DARPA develops light-activated drugs to keep pilots alert

We all know this: a tight deadline, a night shift and the next day we struggle through life like zombies.

For fighter pilots, the last step is not an option. While on active duty, these pilots must be mentally at their best, even if they are sleep deprived (which is common). Usually, treatment consists of a cup of coffee. However, if sleep deprivation is prolonged, pilots are also prescribed stronger stimulants.

But as anyone who has ever had too much caffeine knows, there are side effects. You get nervous. Your hands start to shake. Your mood sinks as the effects wear off and irritability sets in. And then you collapse.

Prescription stimulants like dextroamphetamine have even more serious side effects. As the name suggests, they are in the same family as methamphetamine – or “meth” – and carry the risk of addiction. These drugs stay in the body longer, so when you try to fall asleep after a hard day, they keep parts of the brain in a half-awake state, disrupting sleep patterns. People who take dextroamphetamine often need sedatives to combat the aftereffects, and the chemical treatment takes its toll.

Over time, lack of restful sleep impairs memory, cognition and thinking skills. It also damages the immune system, metabolism and overall health.

The drugs work in short bursts. What if there was a way to turn them on and off at will – giving the brain just a tiny dose when it needs it and quickly turning the effects off again to allow a full night’s sleep?

One solution could be light-activated drugs. The Defense Advanced Research Projects Agency (DARPA) announced a project in June to develop such drugs to combat sleep deprivation in fighter pilots. So-called photopharmacological drugs would add a molecular “light switch” to drugs such as dextroamphetamine.

Pulses of light activate the drugs in parts of the brain when needed. Untargeted brain regions are not exposed to the active version and continue to function normally. Once the pilots are awake, another pulse of light turns off the drug, giving the body time to break it down before bedtime.

To make this vision a reality, the new Alert WARfighter Enablement (AWARE) project has two research strands. One will develop safe and effective dextroamphetamine that can be controlled with light. The second will focus on developing a type of wearable “helmet” that will direct pulses of light to the brain regions responsible for alertness and mental acuity.

“To achieve the beneficial effects of stimulants on alertness without the undesirable effects of the stimulant on mood, restful sleep and mental health, a new approach is needed that allows targeted activation of the drug,” said Dr. Pedro Irazoqui, AWARE program manager, in a press release.

Brain on alert

After a bad night’s sleep, the first thing most of us reach for is coffee. Caffeine, its active ingredient, is the most widely used psychoactive substance in the world. Over 80 percent of people in North America drink a cup of coffee every morning.

While this is also the solution of choice for most fighter pilots, several countries have developed far more powerful concoctions to keep their brigades awake. The most notorious of these is probably methamphetamine, which was first synthesized in the late 1800s. It is best known by its street names – meth, crank or speed – and was used in World War II to keep troops awake before being banned worldwide. Dextroamphetamine, a safer derivative, is currently prescribed to increase alertness and cognition. While effective, it can induce both irritability and euphoric effects – a recipe for potential addiction.

The Air Force has also approved other types of chemical drugs, such as modafinil, to combat fatigue. Studies in mice and humans have found that these drugs can improve many cognitive functions – for example, orientation in space, remembering multiple things, and increasing overall alertness even when severely sleep deprived. Unlike amphetamines, this class of drugs is not as addictive, and its effects are comparable to drinking about 20 cups of coffee without the jitters. However, they can cause throbbing headaches, sweating, and in rare cases, hallucinations.

Light-activated drugs could be another option. These drugs were originally developed for cancer treatment and have a molecular “light switch” component that responds to pulses of light. The switch can be attached to conventional drugs, making it easy to adopt existing drugs such as dextroamphetamine.

The “switch” component changes the shape of the chemical after being irradiated with light of different wavelengths. As with transformers, one form allows the chemical to bind to its usual targets – the “active” state. Other configurations inactivate it.

Light-activated drugs have been tested on cells in petri dishes, but targeting them in the brain presents one hurdle – the skull. Shining a flashlight on the skull obviously doesn’t reach the brain, and invasive brain surgery is out of the question.

There is a solution, however. Low-dose infrared light rays are safe for humans and can penetrate deep into tissue, including through the skull and into the brain. A previous study developed several potential switches that could be turned on with infrared light. And recent advances in artificial intelligence may further aid efforts to develop “a photoswitchable version of dextroamphetamine that is active only in the presence of near-infrared light that activates it,” DARPA wrote.

The other component is a programmable light helmet that sends infrared light to the parts of the brain responsible for alertness, reasoning and decision-making. Over time, the stimulation could be personalized so that people receive only the necessary “dose” to stay awake.

This strategy still floods the brain with stimulants in the form of a pill, but limits the drug’s effects in time and space. With individually adjusted dosages and light as a regulator, this could result in alertness without anxiety, irritability or euphoria in any person. Turning off the drug also allows the brain to “unwind” during a restful night’s sleep.

A three-year plan

AWARE is scheduled to run for three years. DARPA is now accepting proposals that fit the program’s two goals, including developing a light-activated dextroamphetamine called “PhotoDex” that can be rapidly turned on and off in the presence of near-infrared light. All candidate drugs will first be validated in animal studies before being tested in humans.

For the headset, the project envisions a configuration that emits infrared light and reliably activates the necessary parts of the brain with millimeter-level resolution, roughly equivalent to an MRI-based brain scan. The time frame is about a year, and the agency has not provided details on how the headsets will be designed – for example, whether they will be wired or wireless, how they will be powered or what mechanism will turn on the light beams.

“The idea is very ambitious, but recent advances in the development of phototherapeutics and light-emitting devices give good reason to be optimistic,” said Dr. David Lawrence of the University of North Carolina, who is not involved in the project. New scientist.

So far, photoswitchable drugs are not approved for use in humans. If the AWARE program goes as planned, it could open a new avenue for targeted drug treatments not only to combat sleep deprivation but also other brain disorders. The project is aware of the ethical, legal and societal implications and plans to discuss the use of the technology.

Photo credit: US Air Force photo by 2nd Lt. Samuel Eckholm