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Improving Warfighter Alertness Safely Without Off-Target Effects
by Defense Advanced Research Projects Agency
June 7, 2024

Defense Advanced Research Projects Agency’s AWARE program aims to rapidly achieve peak cognitive function following sleep loss through the combination of pharmaceuticals and light.

AWARE combines photo-pharmacology with near infrared light to deliver therapy without side effects. (Image created by USA Patriotism! from Defense Advanced Research Projects Agency courtesy graphics.)
AWARE combines photo-pharmacology with near infrared light to deliver therapy without side effects. (Image created by USA Patriotism! from Defense Advanced Research Projects Agency courtesy graphics.)

Active-duty conditions may lead to sleep loss, which can impair warfighter alertness and performance. Current state-of-the-art approaches for maintaining alertness following sleep deprivation include the use of drugs such as caffeine, and for U.S. military personnel undergoing long-duration training or missions, prescription stimulants, such as dextroamphetamine, may be prescribed.

These stimulants have been shown to improve performance on vigilance tasks, alertness, and cognitive performance, but they can also negatively impact mood, have the potential for addiction, and may demonstrate a long circulation time in the bloodstream, which can negatively impact sleep. Over time, a cumulative lack of restorative sleep can adversely impact not only warfighter alertness and cognition, but also metabolic, immune, and mental health.

Combining light simulation and photo-pharmaceuticals ... a category of drugs that are only active in the presence of certain types of light ... to target specific brain circuits, DARPA’s Alert WARfighter Enablement (AWARE) program aims to safely stimulate brain function to improve alertness for a controlled time period. The AWARE program seeks to develop a combination drug and device to non-invasively increase alertness following sleep loss in humans, without negative side effects such as anxiety, irritability, or euphoria, and with reduced addictive potential.

“To achieve the beneficial effects of stimulants on alertness without the undesirable effects of the stimulant on mood, restorative sleep, and mental health, a new approach is needed to enable targeted activation of the drug,” stated Dr. Pedro Irazoqui, AWARE program manager. “AWARE aims to achieve this goal by modifying currently approved prescription drugs to make them photoswitchable ... to have the ability to change using light ... and to develop wearable light emitters to rapidly activate those drugs in a localized area.”

The goal is to design a new photoswitchable stimulant that while active, behaves in the same manner as regular, unmodified drug. Through non-invasive delivery of near-infrared (NIR) light to specific areas of the brain, the combination of this photoswitchable stimulant and NIR-emitting light could selectively activate the drug and therefore the regions of the brain responsible for executive function, working memory, and decision making, while avoiding off-target effects. The program seeks to demonstrate that by selectively switching the drug from an active to inactive state, they can facilitate on-demand de-transition from alertness and make restorative sleep possible.

The AWARE program will include an ethical, legal, and societal implications (ELSI) plan to include discussions regarding human use of the technology following its development.

Defense Advanced Research Projects Agency (DARPA) | U.S. Department of Defense

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