The Skinny on Psychostimulants, Part 3: Modafinil
Over the past two weeks, we’ve been discussing the psychostimulants amphetamines and methylphenidate, which stimulate the central nervous system by increasing synaptic concentrations of the neurotransmitters dopamine and norepinephrine to varying degrees, and are used in pharmaceutical preparations primarily for treating ADHD, narcolepsy, obesity, and binge eating disorders. They are also used off label to treat cognitive dysfunction and depression in cancer patients and as part of a regimen in chronic pain patients, as well as being used recreationally to get high, study, take tests, improve focus, and/ or stay awake for extended periods of time. In this last installment on psychostimulants today, I’ll discuss a popular drug called modafinil.
While modafinil isn’t technically a psychostimulant, it acts “stimulant-ish,” and ultimately elicits similar effects as its stimulant brethren. It actually belongs to a class of drugs called eugeroics, which are wakefulness-promoting agents, and is also considered a nootropic. Nootropics are “smart drugs,” substances that can enhance brain performance or focus. Strictly speaking, the term nootropic is generally reserved for prescription and over the counter (OTC) pharmaceuticals and supplements that are not taken therapeutically to treat a particular illness, but rather to enhance cognitive function in healthy individuals beyond what is usually considered “normal” in humans. Nootropics or smart drugs can alternatively be referred to as performance enhancers or pharmacological cognitive enhancers (PCE’s). To cover all the bases and avoid ticking off the biohackers, I suppose you could call modafinil a nootropic eugeroic. Whatever!
Originally synthesized in France in the 1970’s, modafinil was approved by the FDA in 1998 and is used primarily to treat sleep disorders, including narcolepsy, shift-work sleep disorder, and residual/ excessive sleepiness in obstructive sleep apnea despite continuous positive airway pressure (CPAP).
It is used recreationally to increase focus and learning, for cognitive and physical performance enhancement, and to stay awake for extended periods of time. Modafinil is taken by mouth, usually once a day. Most people who work during the day take it in the morning on either a full or empty stomach, but shift workers who take it to promote wakefulness do so before their shifts begin. Modafinil is marketed under the trade name Provigil, while its R-enantiomer armodafinil is marketed under the name Nuvigil. If you recall, enantiomers are mirror image molecules, like left and right hands, that generally induce similar pharmacological effects. Indeed, the two are used to treat the same disorders, but armodafinil is a newer compound and has a slightly different side effect profile than its older sibling modafinil. More on that in a moment.
Both forms are Schedule IV drugs, which defines them as having a low potential for abuse and low risk of dependence. Some other examples of Schedule IV drugs are benzodiazepines like diazepam and alprazolam. That said, while I concur that (ar)modafinil has a low risk of abuse and dependence, I beg to differ on the risk of abuse and dependence being comparable to benzos. In my experience, benzos are far more commonly abused, and the incidence of dependence on benzos far exceeds that of modafinil. However, while studies have not shown any significant withdrawal effects from discontinuation of modafinil, any drug that provides stimulant effects to the brain can enforce drug taking to some extent, and thus carry the potential for dependency, which could lead to withdrawal symptoms upon cessation. Anecdotally, people have reported reduced energy, lack of motivation, and depression following discontinuation of modafinil; therefore, modafinil should always be tapered when discontinued if it has been used for a long period of time.
I’ve found that modafinil carries a very low risk of side effects, and a very mild profile when present, one that may be comparable to having an extra cup of coffee. The most common side effects are potentially occasional minor headaches, possibly some jitters, and sometimes trouble sleeping, which is usually related to the time of dosing being too late. But the official list of side effects also includes: dizziness, upper respiratory tract infection, nausea, diarrhea, nervousness, anxiety, agitation, and dry mouth. For armodafinil, you can add upset stomach to the list and take away upper respiratory tract infection. Something you have to be aware of when taking modafinil are the synergistic effects of other stimulants. If you consume coffee, energy drinks, or anything with caffeine, you’re likely to have much stronger stimulating effects, and these may include jitters or anxiety. It is wise to avoid anything else meant to make you or keep you awake when taking modafinil, at least until you are aware of its effects on your system, and even then you should still use great caution. As with any medication, if you take other prescription or OTC medications, be sure to disclose them with your prescribing physician to discuss potential interactions. Modafinil has a half-life of 12 hours, meaning that after 12 hours, the effects will start to wear off, but half of the drug will still remain in your system.
Modafinil’s off label and “lifestyle” use in healthy individuals to stay awake for extended periods of time and increase cognitive alertness and physical performance is well documented and likely exceeds its therapeutic utility as far as numbers go. In some professional groups such as pilots, academics, and scientists, modafinil use is reported in the ballpark of 20 to 30 percent; but I’d like to note that that is the reported use, not actual use, which I think is significantly higher, given how available it is on the internet. Modafinil’s popularity among college students, athletes, and the Silicon Valley techie set isn’t exactly a state secret, but its use among the military literally was until confirmed relatively recently. The US Armed Forces tested modafinil in improving performance despite sleep deprivation and in combating pilot fatigue; in fact, at one point, we led the world in military research on modafinil. I happened to catch part of a television show over the holidays that mentioned modafinil studies in Air Force fighter pilots. The show stated that it induced vigilance (aka kept them awake) for 40 hours, which, the show mentioned, is apparently a desired effect during times that necessitate flying to Iraq quickly. Now, I’ve never flown to Iraq, much less in a fighter jet, but I can’t imagine that it takes 40 hours to get there… but you get the point. If you were exhausted, but needed to get to Iraq all quick like, modafinil may be the compound of choice.
Of course, I had to look into these studies. Captain Obvious says that Uncle Sam has been “officially” dosing our Armed Forces for years, so modafinil is just another in a long line of compounds. I’ve had many patients that were/ are members of the US military, and I’ve been told of the sanctioned use of various drug combinations in all branches of it: hypnotics to induce them to sleep before a mission, followed by stimulants (in the form of dextroamphetamine) “go pills” to switch them back on just before, at “go time.” As far as modafinil is concerned, the experiments relating to sleep deprivation seem pretty ambitious, testing for 40, 60, or even 90 hours without sleep. In some journal articles, scientists speculated that with modafinil, troops might function for weeks(!) on as little as four hours of sleep a night.
Back to fighter pilots: in the study I looked at, Air Force scientists looked at the effects of being awake for 37 hours on pilot alertness and flight performance; this was evaluated through simulator tests repeated every five hours to track the pilots’ level of fatigue. The same experiment was conducted with and without modafinil, and also in a rested state without modafinil for comparison. What did they find? While on modafinil, the pilots’ performance significantly improved, especially at time points after 25 hours without sleep, and the pilots sustained brain activity at almost normal levels despite their sleep deprivation. Further, while under the influence of modafinil, flight performance degraded by 15 to 30 percent. Now that doesn’t sound great, until you consider that performance by pilots without modafinil (and without sleep) degraded by 60 to 100 percent (hell-ooo!!) as compared to rested levels. All of the findings led researchers to conclude that modafinil “significantly” reduced the effects and impacts of fatigue during flight maneuvers, even though sleep deprived pilots on modafinil were unable to maintain the same performance as they exhibited during a rested state off of modafinil. I’ll say… Degraded by 60 to 100 percent?! Bottom line: clearly, if a pilot can’t get sleep, they should get modafinil. Ultimately, they stated that until more research is done, a 100 mg dose of modafinil is viewed as an option to, but not a replacement for, a 10 mg dose of dextroamphetamine.
All of that said, most of us are not fighter pilots, much less operating a complicated machine at mach speed and 50,000 feet, under stress, and sleep deprived… and thankfully so. Most of the people that ask me about modafinil are everyday people looking to focus better at work, get excellent scores on SAT’s to get into a great school, win a medal or a pro poker tournament (pro poker players love modafinil) or maybe beat out somebody at work for a promotion. In my experience, for all of those things and more, modafinil is a safe and effective tool, and lots of folks want it in their tool box. It’s been around long enough to have some significant studies done; all findings echo my experience, and one another: it works well and nobody’s dropping dead at their desks.
The University of Oxford and Harvard Medical School conducted a formal review of all research papers on cognitive enhancement with modafinil in non-sleep-deprived individuals, dated from January 1990 to December 2014. They found and evaluated 24 studies, which included more than 700 participants total, dealing with different benefits associated with taking modafinil, including planning and decision making, flexibility, creativity, and learning and memory. They also surveyed overall performance enhancing capabilities and side effect reporting. Findings were as follows:
Modafinil made no apparent difference to working memory or flexibility of thought, but did improve executive function, the ability to sift through new information and make plans based on it.
As to side effects: (70 percent the of 24 studies looked at the effects of modafinil on mood and the side effects of modafinil) In those where side effects were studied, there were very few side effects overall, although a very small number reported insomnia, headache, stomach ache, or nausea, but these were also reported in the placebo group, meaning those who were unwittingly given a “sugar pill” with no biological action.
As to overall performance enhancing capacity of modafinil: this was found to vary according to the task; the longer and more complex the task tested, the more consistently modafinil conferred cognitive benefits.
Modafinil clearly and reliably enhanced cognition, especially in higher brain functions that rely on contribution from multiple simple cognitive processes.
Some snippets of findings from other studies:
“It has been shown to increase resistance to fatigue and improve mood.”
In healthy adults, modafinil improves “fatigue levels, motivation, reaction time and vigilance.”
Modafinil is effective at reducing “impulse response,” meaning it reduced the incidence of poor decision making.
Modafinil “…improved brain function in sleep deprived doctors.”
Modafinil “enhanced the ability to pay attention, learn, and remember.”
There is some evidence that modafinil only helps people with lower IQ, but I read validated accounts of years of use associated with validated corresponding increases in IQ, though this could theoretically be due to other unrelated factors.
How Does Modafinil Work?
Scientists haven’t gotten it all figured out quite yet, but like the psychostimulants we’ve already discussed, modafinil increases the production of norepinephrine and dopamine in the CNS, the neurotransmitters linked to emotional well being, motivation, memory, and focus. At the same time, modafinil may also reduce the production of neurotransmitters that are known for blocking communication between neurons. It also increases the production of histamine, which increases the oxygen concentrations travelling to the brain, making you more awake, or so it’s theorized. Just as the anti-histamine Benadryl dampens histamine and puts some people to sleep, modafinil boosts histamine levels, which has a tendency to wake you up and increase alertness. If you’ve ever had an acute allergy, especially an anaphylactic reaction, and experienced the typical increase in heart rate and blood pressure associated with it (which is also associated with wakefulness and alertness) then you’ve felt the acute effects of excess histamine production. Obviously, modafinil doesn’t cause this level of histamine release, that’s just an explanation of how the release of histamines from taking modafinil are thought to cause a feeling of wakefulness or alertness: from the increase in heart rate and blood pressure associated with their release. Though scientists aren’t exactly sure how it works, they have elucidated that modafinil also enhances several other CNS neurotransmitters, including serotonin, glutamate, and GABA.
The Ethics of Modafinil Use
Pharmacological cognitive enhancers (PCE’s) like modafinil may be used to treat cognitive impairments in patients, but they are more commonly used by healthy individuals in an effort to improve focus, stay awake and alert for extended periods of time, and boost mental and physical performance. This lifestyle use of modafinil by healthy people is increasing, and in fact, it appears that it far exceeds the therapeutic use of modafinil for cognitive impairment and sleep abnormalities. As it enhances cognition and has effects on attention, learning, memory, planning, and problem solving, this lifestyle use raises a number of ethical issues.
In societies and populations that foster or encourage academic and professional competition, access to knowledge about how to gain a competitive edge and how to perform better in the workplace is a valuable commodity, but not one that tends to be equally distributed across all social groups. As modafinil rises in popularity, will we soon be locked in a productivity arms race, pounding out after-hours spreadsheets with one hand while Googling “latest nootropic advancements” with the other? Some sports organizations already ban the use of prescription psychostimulant drugs- including methylphenidate- without an official ADHD diagnosis, for the same reasons they ban steroids and other performance enhancing drugs. Will employer drug screens soon test for off label modafinil use in an effort to avoid its presence in the workplace? Or will the opposite be the case; will CEOs welcome super sharp workers who never need sleep? Think about the Bezos’ and the Musk’s of the world… will they be adding modafinil to the water coolers?
Considering modafinil’s popularity, you can be sure that more cognitive enhancing drugs are right around the corner. Will everyone be able to compete? What if you can’t get access to a cognitive enhancer, can’t afford it, or can’t take it due to negative interactions or side effects… are you destined to be stuck in a dead end job or hit an impenetrable corporate ceiling while you watch your friends and co-workers climb the corporate ladder? How about your kids? If you think things are competitive now… just wait ten years. Will they be able to get into a good pre-school without putting modafinil or some other enhancer in their kool-aid, or juice, or whatever you’ll put in their sippy cups? Seriously, will they be able to compete… to get into a good school without cognitive enhancement? In a cognitively enhanced society, what happens to the benefits and self-satisfaction of earning something by the sweat of the brow… especially when that’s just. not. good. enough? Could this lead to a devaluation of hard work and generate less engagement with the world? And if so, what happens to a society where few people see the value of civic work or doing something for the greater good rather than getting ahead? These won’t be hypothetical questions for very long. How about things less under our direct control? Will the FDA save us by prioritizing drugs that preserve lives, or will they bow to pressures from big pharma to prioritize drugs that will undoubtedly be more popular among healthy individuals, have a far larger market, and make more money?
Hey people… these are things to think about. Don’t shoot the messenger.
In situations where there is a deficit in performance due to sleep deprivation or fatigue, a medical diagnosis, or learning disorder, there’s no doubt that modafinil can even the playing field. But what about in “normal” healthy individuals? Proponents of modafinil use in healthy individuals argue that it reduces fatigue-related and work-related accidents and improves learning outcomes; in other words, it’s a good thing, so use it. But when it comes to “enhancement” or “optimization” of performance, do the ends always justify the means? To use a sports analogy, does enhancement corrupt the “rules of the game”? If so, does it make the game pointless? Or is enhancement or optimization a slippery slope that leads to the desire to “perfect” human beings? The increase in medical options available to affect human characteristics and abilities over recent decades certainly offers more options to do so, but the desire to want to do so is hardly novel. The difference is that now we’re getting much closer to being able to actually do it. The door is open, and people are walking through it. Some people are running through it. But can we ever turn around to get back to where we were if/ when we find we don’t like what’s on the other side? What happens when average abilities become less the norm, and more of a negative exception… would average people feel fundamentally inadequate?
The ethical implications of the use of modafinil in particular, and smart drugs in general, has become one of the biggest issues in neuroethics and bioethics; it’s got ethics nerds everywhere red faced and arguing, and it’s certainly a favorite topic in the popular media as well, with tons of hype. What about the ethics of biohacking, using any and all, drug and non-drug technologies to improve cognition; ie training and nutrition to boost brainpower, and/ or the application of transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), or brain-computer interfaces (BCI)? There are plenty of biohackers out there- do they have an unfair competitive advantage, or is it mostly acceptable, because a lot of it requires at least more effort and dedication than just swallowing a pill? If most people biohack themselves in order to become cognitively superior, when is superior… superior enough? There could be serious ramifications concerning attitudes towards conventional human abilities in the long term.
I certainly don’t suppose that I have the answers to these questions, but I know that I’m not the only one asking them. The last question I’ll pose that is still unanswered is: when will we be forced to confront all of the above questions… and then some? Because that day is coming. Of that, I have no doubt.
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