Nootropics are substances that enhance cognition through various mechanisms. Nootropics include various substances, ranging from derivatives of neurotransmitters to naturally occurring plants. They are used therapeutically for certain psychological disorders including Alzheimer’s dementia and mild cognitive impairment. More recently, healthy individuals have been shown to consume nootropics to enhance mental processes above baseline levels. Nootropic modes of action vary, but the most supported mechanisms include increased acetylcholine levels in synapses, increased levels of monoamine oxidases, long-term potentiation through neural modulation of glutamate receptors, and decreased adenosine levels. However, numerous side effects can occur when taking nootropics, including insomnia, dependence, nausea, and anxiety. Nootropics also need to be considered when physicians prescribe them, as some individuals who request these drugs are perfectly healthy. In addition, the effects of nootropics are often misportrayed in popular media, leading individuals to think that these substances will give them a drastic increase in their cognitive ability.
Corresponding Author: Jenilkumar Patel
Competing Interests: No competing interests were disclosed.
Grant Information: The author(s) declared that no grants were involved in supporting this work.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Open Access Copyright: © 2024 Patel J et al. This is an open access work distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
For centuries, people have ingested certain substances that they believed would enhance their cognitive skills. In many parts of India, it is still thought that eating four to five almonds every day, especially in the morning, helps to improve memory. Students in Ancient Greece would twist rosemary sprigs and insert them into their hair, convinced that it would enhance their memory and cognition. These substances were often used in other ways, as some religious practices used hallucinogenic substances in an effort to reach an altered state that they believed brought them closer to the gods. Even today, students routinely use stimulants, such as caffeine, to increase mental alertness during periods of prolonged sleep deprivation. More recently, advancements in the fields of pharmacology have led to the development of cognitive enhancing drugs, called “nootropics.” These drugs have been found to be useful for the treatment of neurocognitive disorders, such as attention deficit disorder, schizophrenia, and dementia. The popularity of these drugs has grown, as more recently, healthy individuals use them to improve their cognitive abilities.
Cognition can be defined as the set of collective processes used by an individual to assemble and categorize information. These collective processes include attention (awareness), perception (interpretation and processing of sensory information), comprehension (understanding), and memory (retaining information). These processes are combined to execute a behavior through motor coordination and rationality. Many interventions that aim to improve cognitive function target one or more of these processes. Cognitive enhancement can be defined as augmentation of the core abilities of the mind above the baseline level through the expansion of internal or external systems dealing with information processing.
Even today, cognitive enhancement remains one of the most debated topics in neuroscience. Many people believe that cognition is a human trait, and artificially enhancing it is a form of self-improvement that is not unethical. On the other hand, many still believe that artificially enhancing one’s cognition is unjust, as it gives those with the resources to purchase the drugs an advantage. Still, others are hesitant to take nootropics because many of its effects are unknown, and long-term use has been linked to numerous psychological issues.
A nootropic substance (herbs, drugs, supplements, etc.) enhances cognition and maximizes the brain’s potential. Nootropics are also called “smart drugs” and were developed around thirty years ago to be used for the treatment of cognitive deficits. There are many different kinds of nootropics, and they have different functions ranging from sedation to stimulation. Today, nootropics are one of the most heavily researched topics in the fields of pharmacology and neuropharmacology.
The term “nootropic” was first coined and explained by C. E. Giurgea in 1972. The word “nootropics” comes from the Greek word noos (mind) and tropein (towards), so in Greek, the word “nootropic” signifies “acting upon the mind”. It has been used to describe psychotropic drugs that affect integrative functioning of the cerebral cortex (telencephalic area) through direct and selective action. The key characteristic for defining nootropic drugs are: “Magnification (or enhancement) of learning acquisition, increased resistance of learned behaviors against agents that tend to damage them, facilitation of interhemispheric flow of information, partial enhancement of the general resistance of the brain and specially its resistance to physical and chemical injuries, increase in the efficacy of the tonic cortico-subcortical control mechanisms, the display of above mentioned activities by selective functional impact on higher integrative telencephalic mechanisms, i.e. partial lack of usual psychological and general pharmacological activities”. Using the above criteria, piracetam qualifies as a prototypical nootropic in terms of clinical pharmacology, animal pharmacology, and therapeutics, and it was the first nootropic to be discovered.
Several experimental studies have been conducted to explain the physiological activity of nootropics. The mechanism of action of nootropic substances at the molecular level has not yet been completely elucidated. The accessible findings on the mode of action can be classified into four categories according to Mondadori: “effects on energy metabolism, effects on cholinergic mechanisms, effects on excitatory amino-acid-receptor-mediated functions, and steroid sensitivity”.
One reason for focusing on the mechanism of energy metabolism is the lack of outcomes in classic “transmitter-sensitive” pharmacological experiments. For years, piracetam-induced elevation in adenylate kinase has been the only recognized biological cause. These findings were further supported by the increased uptake of 32 P by phosphatidyl inositol and phosphatidyl chloride in neuronal and glial cells. Additionally, increases in the use of glucose under conditions of decreased oxygen supply and escalated recovery in EEG have also been observed. However, no increase in glucose levels in response to piracetam was also observed. Instead, researchers observed a completely opposite phenomenon, as there was a reduction in glucose utilization levels induced by scopolamine. It is no surprise that there was an absence of noted pharmacological effects.
The search for a pharmacological mechanism then shifted towards cholinergic mechanisms to explain how nootropics work. This search was sparked by reports on cholinergic lesions in Alzheimer’s patients and research revealing the role of acetylcholine (ACh) in learning and memory. Another breakthrough occurred when an increase in choline uptake due to piracetam was noted, which led to extensive research on different nootropics. Likewise, Oxiracetam (a racetam similar to piracetam) was able to lessen several outcomes noted from electroshock treatment in animals, including decreased levels of acetylcholine in the cortex and hippocampus. Another study conducted in rats demonstrated that piracetam increased the density of cholinergic receptors in the frontal cortex, further strengthening the link between ACh and piracetam. Upon closer examination of accessible data, it was observed that not many studies showed similar outcomes on analogous tests due to piracetam-like nootropics. In addition, in some studies, higher or lower doses of piracetam were found to be ineffective for choline uptake in the synaptic terminals of neurons. Several other studies seemed to contradict one another, noting that piracetam and aniracetam enhance memory at “inactive doses.” In comparative studies, it was found that different compositions utilize different methods and produce different results. Therefore, all collected evidence that favors cholinergic mechanisms is unreliable.
Recently, a new line of research has focused on the physiology of long-term potentiation (LTP). This investigation has linked the role of nootropics and their consequences in glutamate transmission. In addition, it has been demonstrated that oxiracetam can partially antagonize the behavioral interference caused by AP5, which is a selective “N-methyl-D-aspartate (NMDA) receptor antagonist”. Additionally, elevated levels of glutamate release due to oxiracetam were found in hippocampal slices. One of the key interests in this regard is that LTP amplifies receptor-mediated activity or the regulation of Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA) receptors by aniracetam. One of the major controversies regarding this mechanism is whether the modifications caused by aniracetam and those produced by LTP are the same.
The likelihood of steroid involvement leading to nootropic effects is due to two features. The first is the feasible existence of internal memory-enhancing mechanisms that can stimulate “flashbulb memories.” Second, autoradiographs captured following the administration of radiolabeled oxiracetam revealed almost no activity in the brain. Interestingly, when the effects of piracetam, oxiracetam, pramiracetam, and aniracetam were studied in animals whose adrenal glands were surgically removed, steroids and the adrenocorticotropic (ACTH) hormone no longer showed any memory-boosting effects, even though the animal’s learning capacity was unaffected even after adrenalectomy. Similarly, aminoglutethimide, which chemically seals the adrenal cortex, resulted in four non-functional piracetam-type nootropics. This is the first indication that adrenocortical products play a role in reconciling the results of piracetam-like nootropics. Likewise, administration of epoxymexrenon, a mineralocorticoid antagonist, entirely blocked the effect of nootropics while leaving the learning capacity unaffected. This further strengthens the notion that steroids have nootropic effects.
Besides these plausible pharmacological effects involved in the mechanism of action of nootropics, some also believe that the “elevation of cAMP levels and ATP/ADP ratio, amplification of brain metabolism by triggering oxidative catabolism, enhancement of phospholipid metabolism and protein biosynthesis, and modulation of ion fluxes” can also play a role in discovering the mechanism of nootropics.
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). 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. 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.
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.
