Cognitive Enhancers

If you’ve seen the movie “Limitless,” you probably want to get your hands on some “NZT” cognitive enhancer:

“You know how they say that we can only access 20% of our brain?” says the man who offers stressed-out writer Eddie Morra a fateful pill in the 2011 film Limitless. “Well, what this does, it lets you access all of it.” Morra is instantly transformed into a superhuman by the fictitious drug NZT-48. Granted access to all cognitive areas, he learns to play the piano in three days, finishes writing his book in four, and swiftly makes himself a millionaire.

… Gary Lynch, a professor in the School of Medicine at the University of California, Irvine argues that recent advances in neuroscience have opened the way for the smart design of drugs, configured for specific biological targets in the brain. “Memory enhancement is not very far off,” he says, although the prospects for other kinds of mental enhancement are “very difficult to know… To me, there’s an inevitability to the thing, but a timeline is difficult.”

In the nearer future, Lynch points to nicotinic receptor agents – molecules that act on the neurotransmitter receptors affected by nicotine – as ones to watch when looking out for potential new cognitive enhancers. Sarter agrees: a class of agents known as α4β2* nicotinic receptor agonists, he says, seem to act on mechanisms that control attention. Among the currently known candidates, he believes they come closest “to fulfilling the criteria for true cognition enhancers.” __BBC

The truth about smart drugs is they are unlikely to be put on any drug company’s fast track. There is still a lot to learn about how the brain responds to various tweaks — no one wants to risk making a big mistake when it comes to human brains, particularly normal brains.

Such “miracle” drugs will first become available to normal people on grey or black markets — just like in the film. And chances are good that a lot of people will pay the price for making guinea pigs out of themselves — just like in the film.

Most journalists and bloggers who write about “smart pills” have a very limited knowledge of how normal brains work — much less how to make a normal brain into an exceptional brain. Most researchers find themselves in the same boat.

It would probably be fair to say that we are still in the first generation of studies to examine the potential for cognitive enhancement in humans. In both healthy individuals and many patient groups, the overall effects of drugs generally seem to be modest. However, there is evidence that there might be more significant effects in subgroups, such as those whose baseline performance is poorest or individuals with a particular genotype. Moreover, new drugs aimed at enhancing the phasic response of neurotransmitter systems, such as direct nicotinic agonists for the cholinergic system [34], might prove to have greater effects than existing modulators that globally increase levels of a neurotransmitter in a tonic fashion. The neurobiology underpinning the effects of cognitive enhancers and the mechanisms that determine responsiveness across individuals promise to be the focus of research in health and brain disorders in the future. _Source

The above article excerpt makes an important point: Brain function is complex, highly orchestrated, and time dependent. Compared to the brain, so-called smart drugs are quite stupid. But don’t give up hope quite yet.

The ongoing study of current cognitive enhancers such as those in the list below and the table at bottom, have given us scattered hints as to what future therapies might offer. Here is a short list of possible future targets for cognitive therapies:

Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. _Source

More reading at these links to interesting targets of interest in the area of synergistic chemistry:
PDE Inhibitors(4,10)
Nicotinic Alpha-7 agonists
mGluR antagonists
5HT6 antagonists

Just because we are in the early stages of research, people are not going to forego using smart drugs if they believe these drugs will give them an advantage.

Compounds such as methylphenidate and modafinil are used by students in pursuit of better grades, military personnel who need to remain awake for long missions, elderly individuals afraid of cognitive decline and even university academics keen to maintain their performance [14–17]. __Cognitive Enhancers by Drugs in Health and Disease

Adderall is another frequently used drug by students, executives, pilots, surgeons, and others.

Of the non-pharmacological approaches to cognitive enhancement, various types of brain stimulation stand out for possible efficacy:

Several studies demonstrated enhancing effects of various brain stimulation methods on learning and memory. Learning enhancing effects have been reported for tDCS and dVNS. These results suggest that the changes in excitability induced by tDCS, TMS and dVNS canhelp memory encoding, while DBS has the potential to directlyaffect the modulation of memorysystems. Anodal tDCS during slow wave sleep also enhanced memory consolidation…

… Cognitive processes can be enhanced by inhibiting other brain regions that would otherwise have an interfering effect. TMS can reduce interference between similar-sounding words in phonological memory, improving recall and reduce distractors in visual search . It has
been claimed that rTMS inhibition of the frontotemporal region produces (besides reduction in immediate recall) savant-like abilities in drawing, mathematics, calendar calculating and proofreading. However, individual variations were large compared to the sample size, undermining statistical power. Other experiments along the same lines have hinted at improved number estimation.
The efficacy of brain stimulation strongly depends on applying it to the right region;… ___ Non-Pharmacological Cognitive Enhancers (PDF)

Of the pharmacological approaches, two of the classes of drugs stand out:

From a neurobiological perspective, two plausible candidate classes have emerged that both target the fast excitatory transmission responsible for communication within cortical networks. One acts on nicotinic receptors (alpha7 and alpha4) that regulate release of the neurotransmitter glutamate while the other (‘ampakines’) allosterically modulates the glutamate receptors mediating the post-synaptic response (EPSCs). Brain imaging in primates has shown that ampakines expand cortical networks engaged by a complex task; coupled with behavioral data, these findings provide evidence for the possibility of generating new cognitive capabilities. __ Likelihood of Cognitive Enhancement

A 2015 review article on Ampakines (PDF) Difficulty level: High …. But this is a very hot area of research.

A much easier (moderate difficulty) 2014 article on pharmacological cognitive enhancers — a useful introduction.

Brain imaging studies then uncovered a remarkable result: the ampakine intensified activity in frontal and temporal cortices but also led to the engagement of a superior parietal region, the precuneus, which was inactive during vehicle trials. The precuneus is thought to be critical for envisioning future actions by humans. In any case, these results in a primate provide an example in which expansion of cortical networks is associated with a lifting of limits on performance in a cognitively demanding problem. __ Lynch 2014 et al

The following drugs represent early and current attempts to achieve cognition enhancing chemicals:

Cognitive enhancer Neuromodulatory mechanism Cognitive functions improved Known brain systems most affected Currently recommended clinical use
Methylphenidate, amphetamine Dopamine and noradrenaline reuptake inhibitors Response inhibition, working memory, attention, vigilance Frontoparietal attentional systems, striatum, default mode networks ADHD, wake-promoting agent
Caffeine Non-selective adenosine receptor antagonist Vigilance, working memory, incidental learning Frontal lobe attentional systems
Nicotine Nicotinic cholinergic receptor agonist Working memory, episodic memory, attention Fronto-parietal attentional systems, medial temporal lobe, default mode networks
Modafinil Unknown, but effects on dopamine, noradrenaline and orexin systems proposed Working memory, episodic memory, attention Frontal lobe attentional systems Wake-promoting agent
Atomoxetine, reboxetine Noradrenaline reuptake inhibitors Response inhibition, working memory, attention Frontoparietal attentional systems ADHD, depression
Donepezil, galantamine, rivastigmine (AChEI) Blocks enzymatic breakdown of acetylcholine Episodic memory, attention Frontal lobe attentional systems Alzheimer’s disease, PDD, DLB
Memantine Noncompetitive, low-affinity, open channel blocker of the NMDA receptor Episodic memory, attention Frontal and parietal lobe Alzheimer’s disease

Table Source
These are the relatively mundane approaches that have been around forever. But things are changing and new ideas are being tested.

You are not likely to learn about the first quasi-NZT drug from your physician or pharmacist. But if you pay attention, you may find out about it before most other people in your pay grade. But be careful.

Not every approach will work equally well for everyone. Some methods which may temporarily give one person genius-like powers, may actually put someone else in intensive care — or kill them. We have a lot to learn before our cognitive therapies are ready for widespread use.

From the popular press:

What is Neurofuse?

The ingredient profile [of Neurofuse] is pretty legit and filled with proven ingredients. I’m not a huge fan of the fact that they use a proprietary blend because you can’t tell exactly how much of each ingredient is in the formula, but it does contain some great ingredients including Bacopa Monnieri, Phosphatidylserine , DMAE, Alpha-lipoic Acid, Pikatropin, Caffeine and more. All of these ingredients have been independently tested for cognitive enhancement and mental improvement which boosted my confidence in the product before even trying it out. — Grandaddy of smart drug reference websites

Nootropics links on Reddit

Bottom Line

If you take any of the “smart drugs” — expecting to have an NZT experience — you will be disappointed. Different people will have different results, depending upon your state of mind and nutrition, your genetics, your innate abilities, and your immediate environment. Be careful with over the counter formulations and imported drugs. Be honest with your physician, if you seek smart pills via the medical route. Don’t sell or lend controlled drugs to others, even if you have a valid prescription.

According to the Al Fin Institute for Cognitive Enhancement, the best approach to becoming more intelligent is to invent a time machine, and travel forward in time to the Idiocracy. Compared to everyone else there, you will be an absolute genius!

More on an interesting approach to improving cognition

Stem cell and genetic engineering tweaks offer the best long term hope for smarter humans, in addition to better cognitive prosthetic devices.

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