THESE BRAIN-ENHANCING DRUGS CLAIM TO MAKE YOU MORE CREATIVE—BUT DO THEY WORK?

Daniel Kunitz

In the early 1960s, a Romanian chemist and psychologist named Dr. Corneliu E. Giurgea synthesized a drug called piracetam. He was working at a pharmaceutical company in Belgium, where he was attempting to concoct a calming drug that would induce sleep. Instead, piracetam was initially used to treat motion sickness. Along the way, Dr. Giurgea found that it had distinctive and useful properties, namely the enhancement of mental faculties.

In 1972, he coined the term “nootropics” (combining the Greek words for “mind” and “to bend” or “to turn”) to identify drugs like piracetam, that, he wrote, “selectively improve efficiency of higher telencephalic integrative activities”—which is a rather garbled way of saying they make you smarter.

For a substance to count as nootropic, Giurgea stipulated in a 1977 paper that it must, among other things, foster “enhancement of learning acquisition,” aid in “resistance to impairing agents,” promote “enhanced resistance to brain ‘aggressions,’” and cause none of the “usual pharmacological effects of neuro psychotropic drugs.”

Today, there are countless substances casually referred to as nootropics or “smart drugs” that don’t meet all of the criteria Giurgea set out; in fact, it’s not clear that any substances can, for instance, protect the brain from disease, pollution, or other “aggressions.” But you can buy—legally, on the internet—any number of chemical cocktails marketed as nootropics, from phosphatidylserine to Bacopa monnieri to other racetams (the class of substances to which piracetam belongs) like aniracetam and oxiracetam. The marketing hype for these drugs—and they are classified as either supplements or drugs by the Food and Drug Administration (FDA)—includes improved memory, concentration, and focus, as well as mood elevation.

Do they live up to the hype? Many of the experts I reached out to, including Dr. Anjan Chatterjee, professor of neurology at Pennsylvania Hospital, wrote back saying that they were unaware of convincing data demonstrating that nootropics enhance cognition. Then again, Dr. Murali Doraiswamy of Duke University, where he is a professor of psychiatry and behavioral sciences, doesn’t go quite so far in his skepticism. The evidence, he said, is modest. “The rigorous, randomized trials for most of these nootropics were done in the ’60s, ’70s, and ’80s,” he said. “And many did meet statistical significance, but most were a bust in the sense that the effect size was not felt to warrant an FDA indication to clear the hurdle for getting them approved. That’s why piracetam and others were no longer developed as prescription drugs.” Today they are sold, quasi-legally, as supplements.

The dream of boosting brain power and creativity with technology is probably as old as the first stone-flaking tools. When nootropics came on the scene, it was mostly athletes, gunning for a performance advantage, who took an interest. In the years between then and now, when the fervor for experimenting with smart drugs comes primarily from the cognitive athletes of Silicon Valley, many new nootropics have been developed: The racetam class has, for example, been greatly expanded. Our definition of smart drugs has broadened somewhat, too. People today are using psychedelics (like LSD and psilocybin) and stimulants in the quest to improve cognition, and there is no doubt that such drugs work, in the sense that they have profound effects. But do they improve creativity or how we think?

According to Dr. Doraiswamy, the drugs with the “most convincing” evidence for cognitive enhancement are the common pick-me-ups nicotine and caffeine, and the dorm-room staples modafinil (which is sold under the brand name Provigil), amphetamines (like Adderall), and piracetam. If, he continued, you want to look at herbs, there is “some evidence” for the effectiveness of ginseng and ginkgo biloba. When it comes to vitamins, he noted, there is very little evidence. “We know vitamin deficiency affects cognition, but there’s very little evidence that vitamin supplementation in otherwise healthy people improves cognitive performance,” he said.

Dr. Doraiswamy also surmises that microdosing psychedelics likely confers some cognitive benefits, but, he said, “we just haven’t found the right dose. And I think that if you can find the right dose of psychedelics that give you a little bit of the psychedelic stimulation, then I think it has tremendous potential to expand creativity.” He laments the fact that the U.S. government has put up large barriers to conducting research into these brain kickers. (In the U.K., the first-ever study into the effects of microdosing LSD began in early September 2018.)

Although there are no legal barriers to studying the non-narcotic smart drugs, the research—especially on healthy people—is scant. In fact, most studies of what we call nootropics have been conducted on cognitively impaired populations. For instance, a 2004 review concluded that while piracetam “may enhance memory and other intellectual functions,” the evidence was not robust enough to recommend using it as a treatment for dementia or cognitive impairment. Similarly, a 1994 overview of recent studies concluded that another popular racetam, aniracetam, “may be of benefit” to elderly patients with “mild to moderate cognitive impairment due to senile dementia.” A study from 2010 found that phosphatidylserine improved the memory of elderly, cognitively impaired patients, while other research suggests that the nootropic herb Bacopa monnieri enhances the cognitive performance of elderly people.

Still, the fact that the research tends to focus on people with cognitive impairment shouldn’t be entirely concerning. Importantly, as Dr. Doraiswamy noted, new tests would need to be developed to measure how a nootropic affects a person without cognitive impairments. “We’re all on a continuum,” he explained. “If someone’s already at a ceiling on those tests, then it would be harder to show an effect. So, you have to develop new kinds of tests where the cognitively normal person is not already maxing out in order to be able to show improvement.” He acknowledged that the fact that nootropics have had a modest effect on cognitively impaired people may mean that they could have an effect on cognitively normal people. By way of comparison, he offered, “the same amphetamine that improves attention in ADHD does improve attention in normal people.”

The problem, it seems, is not in the examined populations, but in how little we really know about these substances. We know quite a bit about amphetamines, yet what we know is that they can be dangerous and addictive, with hazards ranging from high blood pressure to seizures to heart problems. We know far less about the less thoroughly investigated, over-the-internet nootropics. The side effects have never been well-researched, Dr. Doraiswamy cautioned, “because most of the clinical trials have been either very short or in small samples, and the emphasis has been on finding positive benefits, so side effects go under-reported.”

Knowing the potential side effects of individual compounds isn’t enough, however, since the cutting edge of smart-drug usage is in stacking, or consuming these drugs in various combinations. There has been virtually no research into the possible dangers of combining nootropics, so we have little idea where the pitfalls of traveling that path lie. According to Dr. Doraiswamy, what we need is “an independent agency, like the FDA, to assess the quality, run the trials, and give a thumbs up or a thumbs down, because right now you can’t believe the claims that anybody makes,” he said. “You can order all these stacks from various start-ups, but the marketing claims far exceed the scientific evidence. And what people don’t realize is that sometimes when you combine five things that individually are really good, they can cancel each other out or worse, they might have adverse reactions. It’s the wild west, user beware.”

He adds a final caveat. “The brain could be what we call a zero-sum game, so if you’re enhancing one cognitive ability, the resources may need to be drawn from another cognitive ability,” he hypothesized. “That’s why when, for example, you’re driving and need to focus, you turn down the music. That’s why, also, people who train their memory and become memory champions are not necessarily great in other areas.”

Creativity, it turns out, is a symphony rather than a solo act. According to the latest theory, it requires the simultaneous interplay of three brain networks: the default mode network (our idle mode, as in when we daydream), the executive control network (which, among other things, directs attention and decisions), and the salience network (which determines what stimuli matter to us). However, tools like smart drugs are specific; they operate on one thing at a time, meaning that even if you find a drug or an herb that has some positive effect on one or two brain functions—sharpening your recall a bit, say, or extending your attention span—you may be suppressing another, like spontaneous rumination or your ability to seize on just the right detail.

Whether we can turn up the volume on the whole orchestra, rather than cueing one instrument at a time, may just be a matter of finding the right stack or the perfect dose of acid. But for now, the jury isn’t just out—one hasn’t even been picked.

Daniel Kunitz

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