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Nootropics – exciting new frontiers with natural health products for cognition

Published on July 14th, 2021

Nigel Pollard, Director Metavate

‘Nootropic’ refers to any substance that can improve cognitive performance. Nootropics include pharmaceuticals, as well as certain nutraceuticals and botanical extracts. Pharmaceutical cognitive enhancers include amphetamines such as Adderall®, and amphetamine-type substances such as methylphenidate (Ritalin®). A more recent addition to this class of drugs is modafinil, which is prescribed for narcolepsy and daytime sleepiness, but is also used off-label as a cognitive enhancer.

There are several natural products with good evidence as nootropics. These include (amongst others) specific products made from Bacopa monnieri, cocoa flavanols, Ginkgo biloba, Ginseng (both Asian and American), Curcumin, epigallocatechin gallate (EGCG), Salvia (sage), melissa (Lemon balm), and guaraná.

They often have distinct mechanisms of action profiles and the potential for powerful nootropic combination effects are less well researched.

As shown in the figure (right [1]), pharmaceutical nootropics aim to have relatively large effects on single neurotransmitter systems (grey panel). Nootropics can have relative smaller effects on multiple systems relevant to cognitive functioning. These include the processes within the green-shaded area which all influence cognition and represent realistic targets for nutraceuticals. Age and genetics (unshaded area) remain non-modifiable factors. HPA, hypothalamic–pituitary–adrenal axis.

The most widely-used nootropic is caffeine, which improves aspects of cognition – notably attention, as well as having an alerting effect, especially when people are fatigued. Caffeine does, however, have a down-side – people find that at higher doses it can cause jitteriness and tension which is partly due to the fact that caffeine restricts blood flow, including to the brain.

We should also distinguish between acute and chronic cognitive effects. Acute effects occur in the minutes and hours following a single ‘dose’ of a product. On the other hand, chronic effects can take weeks or months of daily administration before they are apparent. They often involve different mechanisms, acute effects can be underpinned by increased blood flow, glucose and oxygen and neurotransmitter effects. Chronic effects are often aligned with the same changes which are associated with age-related cognitive decline such as inflammation and oxidative stress.

From an industry perspective there is great potential for developing novel, natural product-based nootropics. One element of this is that such products do not have to undergo every stage in the usual drug development pipeline. These products often effectively have centuries of ‘field studies’ supporting their safety and tolerability. This means that they can be subject to later stage efficacy trials with confidence that they are well tolerated. The main challenge is to ensure that cognitive outcomes in such trials employ sensitive measures to detect cognitive change. As well as experience in the field this also requires a good knowledge of advances in cognitive neuroscience.

[1] Scholey A (2018) Nutrients for neurocognition in health and disease: measures, methodologies and mechanisms. Proceedings of the Nutrition Society 77, 73-83.

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