain central nervous system depressants), have contributed to rise in memory complaints and disorders in recent years⁴.

In the era marked by increasing cognitive demands and an aging global population, the pursuit of agents that can enhance or preserve cognitive function has garnered significant scientific and public interest. Nootropics also known as cognitive enhancers or smart drugs are supplements or medications that boost cognitive function, including memory, executive function, judgement, reasoning, problem-solving, and decision-making. By increasing the oxygen supply or stimulating neurone growth, nootropics likely change the amounts of neurotransmitters, hormones, and enzymes in the brain⁵. Giurgea first used the term “nootropic” in 1972, combining the Greek words “noo” (mind) and “tropos” (turn)⁶.

The neurotransmitter acetylcholine is crucial for recognition process like memory, and the cholinergic system is involved in learning and memory. The enzyme choline acetylcholinesterase converts choline and acetyl-CoA into acetylcholine in certain neurones. Acetylcholine is broken down into choline and acetate by the enzyme acetylcholinesterase (AchE). Alzheimer’s disease – related findings include decreased choline acetyltransferase activity and cholinergic neurone loss in the hippocampus and cerebral cortex⁷.

Nootropics exert their effects via various pharmacological and neurobiological pathways, including: Cholinergic transmission enhancement (e.g. acetylcholine upregulation), neurotrophic factor modulation (e.g., BDNF, NGF), antioxidant and anti-inflammatory action, modulation of glutamatergic, dopaminergic, and serotonergic systems, Mitochondrial function and energy metabolism support, Synaptic plasticity, and long-term potentiation facilitation. These mechanisms are not mutually exclusive and often coverage to support neuronal integrity, synaptic communication, and overall brain function.

While several synthetic compounds such as piracetam, modafinil have been studied and used for cognitive enhancement, increasing attention has turned to natural nootropics derived from medicinal plants, dietary sources, and traditional medicine systems (e.g., Ayurveda). Phytoconstituents such as flavonoids, alkaloids, terpenoids, and phenolic acids have demonstrated promising nootropic potential through antioxidant, neuroprotective, and neurotransmitter modulating effects⁸.

Recent advancements in experimental and computational neuroscience have facilitated the development of in vivo, in vitro, and in silico models for evaluating nootropic activity. Animal behaviour tests (e.g., Morri’s water maze, Y- maze), primary neuronal cultures, organotypic slices, and computer aided drug discovery platforms (e.g., molecular docking, machine learning) enable a comprehensive assessment of candidate compounds and mechanisms⁹.

Despite considerable progress, the field faces challenges including: Limited clinical translation and human data, Regulatory ambiguities regarding safety and efficacy, Lack of standardization in models and evaluation metrics. This review aims to provide a comprehensive overview of the pharmacological classification and sources of nootropics (synthetic vs natural), Experimental models used for their evaluation (in vitro, in vivo, in silico), challenges and future prospects in herbal drug discovery. By consolidating current knowledge and identifying research gaps, this article seeks to contribute to the rational development, evaluation and application of nootropic agents in the context of both cognitive enhancement and neuroprotection.

Pathophysiology of Cognitive Dysfunction:

Cognitive dysfunction can result from various pathophysiological mechanisms, most of which disrupt communication between neurons or damage neuronal structures. Key mechanisms include:

1. Modulation of Neurotransmitter Systems:

Altering neurotransmitter levels, receptor activity, reuptake, or breakdown. This affects learning, attention, mood, etc.

· Cholinergic system: Enhancing acetylcholine (Ach) via precursors (e.g., choline), ChAT (choline acetyltransferase) activity or inhibiting acetyltransferase.

· Glutamergic system: Modulating NMDA, AMPA receptors to improve synaptic plasticity.

· GABAergic, serotonergic, dopaminergic, adrenergic systems: Boosting dopamine or reducing inhibitory overtones via GABA for alertness, motivation.

2. Enhancement of Cerebral Blood Flow and Oxygen/ Nutrient Supply:

· Neurons require a lot of energy. Better blood flow – more oxygen+ glucose – improved metabolic support for neuronal activity. Also helps clear metabolic waste.

· Agents that dilate cerebral vessels, improve microcirculation, reduce blood viscosity, improve erythrocyte plasticity.

3. Improved Energy Metabolism/ Mitochondrial Function:

· Neurons need ATP for membrane potentials, neurotransmission, plasticity. Dysfunction in mitochondria leads to reduced cognitive capacity.

· Upregulation of mitochondrial biogenesis, increased ATP synthesis, enhancement of enzymes like adenylate cyclase/ cyclic- AMP (cAMP) pathways. Some nootropics also improve glucose utilisation.

4. Neuroprotection/ Antioxidant Action:

· Protection against oxidative stress, inflammation, excitotoxicity, and cell injury prevents or delays cognitive decline.

· Free radical scavengers, reducing lipid peroxidation, anti- inflammatory agents, reducing reactive oxygen species (ROS). Also chelating harmful metals¹⁰.

5. Membrane/ Structural Effects:

· Neuron membranes and synapses must have integrity, fluidity, phospholipid content, cytoskeleton, synaptic structure, dendritic spines need remodelling for learning.

· Effects on phospholipid synthesis, membrane stability, regulation of ion channels (Na+, Ca+2), modulating receptor trafficking, structural plasticity (dendritic spines).

6. Neurogenesis and Synaptic Plasticity:

· Formation of new neurons (neurogenesis, particularly in hippocampus), and strengthening or pruning synaptic connections (plasticity), underlie learning and memory.

· Involvement of neurotrophic factors like BDNF (brain- derived neurotrophic factor), NGF (nerve growth factor), modulation of gene expression/ protein synthesis, long- term potentiation (LTP) mechanisms.

7. Regulation of Stress, Hormonal and Gene Expression Effects:

· Chronic stress, high cortisol, inflammatory cytokines degrade cognitive function. Some nootropics modulate these pathways. Also, changes in gene transcription required for long- term changes in synaptic strength.

· Corticosteroid sensitivity, activation or suppression of gene transcription s, influence on RNA/ DNA, protein synthesis for memory consolidation.

Nootropics work by mitigating these mechanisms, either by enhancing neuroprotection, neurotransmission, or neuroplasticity¹¹.

Fig 1: Mechanism of action of nootropics¹²

Synthetic and Natural Nootropics:

Synthetic nootropics are pharmacologically active compounds developed to improve cognitive functions or treat cognitive deficits. Despite their benefits, synthetic nootropics may have side effects such as insomnia, headaches, and dependency, necessitating cautions use¹³.

Table 2: Medicinal plants and their therapeutic potential

Plant	Active Constituents	Mechanism
Bacopa monnieri	Bacosides	Enhances synaptic transmission and neurogenesis
Gingko biloba	Flavonoids, Terpenoids	Improved cerebral blood flow, antioxidant
Panax ginseng	Ginsenosides	Anti- fatigue, adaptogenic, improves cognition
Withania somnifera	Withanolides	Anti- stress, neuroprotective
Curcuma longa	Curcumin	Anti- inflammatory, antioxidant
Centella asiatica	Asiaticoside	Enhances learning and memory

Table 3: Pharmacological Models

Model	Agent	Mechanism of action	Behavioural tests/ end points	Advantages	Limitations	References
Scopolamine induced amnesia	Scopolamine (muscarinic antagonist)	Blocks central muscarinic Ach receptors, leading to cholinergic dysfunction, also induces oxidative stress, mitochondrial dysfunction, synaptic changes	Y- maze (working memory), passive avoidance, recognition tasks	Reversible model, rapid onset, mechanistic relevance to cholinergic dysfunction in AD	Non- specific behavioural effects (anxiety, attention)	[15]
Okadaic acid induced cognitive impairment	Okadaic acid	Inhibits protein phosphatises 1 and 2A, causing tau hyper phosphorylation, oxidative stress, neuroinflammation, cholinergic dysfunction	Zebrafish/mouse: T- maze, novel tank test	Effective in modelling tauopathy and neuroinflammation, relatively specific mechanism of tau hyper phosphorylation	Does not model amyloid pathology, limited to tau related mechanisms	[16]
Diazepam induced amnesia	Diazepam (GABA- A agonist)	Enhances GABAergic inhibition- reduces neuronal excitability and memory processing	Learning/memory assays, anterograde amnesia tests	Relevant for studying drug induced anterograde amnesia and synaptic pathology without AD like lesion	Not specific to neurodegeneration, mostly an acute amnesia model	[17]

In Vivo Models for Nootropic Activity:

Animal models are widely used for behavioural and pharmacological evaluation of cognitive function.

Table 4: In Vivo models

Test	Model	Mechanism of action	End – points (measured)	Advantages	Limitations	References
Morris water maze (MWM)	Rodents (rat/mice) navigating to a hidden platform	Uses distal visual cues to learn spatial location of hidden platform; relies on hippocampal dependent spatial learning and synaptic plasticity	Escape latency; time/ distance in target quadrant, platform crossings, path length	Reliable, distinguishes spatial vs non- spatial	Stress related due to forced swimming; olfactory cues not assessed	[18]
Y- maze	Rodents exploring a Y- shaped maze wit blocked and then opened novel arm	Relies on rodents’ innate curiosity to explore novel environments; measures working spatial memory via alternation behaviour	No. of entries into arm, percent alternation	Simple, minimal training, low stress, reproducible	Choice bias (50% success by chance); non- spatial strategies possible	[19]
Step- Through Passive Avoidance	Rodents in illuminated compartment learning to avoid dark chamber associated with shock	Uses natural dark preference behaviour, pairing dark entry with mild foot shock; learning I indicated by increased latency	Step- through latency during acquisition and retention (usually 24h later)	Single trail training, well defined acquisition and consolidation times, minimal apparatus	Uses aversive stimulus (stressful), high variability, sensitive to environment	[20]
Novel object Recognition (NOR)	Rodents exploring arena with familiar and novel objects	Relies on innate preference for novelty and object recognition memory, no reinforcement	Time spent exploring novel vs familiar object discrimination index	Non- aversion, adaptable for different memory phases	Susceptible to exploration differences, requires careful object standardization	[21]

In Vitro Models for Nootropic Activity:

In Vitro assays provide an initial screening platform to study mechanisms of action at the cellular and molecular level. Common in vitro techniques include:

Table 5: In Vitro models

Assay	Model	Mechanism of action	End points(measured)	Advantages	Limitations	References
In vitro AChE inhibition in brain slices	Rat or human neocortex slices exposed to cholinesterase inhibitors (e.g. donepezil, physostigmine)	Inhibition of AChE increases synaptic Ach, triggers muscarinic auto receptors that Modulate neurotransmitter release	IC50 values for AChE inhibition, change in extracellular GABA levels	Quantification of drug Potency and indirect effects	Limited duration, requires accurate electrical stimulation	[22]
[3H] Ach release in perfumed brain slices	Slices perfumed with radiolabelled [3H] choline, stimulated to release [3H] ACh	Measures evoked release and Ach re-take mechanisms; AChE hydrolysis makes most of release radiolabelled Ach	Evoked vs spontaneous [3H] Ach release assays, ratio of Ach vs choline release	High specificity, quantitative, discriminates evoked vs spontaneous release	Requires radiolabel use, technical complexity, uptake inhibitors needed	[23]
AChE release from cultured neurons	Neuronal cultures (e.g. shedding vs exocytosis pathway of AChE release)	AChE released by proteolytic shedding (e.g., ADAM proteases) or calcium dependent exocytosis	Measurement of extracellular AChE, pathway specific release detectable with protease or calcium modulators	Mechanistic insight into AChE secretion, delineates release pathways	Cell culture variability, complex molecular mechanism, may poorly recapitulate in vivo neuronal network context	[24]

Advancement In Plant Based Drug Discovery:

In recent years, plant- based nootropic research has been revitalized by combining traditional phytotherapy with modern technologies. Systematic review has consolidated evidence that herbs and other botanicals produce measurable effects in domains such as learning, attention, motor/perceptual speed, and stress/ anxiety modulation.

One major advance is the use of omics technologies (genomics, transcriptomics, proteomics, metabolomics) to understand not just that plant extracts work, but how – which genes, signalling pathways, neurotrophic factors, antioxidant systems are modulated. For example, whole plant extracts are now studied for their synergistic effects on multiple pathways rather than isolating a single “active” molecule.

Computational methods are increasingly applied: virtual screening of plant compound databases, molecular modelling of interactions with cognitive relevant targets (e.g., acetylcholinesterase, NMDA receptors, BDNF pathways), and use of machine learning/ generative models for lead optimization of plant derived molecules. These allow faster identification of promising scaffolds and analogues.

Also, extraction, isolation and standardization methods have improved. Better chemical characterization (using advanced chromatography, mass spectrometry, NMR) ensures consistent quality and reproducibility. Fractionation helps in bioactivity guided isolation of compounds. Advances in formulations (e.g. enhancement of bioavailability, use of nanoparticle carriers) help address the common issue of poor absorption or rapid metabolism²⁷.

Challenges and Future Prospects in Herbal Drug Discovery:

Recent efforts in plant- based nootropics face several key limitations: firstly, chemical variability and standardization issues- plant extracts often differ significantly based on species, location, harvest time, and processing methods, making reproducible efficacy, and dosing difficult. Secondly, bioavailability and neuro- availability remain major hurdles, many promising phytochemicals (e.g., polyphenols like resveratrol) show low absorption or rapid clearance, requiring advanced delivery systems such as nano- encapsulation to enhance brain targeting. Thirdly, the multicomponent nature of herbal preparations demands sophisticated network pharmacology and rigorous preclinical/ clinical validation- isolated compounds rarely recapitulate the synergistic effects of full spectrum extracts. Moreover, lack of high- quality clinical trials including well designed randomized, double- blind studies with diverse participant groups and objective neuroimaging endpoints- is a persistent gap. Finally, regulatory hurdles and intellectual property constraints, particularly regarding complex botanical, consent for bioprospecting, and scalability under current manufacturing standards, continue to slow progress.

Despite these obstacles, the future of herbal nootropic discovery is promising. Integration of reverse pharmacology, where traditional ethnomedical knowledge informs bioactive screening, helps streamline lead identification. Emerging network and polypharmacology, supported by metabolic and cheminformatics tools, enables targeting of multi- factorial cognitive process. Advances in nano- delivery systems offer improved CNS penetration and stable dosing profiles. Finally, the creation of large phytochemical databases (e.g., covering nearly 3000 CNS active metabolites) empowers AI- based prioritization of novel candidates. These technological and methodological tools- when paired with better regulation, ethical sourcing, and thorough clinical evidence- set the stage for next generation, plant derived cognitive enhancers²⁸.

CONCLUSION:

The increasing prevalence of cognitive disorders and the rising demand for cognitive enhancement have brought nootropics into the spotlight of modern neuropharmacological research. Synthetic nootropics offer rapid and targeted benefits but are often accompanied by safety concerns and limited long term data. In contrast, natural herbal nootropics provide a safer, multi targeted approach rooted in traditional medicine and increasingly supported by scientific evidence. Understanding the diverse mechanisms underlying the diverse mechanisms underlying cognitive dysfunction- such as cholinergic deficits, oxidative stress, and neuroinflammation- has enabled the development of robust in vivo, in vitro, and in silico models to screen and optimize nootropic agents. Despite progress, challenges remain in clinical translation, regulatory clarity, and methodological standardization. Future research must focus on bridging these gaps through interdisciplinary approaches, including system biology, artificial intelligence, and translational neuroscience, to fully harness the cognitive and neuroprotective potential of nootropic compounds, particularly from natural sources.

ACKNOWLEDGEMENT:

We extend our heartfelt gratitude to RBVRR Women’s College of Pharmacy, Barkatpura, Hyderabad, Telangana, India, for their constant encouragement, infrastructure facilities, and access to academic resources that greatly supported the completion of this review. We acknowledge that the figures included in this manuscript were created using BioRender (www.biorender.com).

REFERENCES:

1. More et al. Evaluation of Nootropic Effects of Aqueous Extract of Tridax procumbens Linn on Cognitive Functions in Mice. Research Journal of Life Sciences, Bioinformatics, Pharmaceutical and Chemical Sciences. 2018 Nov-Dec; 2454-6348. doi:10.26479/2018.0406.18

2. Bhosale SS, Kumar S S, Jamadagni S, Arulmozhi S. Therapeutic potential of Bhiramiyadhi bhavanai choornam in ameliorate scopolamine- induced impaired learning and memory in rats: neuroprotective effects and mechanistic insights. Research Journal of Pharmacy and Technology. 2024; 17(2): 553-2. doi:10.52711/0974-360X.2024.00086

3. Reddy N et al. Evaluation of nootropic activity of Curcuma longa leaves in diazepam and scopolamine induced amnesic mice and rats. International Journal of Basic and Clinical Pharmacology. 2015 Aug; 4(4): 714-719. doi: 10.18203/2319-2003.ijbcp20150378

4. K Singh et al. Pharmacological investigation of Achras sapota against scopolamine induce amnesia and cognitive impairment in laboratory animals. Toxicology Reports 13 2024 Nov;2214-7500.

5. Tiwari DK, Upmanyu N. Evaluation of nootropic activity of Semecarpus anacardium leaves in rodents. International Journal of Pharmaceutical Sciences and Research. 2021Feb; Vol 12(2): 1310-1319. doi:10.13040/IJPSR. 0975-8232.12(2).1310-19

6. Mali et al. Evaluation of nootropic activity of Limonia acidissima against scopolamine induced amnesia in rats. Turk J Pharm Sci. 2021; 18(1):3-9. doi: 10.4274/tips.galenos.2019.30316

7. Mahadik VJ et al. Cognition Enhancing potential of Sesbania grandiflora fruit extract in scopolamine induced amnesia in mice. Research J. Pharm. And Tech. 2020; 13(11): 5057-5062. doi:10.5958/0974-360X.2020.00886.0

8. 8.Balasubramanian C, Ramaswamy R S. Evaluation of nootropic and neuroprotective properties of Siddha drug Poorna Chandrothaya Chenthuram (PCC) in scopolamine induced amnesia in mice. Phytomedicine Plus 4. 2024 June. doi: 10.1016/j. phyplup2024.100585

9. Zhang L, Jin C, Lu X, Yang J, Wu S, Liu Q, Chen R, Bai C, Zhang D, Zheng L, Du Y Cai Y. Aluminium chloride impairs long- term memory and downregulates cAMP-PKA-CREB signalling in rats. Toxicology. 2014 Sep.

10. Rahman A, Banu Z, Rani R, Mehdiya R. Unravelling Alzheimer’s disease: insights into pathophysiology, etiology, diagnostic approaches, and the promise of aducanumab, lecanemab, and donanemab. J Phytonanotechnology Pharm sci. 2024; 4,1-10.

11. Chaturvedi S, Ganeshpurkar A, Shrivastava A, Dubey N. Protective effect of co- administration of caffeine and piracetam on scopolamine induced amnesia in Wristar rats. Current Research in Pharmacology and Drug Discovery. 2021 Aug.

12. Team, B. (2025). Anti-cholinesterases Mechanism of Action in Alzheimer's Disease (AD). https://app.biorender.com/biorender-templates/details/t-65141eecba95ae765b23241a-anti-cholinesterases-mechanism-of-action-in-alzheimers-disea

13. Alshabi AM, ShaikhIA, Savant C. Nootropic and Neuroprotective effects of ethanol extract of Vateria indica L bark on scopolamine induced cognitive deficit in mice. Tropical Journal of Pharmaceutical Research. 2020 Mar; 19 (3): 587-594.

14. Kumar P, Singh A P, Kaur G, Sharma S, Sharma A K, Kaur K. Exploring the nootropic effect of Junipers recurva extract: Possible involvement of acetylcholinesterase inhibiton. Department of Pharmaceutical Sciences. 2019 Jul- Sep; 13 (3).

15. Saini S, Choudhary M, Garg A. Investigation of nootropic potential of ethanol extract of Elettaria cardamomum Maton fruit (Cardamom): a spice of India. Clinical Phytoscience. 2021; 7:68.

16. Kumar S, Maheshwari KK, Singh V. Protective effects of Punica granatum seeds extract against aging and scopolamine induced cognitive impairments in mice. Afr. J. Traditional, Complementary and Alternative Medicines. 2009; 6 (1): 49-56.

17. Lakshmi. K et al. Terminalia chebula Retz improve memory and learning in Alzheimer’s Model: (Experimental Study in Rat). Research J. Pharm. And Tech 2018; 11(11):4888-4891. Doi:10.5958/0974-360X.2018.00890.9

18. Sulabh G et al. Study comparing the effect of topiramate and pregabalin on learning and memory with phenytoin in albino rats using Morri’s water maze and elevated plus maze. Research Journal of Pharmacy and Technology 2023; 16(7):3451-5. Doi:10.52711/0974-360X.2023.00570.

19. Kumar M N, Virender K. Evaluation of Nootropic Activity of Carica papaya in mice. Biolife An International Quarterly Journal of Biologyand Life Sciences. 2014; 2(3): 721-730.

20. Flood JF, Morley JE (1998) Learning and memory in the SAMP8 mouse. Neurosci Biobehav Rev 22:1-20.

21. Gawande DY, Goel RK. Pharmacological validation of in silico guided novel nootropic potential of Achyranthes aspera L. Journal of Ethnopharmacology. 2015 Dec: 324-334.

22. Athitya L.V.S et al. Screening of Gracilaria Corsicana Extracts for Acetylcholinesterase Inhibitory Activity. Research J. Pharm. And Tech 2018; 11(9): 3848-3850. Doi:10.5958/0974-360X.2018.00704.7

23. Kumar, A., Singh, A., 2015. A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol. Rep. 67 (2), 195–203.

24. Mathiasen, J.R., DiCamillo, A., 2010. Novel object recognition in the rat: a facile assay for cognitive function. Curr. Protoc. Pharmacol. 49 (1), 5–59.

25. Rahman A, Banu Z. Impact of Aluminium Chloride (AlCl3) on brain function: A Review of Neurotoxic Mechanisms and Implications for Alzheimer’s Disease. Trends in Pharmaceutical Sciences and technologies. 2024, 10 (4), 355-366.

26. Banu Z, Poduri RR, Kumar S, Bhattamisra. Phytochemical profiling, in silico molecular docking and ADMET prediction of alkaloid rich fraction of Elaeocarpus angustifolius blume seeds against Alzheimer’s. Natural Product Research. 2025, 1-9.

27. Mesquita, S., Ferreira, A.C., Sousa, J.C., Correia-Neves, M., Sousa, N., Marques, F., 2016. Insights on the pathophysiology of Alzheimer's disease: the crosstalk between amyloid pathology, neuroinflammation and the peripheral immune system. Neurosci. Biobehav. Rev. 68, 547–562.

28. Saraceno, C., Musardo, S., Marcello, E., Pelucchi, S., Diluca, M., 2013. Modeling Alzheimer's disease: from past to future. Front. Pharmacol. 4, 77.

Received on 23.09.2025 Revised on 20.10.2025

Accepted on 11.11.2025 Published on 12.02.2026

Available online from February 14, 2026

Res.J. Pharmacology and Pharmacodynamics.2026;18(1):87-93.

DOI: 10.52711/2321-5836.2026.00011

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Drug class	Examples	Mechanism of action	Uses	Side effects
Cholinesterase inhibitors	Donepezil	Inhibits AchE, increase acetylcholine	Improved cognition, memory, behaviour	Insomnia, muscle cramps, fatigue, loss of appetite
Racetam	Piracetam	Modulate AMPA/ NMDA receptors, acetylcholine, boost neurotransmission and blood flow	May improve memory in cognitive decline	Usually well tolerated, efficacy, and safety not fully established
Natural supplements	Caffeine, L- Theanine	Varies by compound: neurotransmitter modulation, neuroprotection, adaptogenic effects	Enhance focus, relaxation, long term brain health	Mild GI upset, headache, interactions

Method	Principle	Application	Tools/software	Advantages	Limitations	References
Molecular docking	Predicts binding affinity between ligand and target protein	identifies interactions with receptor (e.g., NMDA, AMPA)	Auto dock, GOLD	Cost effective, predicts binding mode/ energy	Static model, does not account for protein flexibility	[25]
Pharmacophore Modeling	Identifies spatial arrangement or features essential for biological activity	Predicts activity of new compounds based on known data	QSAR toolbox, PaDEL - Descriptor	Predictive, suitable for lead optimization	Needs large data set, poor extrapolation	[26]