A Huge, Detailed Guide to Nootropics (Smart Drugs): How They Work and How to Use Them

Ever wished you were smarter? That you could memorise everything you read and ace every exam? That you could run rings around people in conversation so that you always emerged victorious? That you could come up with amazing ideas that would gain you fortune and adulation? Well so has just about everyone else, which is why nootropics – or ‘smart drugs’ – are a source of such discussion and attention across the web.

But are nootropics really a safe way to increase your brain power? How do they work? And how do you go about using them in the most effective manner possible? Consider this your complete beginners’ guide to hacking your brain with supplements. If you’re interested in getting started, then this will help you to understand the subject and to avoid common mistakes and pitfalls.

What Are Nootropics?

Nootropics are any compounds that can increase brain power in a specific capacity; whether that means memory, focus, creativity or verbal fluency. Often the term is used to describe specifically those things that affect the brain in an acute manner: which can be taken immediately before revising or before writing in order to benefit that specific task.

The most famous example of a nootropic in fiction, is perhaps ‘NZT’ which was featured in the film ‘Limitless’ (itself based on the book ‘The Dark Fields’). While on NZT, the protagonist is able to play the stock market, write best-selling literature, network his way through organisations and recall information thought long forgotten. That’s the aim of nootropics, but the reality is generally a lot less extreme.

Another very ‘famous’ example of a nootropic, and one that pretty much everyone has used at some point or another, is caffeine. Caffeine is a substance that is able to increase our ability to focus, to stay awake and to remember details and for many it’s a crucial part of their ritual when waking up first thing in the morning.

What Is and Isn’t a Nootropic?

Now, caffeine does actually have some side effects and some negative effects on cognition. It can make you jittery and jumpy, it can cause headaches, it can negatively affect sleep and in the long-term it can lead to tolerance – meaning that your brain changes in such a way as to ‘adapt’ to the caffeine you’re giving it. In other words, because things like dopamine and norepinephrine get elevated when taking caffeine, this then means that your brain can adapt by reducing the amount of those neurotransmitters that it produces naturally to try and re-establish an equilibrium. This can lead to withdrawal, and actually that’s the reason that many people feel groggy in the morning until their first coffee – they’re experiencing withdrawal symptoms!

Some people thus conclude that caffeine doesn’t count as a nootropic – because it doesn’t purely improve the brain. Some take the stance that to classify as a nootropic, that substance must only be beneficial for cognition. Then again though, the argument could be made that all substances are both positive and negative for the brain as we will see…

It could also be argued that something like an antidepressant would be a nootropic. Say a SSRI (Serotonin Re-Uptake Inhibitor) increases your mood effectively, and at the same time potentially improves motivation and productivity, you might then conclude that it has enhanced your brain and is thus a nootropic. The term isn’t normally used this way, but really there’s no right or wrong answer – which is also an issue surrounding transhuman technologies (is plastic surgery ‘transhumanism’?).

You could even go so far as to argue that alcohol or marijuana are ‘nootropic’ in some senses – as they help to relax the brain and thereby (some argue) help to stimulate creativity.

How They Work

There are a large range of nootropics, some of which are synthetic compounds, others of which are herbal extracts and others still that are vitamins, minerals and other nutrients in potent combinations.

All of these nootropics work differently, but generally they have the same basic underlying mechanism – which is that they affect the neurotransmitters. Neurotransmitters are the chemicals that get sent between neurons in order to provide additional information during ‘action potentials’ (the firing of one neuron to communicate the next). Webs of neurons in our brain represent our memories and provide us with all of our cognitive skills, and it’s the neurotransmitters that get fired across the ‘synaptic gap’ (between the neurons) that add to the data exchanged between them. Norepinephrine for instance helps to tell us that something is important and worthy of our attention, while other neurotransmitters add emotional content or encourage memory. Other neurotransmitters have a wider effect and make us feel tireder, or more alert overall. By increasing and decreasing the amounts of these various chemicals, nootropics can thus trigger a range of responses.

The way that nootropics control the amount of neurotransmitters in the brain varies however. In some cases they work by preventing them from being reabsorbed (thus increasing the amount of available neurotransmitters), in others they block them from working by mimicking their ‘shape’ and filling the ‘receptors’ that normally register them (thus decreasing their impact on the brain – which might increase the amount of other neurotransmitters in turn), while in others they simply provide the brain with more of said neurotransmitter by providing more of the specific building blocks. For instance, the nootropic stack known as ‘CILTEP’ contains an amino acid called L-phenylalanine, which is a precursor to dopamine.

For more information on how neurons and neurotransmitters work, read my guide to the basics of neuroscience.

A List of Popular Nootropics

There are countless different nootropics you can use to increase your brain power and this is not the place for an exhaustive list (that’s coming!). Nevertheless, this should give you a pretty in-depth overview of the main nootropic classes and how they work. It will further your understanding of nootropics, but if you want to skip ahead for now then feel free to go ahead.

Racetams: Racetams are one of the oldest and most popular groups of nootropics. The best known is Piracetam (my experiences), and most others are derivatives of that (such as aniracetam, oxiracetam etc.). These nootropics are particularly effective in improving attention, memory and learning and work by increasing the activity of acetylcholine – a neuromodulator (meaning that it modulates a range of neurons rather than being used directly in synaptic transmissions) that is implicated in learning and ‘long term potentiation’. Acetylcholine is the most common neurotransmitter in the brain and was the first to be discovered. Piracetam is a cyclic derivative of GABA, and enhances acetylcholine receptors.

Cholinergics: Another way to increase the activity of acetylcholine in the brain is simply to provide the body with the building blocks of acetylcholine itself. The best way to do this is with choline, which is a precursor and is found in eggs among other things. When using racetams like Piracetam, it makes sense to consume extra choline. You can also get choline from sources like alpha GPC – a substance found naturally in breast milk which provides readily bio-available choline and easily crosses the blood-brain barrier. It is thought that alpha GPC may help to increase the IQ of those children who are breastfed.

Acetylcholinesterase Inhibitors: Acetylcholinesterase is an enzyme that breaks down acetylcholine. Acetylcholinesterase inhibitors work by reducing acetylcholinesterase (try saying this sentence ten times quickly), thereby increasing acetylcholine. A good example is huperzine A, which is also an NMDA receptor agonist – meaning it promotes the growth of nerve cells via nerve growth factor. It may be effective in increasing neuroplasticity. Galantamine is another substance that works by regulating the activity of enzymes in the brain.

Ampakines: Ampakines work to promote alertness, mental energy and memory span by activating glutamatergic AMPA receptors. AMPA receptors are responsible for the regulation of synaptic transmissions. Ampakines such as sunifram are also stimulants.

Eugoeroics: Eugeroics are substances that increase wakefulness and alertness, but without some of the negative side effects associated with other stimulants. These work by increasing neurotransmitters associated with attention and excitability, including epinephrine, norepinephrine and dopamine. Two of the most popular examples are adrafinil and modafinil. Modafinil was originally developed in order to be a treatment for narcolepsy, but has become popular for its off-label use as a productivity aid, particularly among ‘executive’ types.

See more detail on the mechanisms of Modafinil here, and my review here.

Adderall is also a popular ‘stimulant’-type nootropic, which was originally intended for use by ADHD sufferers. Adderall is an amphetamine (like speed) and increases norepinephrine, dopamine and serotonin. Ritalin is a popular alternative and another psychostimulant that works to affect the central nervous system. In this case, Ritalin works by preventing the re-uptake of dopamine – a neurotransmitter highly implicated in attention and goal-oriented behaviour.

GABAergics: GABAergics are nootropics that interact with GABAergic neurons. GABA is a neurotransmitter that is implicated in sleep and relaxation and which can help prevent stress and anxiety. They can also be used to treat insomnia, and some bodybuilders use them to increase growth hormone production during the night. One of the easiest ways to stimulate GABA is with pure GABA – an amino acid derived from vitamin B6 and glutamate. Direct supplementation is potentially pointless however as it cannot cross the blood-brain barrier. Nevertheless it continues to be sold in a pure form. Phenibut is a derivative of GABA which can be used to elevate levels in the brain. It also aids in the communication of the brain across hemispheres, potentially increasing creativity. It can however cause side effects and lead to tolerance.

Serotonergics: Serotonergics meanwhile impact the availability of serotonin – a feel good neurotransmitter implicated in mood and, pleasure and stress relief. Tryptophan is one serotonergic that can be found in dairy food, eggs, soybeans and poultry. As a precursor to serotonin it can improve the mood and prevent stress. Tryptophan is also a building block for melatonin – the sleep hormone – and thus may help improve sleep. 5 HTP meanwhile is the chemical pre-cursor of serotonin (the by-product of tryptophan metabolism) which makes it useful for cutting the middle man as it were.

Dopaminergic: Dopaminergics are nootropics that impact specifically on dopamine levels. A good example is Tyrosine which is converted into dopamine, epinephrine and norepinephrine increasing alertness and attention. Theanine meanwhile, available in green tea, is a pre-cursor to serotonin as well as being able to stimulate dopamine levels. It can be used alongside caffeine to reduce anxiety and jitters.

Neurohormones: Neurohormones are hormones created by neuroendocrine cells. These are released into the blood but can also work as neurotransmitters in the brain when processed in the hypothalamus and released through axon terminals along with other neurochemicals. Examples include dopamine, epinephrine and oxytocin. Thus, substances that increase these specific hormones might also have impacts on brain function. DHEA for instance is a neurohormone with steroid-like functions acting as a building block for testosterone and oestrogen. It is protective against certain age-related decline and may help adrenal fatigue. Vasopressin meanwhile is an amino acid peptide (and antidiuretic) produced in the pituitary gland. It appears to be useful for improving short term memory and increasing deep memory imprinting. Melatonin of course is popular as a sleep aid.

Cognitive Metabolic Enhancers: Cognitive Metabolic Enhancers work by increasing energy available to human brain cells via improved metabolism. This can occur through increased vasodilation (increasing the diameter of blood vessels to carry more blood to the brain) or by improving the function of the mitochondria – our cells’ energy factories. In turn, this leads to more energy in the brain and stimulates the production of certain arousal-promoting neurotransmitters. One example is Alpha Lipoic Acid (ALA) which creates more energy via the ‘Krebs’ cycle or breakdown of carbohydrates. You could also consider MCT Oil in this category, which stimulates the production of ‘ketones’ – an alternative energy source to glucose favoured by the brain for certain functions. Creatine – the supplement used by many athletes – has also been shown to help increase available energy in the brain and thus increase focus and mental energy.

Xanthines: Xanthines are stimulants and derivatives of – you guessed it – xanthine. Xanthines reduce the effects of adenosine, the build-up of which leads to sleepiness. They also increase respiration and alertness. The most famous example of a xanthine is caffeine (see HERE for more on caffeine), while theobromine, found in dark chocolate, is also commonly available.

Nutrients: Many more vitamins, minerals and nutrients can be considered nootropics due to their important roles in building and maintaining the structures of the brain. Everything from amino acids, to vitamins, to antioxidants, to fatty acids (especially omega 3 fatty acid) can help to improve brain function in both the long and short term and protect against age related decline.

Using Nootropics: What is it You’re Trying to Achieve?

When setting out to use any new nootropic, it is absolutely imperative that you first decide what it is you are trying to accomplish. Nootropics as you’ve seen, will work by increasing specific neurotransmitters within the brain in order to stimulate specific results. The point here, is that no neurotransmitter is going to automatically make your brain ‘better’ across modalities, but rather it will improve you in specific capacities. It is thus crucial that you take the right nootropic for the right job.

For example, if you were trying to increase creativity, you might want to take nootropics that helped to relax the brain and increase communication between neurons. For this a good option could be a GABAergic like phenibut. On the other hand, if you want to increase your focus and attention, then you would do better to take a xanthine, or a dopaminergic. Attention and focus mean we concentrate on one idea, or one stimulus. On the other hand, creativity means allowing the mind to ‘wander’ between different ideas. The two states are antithetical, so anything you take to increase your focus may actually deaden your creativity (see here).

Likewise, using a GABAergic would be a bad idea if you were trying to promote wakefulness. And if you wanted to improve memory and ‘long term potentiation’/plasticity, then you would want to look more into racetams and cholinergics.

If you’re interested in the different areas of intelligence and how intelligence is born from activity across the brain, then check out THIS recent post.

Understanding Stacks

Some nootropics make natural partners for each other and thus enthusiasts will often use ‘stacks’ in order to get the maximum benefit. These are groups of nootropics that they take together in order to get the best effects.

So something like Piracetam, choline, tyrosine theanine and caffeine for example would be a great ‘stack’ for learning. That’s because the tyrosine, theanine and caffeine would increase the amount of dopamine in the brain as well as epinephrine – improving your ability to focus and pay attention. Meanwhile the theanine would also be able to reduce some of the jitteriness created by the caffeine. Finally, the Piracetam would increase the availability of acetylcholine receptors, while the choline would increase the amount of choline for them to utilise – a combination that would ensure you retained more of what you focused on.

Nothing Operates in a Vacuum

What’s also important to consider though is that raising one neurotransmitter will almost always lead to an increase or reduction in others.

For instance, increasing dopamine leads to generally increased activity throughout the brain. Thus your body interprets this as something important happening to create such arousal and it thus produces epinephrine as a result (as part of the ‘fight or flight’ response) to increase your attention. Thus, it’s possible that you might use a dopaminergic with the intention of raising dopamine, but will also raise epinephrine as a result. Sometimes this might also lead to production of cortisol – which is the stress hormone and which can increase feelings of anxiety as well as leading to snacking. An elevation of cortisol meanwhile will often lead to an elevation of serotonin however as the brain tries to regulate the memory. Thus, in this scenario you have attempted to target one neurotransmitter but have instead caused a cascading effect to alter many.

Sometimes a ‘stack’ will attempt to account for this, by using other nootropics to counteract unintended elevations or reductions in other neurotransmitters. These nootropics however will often only create other unintended effects leading to something of a never-ending cycle.

When taking any nootropic, you will almost certainly alter levels of countless neurotransmitters in the brain – and probably several that we don’t even know about. This can lead to detrimental side effects, so it’s important to monitor the outcome carefully.

Measuring Effectiveness and Side Effects

Taking nootropics blindly and hoping you’ll turn into Albert Einstein is a fruitless way of using them. You are not going to notice profound effects throughout all your mental faculties – generally these are mild impacts at best and if you aren’t measuring them in some way, it might be hard to know whether you’re genuinely seeing results in the areas that matter.

Some people then will use some ‘test’ of their mental performance in order to measure the effectiveness of certain nootropics and will attempt to remove confounding factors such as sleep and diet changes. When attempting to improve working memory for instance, some people will use the ‘Dual N-Back’ test and then look for improvements in their score. How they account for improvements due to practice, I am unsure. If you were really serious you could even conduct your own ‘double blind’ experiment by getting someone to give you either the real nootropic or a sugar pill (without even them knowing which) and then measuring your performance over a few days in order to counteract any placebo effect.

Personally I find it more useful simply to measure my performance in the specific activity I’m hoping to improve in (I find that I don’t tend to need to perform the N-back test all that often). For me that usually means writing articles – and I can thus measure the effectiveness of a placebo by looking at word count and how often I get distracted. Is it a placebo effect? It doesn’t matter – as long as I’m writing more and getting distracted less, that’s all that counts.

Be Wary of Tolerance

Another factor to be cautious of with nootropics though is ‘tolerance’. Tolerance is what happens when we take too much of a nootropic over an extended period of time leading to chemical changes in the brain. In some cases this can mean you then need more of the nootropic to achieve the same effects. In other cases, it might mean that you permanently alter your brain chemistry for the worst. In others it can lead to dependence, addiction and withdrawal.

For instance, if you are constantly using supplements that increase dopamine in your brain, your brain may react by reducing the amount of dopamine it usually produces – or even reducing the number of dopamine receptors. Thus you might actually make yourself less motivated when you’re not using the nootropic.

Does this, along with the potential for side effects, mean that you shouldn’t use nootropics at all? Not necessarily – it just means you need to be very careful and you need to recognise that there’s ‘no such thing as a free lunch’ (as Tim Ferriss says). Remember that even the foods you eat, sunlight, sleep and exercise alter brain chemistry and thus change your mental performance – using nootropics means you’re simply taking conscious control of this manipulation. You just have to be careful.

Best Practice

Once you have found what works for you, the best way to avoid tolerance is to avoid taking any nootropic that has a powerful acute effect for long periods of time. This way you not only avoid permanent, unintended changes to your brain chemistry, but you also ensure that the nootropic remains potent and effective. For instance, modafinil is a substance I have spoken about in the past and found to be very effective though also potentially risky due to numerous side effects. The only safe way to use it, would be to take it very rarely when doing an intense cramming session. The same would go for any other stimulant-type or relaxation-type nootropics. Consider these tools to be used with laser precision. Personally though, I don’t actually recommend the use of modafinil specifically at all (remember too though, everyone is different and everyone reacts differently to different nootropics).

On the other hand, those vitamins, minerals and nutrients that act to maintain and improve brain health over the long term such as omega 3 fatty acid and antioxidants are safe and recommended for long-term, regular use. These won’t lead to huge, immediate benefits, but they will help to improve your brain’s health and general performance.

Even more important are lifestyle considerations such as ensuring you get enough sleep (the number one ‘nootropic’) as well as exercise (which stimulates endorphins as well as neurogenesis – the birth of new brain cells). Brain training also has its place when used correctly (and particularly when used in conjunction with nootropics).

And that’s an article for another time…

5 Comments

1. Gav says:

   November 23, 2014 at 9:13 pm

   One of the few accurate, balanced articles on nootropics I’ve come across – well done.

   Reply
   • thebioneer says:

     November 24, 2014 at 12:07 pm

     Thanks a lot! I’m glad you enjoyed it 🙂 If you’re interested, this article: https://www.thebioneer.com/best-nootropic-stack/ deals with my most up-to-date views on the subject as well as my current stack. Thanks for reading!

     Reply
2. Silk says:

   September 16, 2015 at 11:19 am

   Great Job Adam, you articles about nootropics have helped a great deal in understanding the topic better. Nevertheless, I haven’t find any articles where you have been talking about adaptogens like bacopa, rhodiuma, ginseng ashwagandha. Maybe I missed it out, but if not it would be great to hear your opinion about it.

   Reply
3. Robert Dinse says:

   September 14, 2016 at 3:34 pm

   Generally a very good introduction to nootropics however there is one error.

   “Cognitive Metabolic Enhancers: Cognitive Metabolic Enhancers work by
   increasing energy available to human brain cells via improved
   metabolism. This can occur through increased vasodilation (increasing
   the diameter of blood vessels to carry more blood to the brain) or by
   improving the function of cell membranes (mitochondria)”

   Mitochondria are not cell membranes, they are organelles within the cell that are the cells energy factory producing ATP. There are substances that help the function of mitochondria and/or stimulate their proliferation so that there are more mitochondria within the cells, PQQ comes to mind, and there are substances which improve the function of cell membranes, omega3’s come to mind, but they are two distinctly separate things.

   Reply
   • thebioneer says:

     September 16, 2016 at 5:14 am

     Yes thank you very much for pointing that out! I wrote this one a whiiile back and got a bit muddled there it seems – I wasn’t aware it said that 🙂 It is fixed now, thank you. And thanks for reading!

     Reply