Nootropic supplements for students – what to choose?

The exam period regularly increases interest in substances that are expected to provide better mental performance. It’s worth starting with something that almost all reports on this topic leave out: this population has been studied separately, there is a systematic review devoted to it, and its conclusions are more cautious than the promises circulating on the Internet.

This article discusses the substances most frequently mentioned in this context – huperzine A, kava, sulbutiamine, methylene blue and several compounds with investigational status only. For each one, we provide the mechanism, the state of evidence and the legal status, because in this category it differs greatly between the ingredients. The text does not contain doses or combination schemes.

Status information. Some of the substances discussed in this article are not authorized as food ingredients or registered as medicinal products in the European Union. The material is informative and intended for adults. It does not constitute medical advice. A map of the legal status of the entire category is included in our material on nootropic substances.

What do studies on this population show

The use of cognitive-enhancing drugs by students has been subjected to a systematic review covering both the prevalence of this phenomenon and its effects (Sharif et al., 2021, PMID 33802176). This is the most adequate source for this topic and a starting point that cannot be replaced by any list of mechanisms.

A broader context is provided by meta-analyses assessing the impact of a single administration of the substances most commonly used for this purpose – modafinil, methylphenidate and D-amphetamine – on cognitive functions in healthy adults (Roberts et al., 2020, PMID 32709551). The picture emerging from this literature is much more subdued than popular culture suggests: the effects are sometimes small, depending on the type of task and the initial level of performance. Improvement in a person with reduced cognitive function does not automatically translate into improvement in a healthy and well-rested person.

A foundation that no preparation can replace

This is not filler, but a conclusion resulting directly from the physiology of memory. Memory consolidation occurs during sleep, and sleep deficit reduces the performance of cognitive tasks to an extent that no substance can compensate. Dehydration and long-term energy deficiency have a similar effect.

Practical consequence: if sleep is shortened and the day is disorganized, the search for a chemical compound solves the problem from the wrong side. The substances discussed below – regardless of their mechanism – do not replace sleep.

Huperzine A

Mechanism

Huperzine A is an alkaloid obtained from Huperzia serrata. It acts as an acetylcholinesterase inhibitor – an enzyme that breaks down acetylcholine in the synaptic cleft. The mechanism is therefore the opposite of choline precursors: it does not provide a substrate, but slows down the breakdown of the already released neurotransmitter. This is the same class of mechanism used by medicines for Alzheimer’s dementia.

State of evidence

Huperzine A was evaluated in a Cochrane review in the context of Alzheimer’s disease (Li et al., 2008, PMID 18425924) and in a systematic review with meta-analysis of randomized trials (Yang et al., 2013, PMID 24086396). The reviewers of both studies drew attention to the methodological limitations of the included studies.

For the learning population, there is one frequently cited study from 1999, including 34 pairs of matched students (Sun et al., 1999, PMID 10678121). It is worth maintaining proportions: this is a very small study, from over a quarter of a century ago, published in a journal with limited availability. It does not constitute a basis for claims of “marked improvement in recall of facts”.

Status

In the European Union Huperzine A is not an authorized ingredient of food supplements, regardless of its source. A review on adulterated cognitive enhancement products noted that it was the subject of 27 reports between 2020 and 2023 (Paiva et al., 2024, PMID 38540898).

Kava – the most serious case in this list

Kava (Piper methysticum) requires separate treatment from other substances because it is the only one in this list with a documented history of safety withdrawals from the market. We describe it directly because remaining silent would be misleading.

Mechanism and data on effectiveness

Kavalactones are responsible for the action, associated with the modulation of GABAergic transmission. The effectiveness of kava extract for anxiety was assessed in a Cochrane review (Pittler and Ernst, 2003, PMID 12535473) and in a previous systematic review with meta-analysis (Pittler and Ernst, 2000, PMID 10653213). There is a signal of efficacy in this indication – and that is what makes it difficult, because we are not dealing with a compound without any effect.

Hepatotoxicity and market restrictions

In November 2001, European regulatory authorities introduced restrictions on the trade of food supplements and herbal products containing kava. Concerns about liver damage have led to recalls or bans in some countries – including France, Switzerland, the Czech Republic, Spain, the UK, Hungary, Portugal and Germany – and in Canada. In some jurisdictions, these decisions were subsequently challenged; in Germany, the courts overturned the ban, finding it disproportionate.

Regardless of these disputes, an important regulatory fact remains: kava is not included in the EU list of novel foods, which translates into no basis for marketing it as a food in the European Union.

The clinical picture of kava-related liver damage is discussed in a review dedicated exclusively to this issue (Teschke, 2010, PMID 20720265), and the components of the extract potentially responsible for this effect in a separate review (Olsen et al., 2011, PMID 21506562). The broader context of drug-induced liver injury of herbal origin is presented in a systematic review with meta-analysis (Ballotin et al., 2021, PMID 34307603).

The claim that kava “relaxes without causing drowsiness or cognitive decline” is a declaration of the lack of side effects – and such a result cannot be formulated for this raw material.

Sulbutiamine

Sulbutiamine is a synthetic derivative of thiamine (vitamin B1) with increased lipophilicity, which translates into better penetration into the central nervous system than thiamine itself. The association profile was summarized in the review (Starling-Soares et al., 2020, PMID 32399290), and clinical studies primarily focused on weakness and fatigue in the context of disease — for example, in people with multiple sclerosis (Sevim et al., 2017, PMID 28755683).

This distinction is important: the studies were conducted in diagnosed populations in which fatigue is a symptom of the disease, not in healthy people studying for an exam.

The sports context is worth noting separately – sulbutiamine was discussed in the anti-doping literature (Sobolewski and Rodchenkov, 2010, PMID 21204296). In the European Union, the compound is neither authorized as a food ingredient nor registered as a medicinal product.

Methylene blue – an interaction you need to know about

In an article addressed to learners, this fragment is more important than the description of the mechanism, so we put it before it.

Methylene blue is a strong inhibitor of monoamine oxidase A (MAO-A) — this was demonstrated directly, confirming the previously predicted relationship (Ramsay et al., 2007, PMID 17721552). This property creates a risk of serotonin syndrome with simultaneous exposure to drugs with serotonergic effects.

In October 2011, the US FDA issued a safety announcement regarding serious – in some cases fatal – interactions of methylene blue with psychiatric drugs with serotonergic effects: serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine uptake inhibitors (SNRIs), tricyclic antidepressants and MAO inhibitors. Descriptions of severe cases of serotonin toxicity associated with methylene blue have also been published in the anesthesia literature (Rosenbaum and Gillman, 2016, PMID 27415030).

Why is this particularly important in this article: SSRI antidepressants are among the most commonly used in the student population. A person taking such a drug may not associate it with the risk of interaction with a preparation described as a “nootropic”. Describing MAO inhibition as an advantage without providing this information is an omission with real consequences.

As for the cognitive mechanism itself – the effect of methylene blue on mitochondrial function and neuroprotective pathways has been reported, primarily in preclinical models (Tucker et al., 2018, PMID 28840449).

Compounds with no data in humans

Three substances from the original list require a separate category because none of them have been clinically tested in humans.

• 9-methyl-β-carboline (9-Me-BC) — studied in the context of dopaminergic neurons, described as inhibiting monoamine oxidase activity and affecting the expression of neurotrophic factors in astrocytes (Keller et al., 2020, PMID 32285253); considered as a research direction in Parkinson’s disease (Polański et al., 2011, PMID 21651332). All these data come from cellular and animal models.
• Dihexa — a peptide compound described as a hepatocyte growth factor mimetic, tested in animal models (Uribe et al., 2015, PMID 25674052). This is a research reagent with no human use. Describing it as a tool for “a leap in cognitive abilities” is not supported by data.
• Emoxypine – a compound registered as a medicinal product in Russia, without registration or authorization in the European Union. The clinical literature on it is mostly in Russian, which limits the possibility of independent verification.

Table of the status of the substances discussed

Harm reduction

• Medication interactions are a real risk, not a formality. This is especially true when using antidepressants concurrently – see section on methylene blue.
• Lack of authorization means there is no established level of safe use. There is no value to refer to because no one has set it.
• Compatibility of the composition with the label can be a problem. Undeclared medicinal substances have been detected in preparations supporting cognitive functions (Cohen et al., 2021, PMID 34484905); this is described in more detail in a review devoted to unauthorized ingredients in this category (Jędrejko et al., 2023, PMID 37357012).
• Difficulties with concentration may be a symptom. Persistent problems with attention, memory or mood require diagnosis, not the selection of a preparation. This requires consultation with a physician.
• For athletes – anti-doping control covers this category. Some nootropic compounds are on the WADA Prohibited List, and the general clause covers substances with a similar effect.

Frequently asked questions

Are these substances legal?

It depends on the substance, and the differences are large. Some of the compounds discussed are not authorized as food ingredients or registered as medicinal products in the European Union, kava is not on the EU list of novel foods, and 9-Me-BC and Dihexa are reagents intended only for research. Treating them together as “legal supplements” is inaccurate.

Are nootropics addictive?

It is impossible to answer in one sentence for the entire category. For some of the substances in question, no tests have been carried out to assess their addictive potential, so the statement “they are not addictive” has no basis – the lack of testing does not prove the absence of risk. Compounds with a dopaminergic mechanism remain a separate issue, in which the question of tolerance and dependence is justified by pharmacology.

Can I combine them with the drugs I take?

This is a question for a doctor or pharmacist, not for an article. Particular caution is required when using antidepressants concurrently – the case of methylene blue described in the text concerns interactions with documented serious consequences.

Is the use of nootropics before an exam dishonest?

This is an ethical question, not a pharmacological one, and this article does not resolve it. It is worth noting, however, that the regulations of some universities and anti-doping regulations in academic sports refer to substances with a stimulating effect – this is an issue that can be checked in specific regulations.

Why does the article not provide doses?

Because there is no established dosage for most of the substances in question – establishing one requires a registration process, which these compounds have not undergone. The values circulating on the Internet do not come from registration studies.

Summary

Substances mentioned in the context of science do not form a homogeneous group – they differ in mechanism, quality of evidence and legal status, and these three dimensions do not overlap with each other. For the student population, there is a dedicated systematic review, and meta-analyses in healthy adults provide conclusions that are clearly more cautious than the popular picture. Huperzine A has a documented mechanism and Cochrane reviews in the context of dementia, but is not an authorized food ingredient in the European Union. Kava requires separate treatment: a signal of effectiveness in anxiety exists and was described in a Cochrane review, but the raw material has a documented history of liver damage and market withdrawals in some countries, and in the EU it is not included in the list of novel foods. Methylene blue is a strong MAO-A inhibitor and is associated with the risk of serotonin syndrome when using antidepressants – information of real importance for this group of recipients. No human studies have been conducted for 9-Me-BC and Dihexa. None of the substances discussed replaces sleep, which remains a condition for memory consolidation.

Product documentation

Material cards along with batch analytical documentation are available in the category advanced nootropics. Materials intended for adults; some of them are reagents for research use only.

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