The PIED Piper of Nootropics Science-Based Medicine

Posted by Steven Novella on May 20, 2015

Nootropics are an emerging class of drugs that are designed to enhance cognitive function. They are part of a broader category of drugs known as performance and image enhancing drugs (PIED) which are used for enhancement of memory and cognition, sexual performance, athletic performance or musculature (also called lifestyle drugs).

It will probably come as no surprise to regular readers of SBM that nootropics and PIED are being abused and hyped without adequate evidence. One of the primary problems is that they are sold as supplements or as drugs, often over the internet without adequate regulation. One simple fix is to properly classify these drugs as drugs, and to properly regulate them as drugs.

Many of the cognition-enhancing supplements on the market make all the usual claims about natural enhancement meanwhile they predictably contain just vitamins, herbs which have not been shown effective, perhaps nootropics (see below), and often a stimulant, like caffeine. The only drug in the mix which is likely to have a noticeable effect by the user is the stimulant.

The risk of overuse of stimulants in supplements is well known.

Meanwhile, what does the science say about the safety and effectiveness of specific nootropics for specific indications? In short, sufficient high-quality studies to make definitive determinations are lacking. For many, however, there is some preliminary and pre-clinical data.

The concept behind nootropics is to target some metabolic or nutritional aspect of brain function, especially a function involved with memory or attention, and then to provide a nutritional precursor to that metabolic pathway, or a drug that enhances the activity of a neurotransmitter, enzyme, or other metabolic factor.

This is not an unreasonable line of research, but tweaking metabolic pathways is not a simple business, and our ability to extrapolate from the petri dish to animals and finally to net clinical effects in humans is very limited. No matter how promising a treatment looks in theory, we need clinical data to see if it has a measurable and lasting clinical effect.

The primary plausibility problem with the PIED category of drugs is that they are further extrapolating from data in disease states to the enhancement of otherwise healthy function. Just because a drug may enhance memory function in someone with Alzheimers disease, that does not mean it will enhance memory function to supernormal in a healthy individual.

It is true and likely relevant that the brain is a very metabolically hungry organ. Optimal brain function depends upon most metabolic and physiological parameters functioning well. For this reason the brain is often the canary-in-a-coalmine of biological function the first thing to go when something is off. Sick hospital patients, for example, are often sleepy or confused because their bodies are simply under stress, or their metabolic parameters are off. It can often be challenging to figure out exactly what is making a patient confused, because so many things can affect brain function.

Further, in everyday healthy life our brain function can be off simply from having insufficient sleep, not eating well, being depressed, or being physically or mentally exhausted.

Given our brains sensitivity it does make superficial sense that giving it a specific metabolic boost might help cognitive function. This is essentially what stimulants do. It still needs to be determined, however, that a specific metabolic tweak will have the desired effect. One potential problem with predicting whether a specific intervention will help is determining if that metabolic factor is the limiting factor in brain function.

Enhancing acetycholine (the primary neurotransmitter involved in memory formation) may enhance memory, but what if there is already plenty of acetylcholine and the limiting factor in memory function is something else entirely? This is probably why we cannot extrapolate from a disease state to a healthy state the limiting factors on function are likely different.

Therefore, from a plausibility standpoint, the idea of nootropics is possible, but very complicated, and we cannot make confident predictions from pre-clinical data alone or extrapolate from one condition to another. We need high-quality clinical studies for each specific clinical claim.

One of the most popular nootropics is piracetam. This is actually one of a large and growing class of drugs with many neurological indications, including seizure control and treatment of anxiety and depression. Piracetam has been studied specifically for memory and cognitive enhancement in dementia or cognitive impairment.

A Cochrane systematic review (last updated in 2012) found:

At this stage the evidence available from the published literature does not support the use of piracetam in the treatment of people with dementia or cognitive impairment. Although effects were found on global impression of change, no benefit was shown by any of the more specific measures.

They concluded that the data supports further research, but not current clinical claims or use.

In healthy individuals there are only a couple small studies, and they do not show any significant benefit. Therefore, even though piracetam is a popular smart drug the evidence for any significant effect is lacking, especially in healthy individuals.

Another highly popular cognitive enhancer is modafinil. This is a stimulant drug used for narcolepsy, ADHD, and cognitive fatigue resulting from neurological disease or injury. It is a controlled prescription drug, but has still managed to become highly popular as a cognitive enhancer, especially among students.

A recent study, however, highlights the difficulty in extrapolating from disease to healthy states. The researchers compared test performance on healthy subjects taking modafinil vs placebo. They found that the responses were delayed from subjects taking modafinil, but were not more accurate. In hindsight, this result makes sense.

As a stimulant modafinil increases brain function, including frontal lobe executive function. When performing a cognitive task there is often a tradeoff between speed and complexity of processing. Executive function sacrifices speed for complex higher cognitive function. If you have impaired executive function, this tradeoff is worth it. Modafinil can shift the balance back towards a more optimal state.

In the healthy individual, however, you are shifting the balance away from an optimal state, slowing things down without any further gains in accuracy. Therefore modafinil can be a net gain in individuals with ADHD, but a net loss in healthy individuals, and that is what the preliminary clinical data shows.

There are other nootropics but with a similar story basic science research which is used for marketing hype, but does not establish that the drugs (often sold as supplements) actually work.

Nootropics are an interesting and potentially very useful class of drugs which deserve further research. Their greatest potential is likely in various states of neurological disease or injury. Their use as smart pills, however, is dubious from a plausibility standpoint and lacks sufficient evidence.

Many smart pill products on the market cheat by including a regular stimulant, like caffeine. The effects of stimulants on healthy individuals is interesting while they create the subjective experience of being more alert and higher performance,
it is unclear if they actually improve performance, and in fact they may even decrease performance. Even if they do work, their effects typically develop tolerance quickly. Daily use of caffeine, for example, develops tolerance within three weeks, after which regular users are just staving off caffeine withdrawal and experience an overall net negative effect on their alertness.

Stimulant use is therefore potentially useful for alertness in the short term or for intermittent use, but it is unclear if it has a positive effect on cognitive performance. They are good for creating the illusion of cognitive enhancement, however.

Current non-stimulant nootropics are likely useless in healthy individuals.

If you are otherwise healthy and want to optimize your cognitive function, there are some things you can do that are likely to have a dramatically greater benefit than any smart pills on the market:

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The PIED Piper of Nootropics Science-Based Medicine