Limitless is a film about Eddie Morra, a man who just wants to do his best. He’s ingesting a smart drug, or nootropic, named NZT-48 to take his cognitive abilities to the next level. His new powers propel him to soaring heights as he learns languages, discovers the grand formula of the stock market, and fights the bad guys with ease. Despite a handful of scientific inaccuracies, this action-packed techno-thriller is definitely fun to watch. However, long after the popcorn aroma has wafted away, curious filmgoers may continue to ponder if a nootropic of this magnitude is even possible. Could a single drug ever produce these kinds of results? Probably not. If such a drug existed, it would have to overcome the natural limits of the human brain. In our Body Version 1.0, drugs can only enhance cognition to a point, because they work within a preset biological framework. Right now, our gray matter is not so limitless, and cosmetic pharmacology – using drugs for the betterment of well people – can only take us as far as our brains will allow.

Is NZT For Real?

The trailer above is riveting, and the make-believe drug commercial makes for a good laugh. Nonetheless, nitpicking brain scientists could be mildly irked by the movie’s claims. Take NZT’s proposed mechanism: “You know how they say we can only access 20% of our brain? This lets you access all of it.” Either this claim is a clever marketing trick by the film’s underground pharmacist, or he simply doesn’t know that this is a well-known myth in that scientific community. The drug’s faux promotional website elaborates on the mechanism of action, suggesting that it works by increasing synaptic serotonin and norepinephrine. However, there are already drugs on the market that accomplish this, and none of the patients prescribed these medications for depression exhibit superhuman powers. The website also claims NZT increases inter-modular communication among the hippocampus, amygdala, and striatum. This would essentially increase activation of the limbic system and basal ganglia, systems primarily linked with emotionality/new memory coding and motor function, respectively. I highly doubt that a drug could cause the effects seen in this film without modulating the neocortex – the brain structure implicated in higher order thought processes. Promotional NZT was sent to a select group prior to the film’s release, so maybe they could prove me wrong.

Okay, we get it, Jeremy. NZT is make-believe. This is a movie, not a manuscript open to scientific peer-review. Alright, alright. But the more fundamental question still looms. Could any drug endow the user with near god-like mental capacities? Don’t get your hopes up, folks. To begin illustrating my point, check out a few deceptive shortcuts shown in the table below. In the film, Eddie Morra nearly dies from NZT withdrawal. As you can see, these nootropics also have a dark side. Warning : Singularity Hub in no way condones the use of these substances without the consent of a prescribing physician.

Receptor Promiscuity

Due to some dangerous side effects, it’s easy to “just say no” to the nootropics in the list above. This arises from the fact that pharmacological intervention is always “dirty” in a sense. To quote Dr. Henrik Dohlman, a professor of biochemistry and biophysics at UNC-Chapel Hill, “No drug is 100 percent effective, 100 percent free of side effects, and 100 percent safe.” For example, consider a compound that targets your run-of-the-mill serotonin receptor. After crossing the blood-brain barrier, it exerts non-specific effects by hitting multiple receptors and receptor subtypes in different regions of the brain. This reminds me of a variation of Abraham Maslow’s maxim, “If you only have a hammer, you tend to see every problem as a nail.” In pharmacology, you have a hammer, but you don’t know if you’re hitting a nail, a screw, or Bigfoot (yet to be discovered drug targets). Even worse, it’s hard to determine what it means on a circuit or systems level if you hit all three.

Limitless appropriately highlights the inherent safety issues with drugs when Eddie Morra “skips frames” and cannot account for a whole day of his life after mixing alcohol and NZT. However, given the promiscuous nature of receptor binding, it would be extremely difficult, if not impossible, to tease apart and enhance cognitive processes to the extent seen in this film with a single compound. In the history of psychopharmacology, boosting a distinct neural circuit or brain faculty with full efficacy, while leaving others untouched, has never been achieved.

Homeostasis and Neuroplasticity

Besides problems with receptor promiscuity, rebound effects present additional challenges in nootropic development. The body is inclined to homeostasis, fluctuating around a set-point to maintain biochemical balance. This principle is no less true in the brain. Ask any methamphetamine user about the drawbacks of tweaking, and they will invariably mention the ensuing “crash” – an anhedonic state characterized by dysphoria and soul-sucking ennui. In Limitless, NZT’s crash is potentially fatal. It appears that the farther you stretch the brain past its evolutionarily determined set-points, the harder it snaps back.

Some may object to my claims of a static set-point by calling attention to neuroplasticity – the ability of the brain to restructure itself. In the film, Eddie Morra eventually weans himself off NZT, using the drug as a catalyst to induce long-lasting cogno-enhancement. Indeed, the brain can self-sculpt through neurogenesis and synaptogenesis, but there are upper bounds to this phenomenon in the adult brain. It’s highly unlikely that the cortex and language centers of the brain could rewire at a rate high enough to learn Mandarin, French, and Italian in a matter of days, as portrayed in the movie. Yes, the brain can change, but not that quickly. Furthermore, drugs that transiently enhance mood or cognition do change the brain, but not for the better, as in the case of cocaine addiction. Clearly, taking psychoactives to reboot your neural equilibrium is not a feasible path to god-like intelligence.

Future Neuro-Enhancement and Mind-Hacking

Due to the safety problems, rebound effects, and physical limitations, conventional nootropics are impractical as long-term, effective brain enhancers. So how can neuro-engineers circumvent these issues? The goals, of course, must be circuit specificity and the persistence of enhanced abilities over time. There has already been progress on the specificity front with deep-brain stimulation (DBS) and the TMS thinking cap. DBS is relatively high resolution, but this invasive technique is intended for Parkinson’s and severe depression patients, not for brain-boosting the well. TMS is less neuro-specific than DBS, but it’s practically risk-free. However, this technique is still in the tinkering stages.

For long-lasting enhancement, targeted gene therapy may provide solutions. For example, increasing NR2B expression in the hippocampus could improve learning, as it has in the genetically-modified doogie mouse. Of course, cosmetic gene therapy is years away, and we’ll have to change much more than one gene for the best results.

In addition to manipulating genes, future neuro-engineers may find that the physical and computational limits of neurons to be sub-optimal, and theycould seek to either supplement them with BCI or replace them with artificial neurons. These technologies, while promising, are still at the dawn of their development, and they are far from human cogno-enhancement applications. While these technologies are limited right now, it seems machine interfacing and bio-engineering could be the only means of making us truly limitless.

In mean time, as avid Hub followers should know, you can build your cognitive prowess without pharmacological or technological intervention. Firstly, start by getting plenty of sleep every night and exercising to increase hippocampal volume. If you find the improvement negligible, try meditation, which has been shown to attenuate stress-induced cognitive deficits. You could also master the art of mnemonics to broaden your memory capacity several fold. Forward-thinking futurists may refer to this as “mind-hacking,” but these tricks are nearly as old as civilization itself.

To Enhance or Not to Enhance

Despite the potential of neuro-enhancement, bio-conservatives argue that we should stick with these “natural” means of improving cognition, leaving the smart drugs, genetic engineering, and BCI to science fiction. There are also those who compare smart drugs to steroids, claiming it’s unethical to use any substance as a performance enhancer. If taken to boost an SAT score, then I would agree. However, to both bio-conservatives and performance ethicists, I say there are scenarios where it’s morally imperative to utilize neuro-enhancement, especially when it could reduce suffering in the world.

How, you say? While athletic performance can uplift a nation (as seen in the film Invictus), cognitive performance can bring about novel insights about the world. As we’ve covered, brain-doping is already common in scientific circles. There’s even speculation that Francis Crick envisioned the double-helix structure of DNA on LSD, and fellow Nobel Laureate, Kary Mullis, outright admitted that the drug influenced the development of PCR. Undoubtedly, the downstream fruits of these platform biotechnologies have the potential to reduce suffering on a global scale. If you “cheat” to hasten trailblazing discoveries, through drugs or other neuro-enhancements, should you be condemned and vilified? With any luck, we’ll reach consensus on this issue by the time safe, effective, and reliable cogno-enhancers enter the scene. Until then, feel free to call me a pharma-fuelled fraud for a stimulating nootropic – a double-shot dirty chai – expedited the writing of this article. Guilty as charged. Now pass the NZT!

<Images: Virgin Produced (modified), Wikimedia Commons>

<Videos: Virgin Produced>

<Sources: Virgin Produced, Erowid, Essential Psychopharmacology>