DARPA’s AWARE Program: A Leap Forward in Warfighter Alertness Post-Sleep Deprivation

The Defense Advanced Research Projects Agency (DARPA) has recently launched an ambitious initiative aimed at addressing a critical challenge for military personnel: maintaining alertness following sleep deprivation. The program, named AWARE (Advanced Wakefulness and Response Enhancement), seeks to develop a groundbreaking solution that combines a photoswitchable drug with a wearable device, offering non-invasive, on-demand alertness without the adverse side effects commonly associated with traditional stimulants.

The Challenge: Enhancing Alertness Without Compromise

Maintaining high levels of alertness and cognitive performance during extended wakefulness is essential for military operations. Current methods, such as caffeine and prescription stimulants like modafinil and dextroamphetamine, provide temporary boosts in alertness. However, these solutions often come with significant drawbacks, including mood alterations, euphoria, and a high potential for addiction. Additionally, the prolonged half-life of these stimulants can interfere with restorative sleep, leading to chronic sleep deprivation and its associated health risks.

Research has shown that dextroamphetamine outperforms modafinil and caffeine in enhancing vigilance after sleep loss. This drug boosts alertness and cognitive performance by increasing extracellular dopamine concentrations in the brain. However, despite its effectiveness, dextroamphetamine can have negative side effects, including increased irritability, which can impair team dynamics. Additionally, its euphoric effects pose a risk of addiction. The drug’s prolonged half-life of 10 to 12 hours can also conflict with mission schedules, as it impedes the ability to nap during downtime. Although sedatives may be used to promote sleep, they are often insufficient in counteracting the lingering effects of stimulants, preventing restorative sleep when needed. Over time, this cumulative lack of restorative sleep not only diminishes alertness and cognitive function but also negatively affects metabolic, immune, and mental health.

DARPA’s AWARE program is designed to overcome these challenges by creating a more controlled and selective means of enhancing alertness. The goal is to develop a photoswitchable version of dextroamphetamine—termed “PhotoDex”—that remains biologically inert until activated by near-infrared (NIR) light. This approach aims to provide the cognitive benefits of dextroamphetamine while minimizing its undesirable effects.

A Novel Approach: The AWARE Program

The AWARE program is focused on developing a combined drug and device solution to enhance alertness after sleep deprivation while minimizing negative side effects such as anxiety, irritability, euphoria, and addiction risk. To replicate the alertness-boosting benefits of dextroamphetamine without its adverse effects on mood, restorative sleep, and mental health, AWARE aims to create a photoswitchable version of dextroamphetamine, known as PhotoDex. PhotoDex remains inactive until activated by near-infrared (NIR) light. The program will also develop a non-invasive device that delivers NIR light to specific areas of the brain, selectively activating PhotoDex only where and when needed.

By combining the ingestion of PhotoDex with targeted NIR light emission, the AWARE technology will precisely stimulate neural pathways associated with executive function, working memory, and decision-making, avoiding deep brain regions like the amygdala and striatum that are linked to mood alterations and addiction.

Once activated, this photoswitchable drug is expected to function similarly to traditional dextroamphetamine. The technology’s temporal selectivity will allow the drug’s effects to be turned off by stopping NIR light exposure, with built-in kinetics ensuring the drug reverts to its inactive state. Additionally, the timing and duration of NIR light pulses can be adjusted to control the dosage of activated drug, enabling personalized treatment tailored to individual needs and mission requirements while further reducing side effects and addiction potential

The AWARE program’s strategy involves two key components:

1. PhotoDex Molecules: These are modified dextroamphetamine molecules designed to be biologically inactive in the absence of light. When exposed to NIR light within a specific wavelength range (750-900 nm), these molecules become active, targeting brain regions responsible for executive function, working memory, and decision-making. By selectively activating these areas, the program seeks to enhance cognitive performance without affecting deep brain structures associated with mood alterations and addiction.
2. Wearable NIR Device: A complementary wearable device will emit NIR light at 850 nm, capable of penetrating up to 1.5 cm into brain tissue. This device will be integrated into a headband or helmet liner, allowing military personnel to activate the drug on demand. The device’s design ensures precise control over the drug’s activation, limiting its effects to specific brain regions and enabling rapid deactivation when no longer needed.

Program Phases and Goals

The AWARE program is structured into three phases over a 36-month period: Phase 0 (15 months), Phase 1 (9 months), and Phase 2 (12 months).

• Phase 0 (15 months): This initial phase focuses on developing and testing PhotoDex molecules and the NIR-emitting device. The goal is to validate the ability of the NIR device to achieve the necessary spatial resolution and penetration depth in tissue-mimicking models. In Phase 0, the program is divided into two Technical Areas (TAs). TA1 focuses on developing and testing a photoswitchable version of dextroamphetamine, known as “PhotoDex,” which can be activated by near-infrared (NIR) light. Meanwhile, TA2 is dedicated to creating NIR-emitting devices capable of non-invasively penetrating up to 1.5 cm of tissue with high resolution. The teams in both TAs will work independently to demonstrate the capabilities of their respective technologies.
• Phase 1 (9 months): In this phase, the combined drug and device system will be tested in rodent models to assess its impact on cognitive performance during extended wakefulness. Preclinical safety and efficacy studies will also begin. Phase 1 combines the efforts of TA1 and TA2 teams to conduct in vivo behavioral tests on rodents, evaluating the cognitive effects of NIR-activated PhotoDex following sleep deprivation. This phase aims to compare these effects with those of standard dextroamphetamine and placebo controls.
• Phase 2 (12 months): The final phase involves completing preclinical studies, integrating the system for human use, and securing regulatory approval for a first-in-human study. DARPA plans to transition the technology to a government partner for further testing and potential deployment. Phase 2, teams will transition towards human studies by conducting preclinical safety and efficacy trials, integrating the NIR devices for human use, and pursuing regulatory approvals through the FDA.

Ultimately, the program intends to transition the technology for first-in-human trials, assessing the potential of non-invasive NIR-activated PhotoDex to enhance cognitive performance during extended wakefulness.

Phase 0 Goals and Metrics: Phase 0 sets specific goals and metrics for TA1 and TA2. TA1 focuses on designing and synthesizing PhotoDex molecules that are biologically inert in the dark but can be activated by NIR light (750-900 nm). Successful candidates must demonstrate activation of at least 50% of molecules under continuous NIR illumination and maintain minimal activation outside this wavelength range. TA1 also includes pharmacokinetic studies to ensure the PhotoDex molecules’ behavior is comparable to standard dextroamphetamine. Animal subject research protocols must be approved by relevant committees to proceed with in vivo testing.

TA2 is tasked with developing NIR emitter elements that can be integrated into wearable devices, such as a headband or helmet liner. These devices must deliver NIR light effectively to specific brain regions, achieving the necessary penetration depth and spatial resolution. The emitters should be lightweight, compact, and capable of continuous operation for extended periods. TA2 teams will collaborate with TA1 teams to ensure the integration of NIR devices for Phase 1 rodent experiments.

Phase 1 and 2 Goals: Although the current solicitation only addresses Phase 0, subsequent phases aim to refine and expand on the initial work. In Phase 1, teams will test the efficacy of NIR-activated PhotoDex in improving cognitive performance in rodents, with a target of at least a 15% improvement in cognitive tests compared to control conditions. Phase 2 will further optimize these parameters and aim for at least a 30% improvement in cognitive performance and recovery sleep post-PhotoDex inactivation. FDA approval for human trials will be a critical objective, with the ultimate goal of transitioning the technology to a government partner for first-in-human studies.

The Road Ahead

The AWARE program represents a significant leap forward in the field of cognitive enhancement, offering a solution that balances the need for heightened alertness with the imperative to avoid harmful side effects. By enabling precise, on-demand activation of a stimulant drug, this approach could revolutionize how military personnel manage sleep deprivation, ultimately enhancing their performance and well-being in high-stakes environments.

As the program progresses, DARPA’s innovative approach may pave the way for broader applications, potentially benefiting not only military personnel but also civilians in professions requiring extended periods of wakefulness and alertness. The success of AWARE could mark a new era in cognitive enhancement, where technology and pharmacology converge to support human resilience and performance.