The use of smart drugs is becoming trendy. Lots of people are taking various substances regularly, many others try them from time to time. The idea of enhancing the brains ability, or tapping into its unused reservoir is definitely sexy, and many people are actively looking for information on this subject.

The shortage of scientifically verified information is exactly the reason Im writing this article. Although thousand of publications on smart drugs, cognitive enhancers, and nootropics etc. can be found online, the overwhelming majority of claims are unsubstantiated or unashamedly commercialized. This means that the info you come across mostly consists of descriptions of personal opinions or experiences, or compilations of facts published elsewhere, or just articles from popular media where people can write whatever they want.

Multiple websites publish all kind of rubbish just to convince you to buy yet another wonderfully effective smart drug. Few people make an effort to refer to their sources of information, not to mention to present scientific and statistical data backing their claims. This is particularly enigmatic when these articles provide recipes for various drug combinations and claim the superiority of some of these combinations/compounds over the others. However, even scientific data on the subject is rather incomplete. Many studies were done using only a small number of participants, or in the absence of any reasonable controls. On their own, studies of such kind are of little, if any, value.

Fortunately, several systematic reviews and meta-analyses on the use of nootropics were published in the last couple of years. Systematic reviews and meta-analyses combine data from multiple individual studies, thus making the data statistically significant. This is a better way of assessing the efficacy of different drugs in the general, healthy population, and these are the publications that I will mostly use as reference points in this article.

How to prove that a smart drug is really smart?

Smart drugs (e.g., nootropics and cognitive enhancers) are defined as substances that improve cognitive function, particularly executive functions, memory, creativity, or motivation, in healthy individuals. The last bit is important: there are many drugs that were specifically developed to enhance brain functions in people with various cognitive disorders or deficits. Such drugs wont necessarily smarten up healthy people, and when they do, they are not necessarily safe. Nootropics may come in many forms, from classical pharmaceutics in the form of pills to herbal supplements and functional foods.

There are only few smart drugs that are proven to improve some aspects of cognition. Proving that a compound has the properties of a nootropic is not a simple task. There is no straightforward way of measuring whatever cognitive enhancement you may experience once the pill is taken. The drug may indeed work and visibly increase your productivity. But it may also simply improve your mood if you anticipate a positive effect. On top of this, any given drug may work for some people and not work for others. Furthermore, the use of any drug is associated with potential side effects (e.g., headaches) that might eliminate its advantages in productivity and creativity. If the changes in productivity can be measured using some tests, creativity still remains something arguably impossible to quantify.

How smart drugs work?

There are several mechanisms that can be involved in the functioning of smart drugs. Some drugs can increase the blood flow (and thus oxygen supply) to the brain. Others can accelerate neuronal communication through increased release of certain neuromediators or through agonistic effects on the receptors of these neuromediators. Some compounds can serve as biochemical precursors of neuromediators, others may prevent oxidative damage to brain cells or provide them with a source of energy. Some of these changes can be achieved quickly making the drugs work almost instantly. Others, such as amendment/prevention of neuronal damage, manifest themselves only after prolonged use of the drug, thus making any changes in cognitive functions not so fast and not so obvious (although they can still be substantial).

Short overview of most popular nootropics

Amphetamines are a class of pharmaceuticals that include adderall, dextroamphetamine, and lisdexamphetamine. The drugs were developed to treat people with ADHD (attention deficit hyperactivity disorder) and this is where their effects are the most prominent. The drugs were also demonstrated to improve episodic memory, working memory, and some aspects of attention in the general population. At low doses they improve memory consolidation, recall of information, and motivation to perform tasks that require high degree of attention. Ritalin is structurally different from amphetamines and works through different mechanisms, although produces similar effects. Both amphetamines and ritalin improve cognitive functions, albeit only at lower doses. At high doses they stimulate other neural pathways not involved in learning that effectively cancel their positive effects on cognition.

Wakefulness-promoting agents, such as modafinil and armodafinil, increase alertness, counteract fatigue, and increase productivity and motivation. Modafinil is praised for its ability to improve reaction time, logical reasoning, and problem-solving. The drug is clinically prescribed for a number of conditions including sleep apnea, narcolepsy, and shift work sleep disorder.

Compounds from the racetam family (piracetam, oxiracetam etc.) are more extensively studied compared than the newer nootropics. Piracetam was developed back in the 1960s and has an almost perfect safety profile. Convincingly, it was shown to improve cognitive abilities, particularly in older people and those with cognitive impairment. Although piracetam is officially recognized as a nootropic, its brain-enhancing effects in healthy people are considered to be moderate. There is a number of other derivatives from this group of drugs which, allegedly, work better. A good example is phenotropil. This compound was developed in Russia where it is available as a prescription drug. It was demonstrated to have a memory enhancing effect. The drug can be used as a stimulant and enhances resistance to extreme temperatures and stress. Due to its stimulating effect, phenotropil is banned by the World Anti-Doping Agency, which means that it cannot be used by athletes intending to compete in official events.

Xanthines, such as caffeine, are some of the most commonly used compounds with nootropic effects. In particular, they increase alertness and performance levels. Caffeine is not what comes to mind when we think of nootropics, but apparently its effect is comparable to many pharmaceuticals.

L-Theanine, a chemical component of green tea, is very well studied and its effects on promoting alertness and attention are confirmed by multiple research.

When it comes to nutraceuticals and herbal supplements, recent studies appear to be contradictory. Some data do support the memory-enhancing effects of such plants as Gingko biloba, Asian ginseng, and Bacopa monnieri, but systematic reviews do not find convincing evidence of their effectiveness. It is likely that herbal supplements may work well over longer periods of time and improve cognitive abilities, but in the short term their effects are not particularly obvious. The same applies to many vitamins, such as vitamin E and B group vitamins, as well as Omega-3 fatty acids: the evidence supporting their benefits are limited at the present time.

To conclude, only few drugs are scientifically proven to be associated with moderate cognitive enhancement effects in the healthy population. Being sceptical when assessing information on smart drugs from the internet is a good idea: lots of ridiculous rubbish is published online. Most nootropics are relatively safe, but side effects are always a possibility since the response to nootropics is highly individual.

References:

Spencer BC et al. (2015) The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex. Biological Psychiatry 77,940950. doi:10.1016/j.biopsych.2014.09.013

Ilieva IP et al. (2015) Prescription Stimulants Effects on Healthy Inhibitory Control, Working Memory, and Episodic Memory: A Meta-analysis. J Cogn Neurosci. 27, 1069-1089. doi:10.1162/jocn_a_00776

Bagot KS and Kaminer Y (2014) Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review. Addiction 109, 547557. doi:10.1111/add.12460

Linssen AMW et al. (2014) Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies. Int J Neuropsychopharmacol 17, 961-977. doi:10.1017/S1461145713001594

Urban KR and Gao WJ (2014) Performance enhancement at the cost of potential brain plasticity: neural ramifications of nootropic drugs in the healthy developing brain. Front. Syst. Neurosci.| doi: 10.3389/fnsys.2014.00038

Winblad B (2005) Piracetam: a review of pharmacological properties and clinical uses. CNS Drug Rev. 11, 169-182. PMID:16007238

Zvejniece L et al. (2011) Investigation into Stereoselective Pharmacological Activity of Phenotropil. Basic & Clinical Pharmacology & Toxicology 109, 407412. doi: 10.1111/j.1742-7843.2011.00742.x

Rogers PJ (2007) Caffeine, mood and mental performance in everyday life. Nutrition Bulletin 32, 8489. doi: 10.1111/j.1467-3010.2007.00607.x

Camfield DA et al. (2014) Acute effects of tea constituents L-theanine, caffeine, and epigallocatechin gallate on cognitive function and mood: a systematic review and meta-analysis. Nutr Rev 72, 507-522. DOI: https://doi.org/10.1111/nure.12120

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Nootropics: How Smart Can You Get on Smart Drugs? - Brain Blogger (blog)