New Clinical Trial Demonstrates Solriamfetol Enhances Alertness and Occupational Safety for Early Morning Shift Workers

While the traditional 9-to-5 workday remains the standard for many, a significant and growing portion of the global workforce operates during the pre-dawn hours, often starting their shifts between 3:00 a.m. and 7:00 a.m. This demographic, though more numerous than overnight workers, has historically been overlooked in clinical research regarding sleep health. A breakthrough clinical trial led by researchers at Mass General Brigham has now provided the first evidence that solriamfetol, a wake-promoting medication marketed as Sunosi, significantly improves alertness and functional performance in early morning shift workers suffering from shift work disorder (SWD).

The study, published in the journal NEJM Evidence, marks a pivotal moment in circadian medicine. For the first time, a pharmacological intervention has been rigorously tested specifically for those who begin their labor when the human biological clock is at its lowest point of alertness. The findings suggest that solriamfetol can mitigate the severe fatigue and cognitive impairment associated with early starts, potentially reducing the high rate of workplace accidents and commuting mishaps that plague this population.

The Hidden Epidemic of Early Morning Fatigue

Shift work disorder is a circadian rhythm sleep-wake disorder characterized by excessive sleepiness during work hours and insomnia when the individual attempts to sleep during the day. While public attention often focuses on the "graveyard shift" (midnight to 8:00 a.m.), the "early bird" shift is statistically more prevalent. Millions of individuals—including airline pilots, healthcare professionals, logistics workers, and transit operators—must wake up as early as 2:00 a.m. to begin their duties.

"Until now, no clinical trial had tested a treatment for shift work disorder in early-morning shift workers, even though this is the most common type of shift schedule," stated senior author Charles A. Czeisler, PhD, MD, chief and senior physician of the Division of Sleep and Circadian Medicine in the Mass General Brigham Department of Medicine. Dr. Czeisler noted that the study addresses a major gap in occupational health by focusing on workers who are often excluded from the "shift worker" label because their schedule is perceived merely as an early start rather than an overnight commitment.

The biological reality, however, is that waking up at 3:00 a.m. forces the brain to function during the "circadian trough"—the period when core body temperature is at its lowest and the drive for sleep is at its physiological peak. For many, this results in a persistent state of brain fog and reduced reaction times, which cannot be fully remedied by caffeine or willpower.

Clinical Trial Methodology and Chronology

The researchers at Mass General Brigham conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of solriamfetol. The study spanned several months and involved 78 participants who were diagnosed with shift work disorder and worked at least three early morning shifts per week.

The trial followed a strict four-week protocol:

1. Screening and Diagnosis: Participants underwent rigorous screening to ensure their sleepiness was a direct result of their work schedule and not underlying conditions such as untreated sleep apnea or narcolepsy.
2. Randomization: The cohort was divided into two groups. One group received a daily dose of solriamfetol on workdays, while the other received a placebo.
3. Controlled Assessment: Throughout the four weeks, participants were monitored using the Maintenance of Wakefulness Test (MWT), which measures an individual’s ability to remain awake in a dark, low-stimulation environment—a proxy for the monotonous conditions often found in early morning commuting or monitoring tasks.
4. Functional Reporting: Researchers utilized the Epworth Sleepiness Scale (ESS) and the Patient Global Impression of Change (PGI-C) to track subjective improvements in daily life and work performance.

The trial concluded with a comprehensive analysis of both objective sleep latency data and subjective reports from both the participants and their supervising clinicians.

Supporting Data: Measurable Gains in Alertness

The results of the trial demonstrated a statistically significant difference between the solriamfetol and placebo groups. After four weeks, participants taking the medication showed a marked increase in their ability to stay awake during the MWT sessions that coincided with their typical work hours.

Beyond the laboratory measurements, the real-world implications were evident in participant feedback. Those treated with solriamfetol reported a substantial reduction in the "heavy-lidded" sensation that typically occurs mid-shift. Clinicians observing the participants noted that their overall functioning—including their ability to manage complex tasks and maintain concentration—was significantly improved.

A key differentiator for solriamfetol compared to other stimulants like modafinil is its duration of action and its impact on subsequent sleep. Traditional stimulants can often linger in the system, making it difficult for workers to fall asleep once they return home. Solriamfetol, a dual dopamine and norepinephrine reuptake inhibitor (DNRI), appeared to provide the necessary boost during the shift without causing significant sleep onset latency when the participants finally had the chance to rest.

The Biological Burden and Safety Risks

The necessity of this research is underscored by the high risks associated with circadian misalignment. According to data from the National Highway Traffic Safety Administration (NHTSA), drowsy driving is a factor in approximately 100,000 police-reported crashes annually in the United States, resulting in 1,550 deaths and 71,000 injuries. A disproportionate number of these incidents occur between the hours of midnight and 6:00 a.m., precisely when early morning shift workers are commuting to their jobs.

"People who start work between 3 a.m. and 7 a.m. are waking up at a time when the brain is biologically programmed to sleep," explained first author Kirsi-Marja Zitting, PhD. "They are often dealing with a double burden—excessive sleepiness during work hours and difficulty sleeping enough when they have the chance to rest."

This "double burden" creates a cycle of chronic sleep debt. When an individual is forced to work against their internal clock, the brain experiences "microsleeps"—brief, involuntary moments of sleep that can last from a fraction of a second to several seconds. In a high-stakes environment, such as operating heavy machinery or a commercial vehicle, a microsleep can be fatal.

Broader Implications for Public Health and the Economy

The implications of the Mass General Brigham study extend far beyond the pharmacy counter. From an economic perspective, shift work disorder is a major driver of "presenteeism"—a phenomenon where employees are physically present at work but functionally impaired due to illness or fatigue. Estimates suggest that sleep-related productivity losses cost the U.S. economy over $400 billion annually.

By providing a validated treatment for early morning workers, healthcare providers can now offer more than just "sleep hygiene" advice, which is often insufficient for those whose schedules are dictated by the demands of a 24/7 global economy.

Furthermore, the study highlights a critical social equity issue. Many early morning shifts are held by essential workers in transportation, sanitation, and food supply chains. These individuals provide the infrastructure that allows the rest of society to function, yet they bear a disproportionate share of the health risks associated with sleep deprivation, including increased rates of cardiovascular disease, obesity, and metabolic disorders.

Analysis of Treatment Evolution

The medical community’s approach to wake-promoting agents has evolved significantly over the last two decades. Earlier treatments often relied on amphetamine-based stimulants, which carried a high risk of dependency and cardiovascular side effects. The introduction of modafinil and armodafinil provided a safer alternative, but their efficacy in specific subpopulations like early morning workers remained anecdotal.

Solriamfetol’s success in this trial suggests a more nuanced approach to treating SWD. Because it targets specific neurotransmitters without the same level of peripheral stimulation as older drugs, it offers a more "refined" alertness. However, researchers are quick to point out that medication should be part of a broader management strategy that includes optimized lighting, scheduled naps, and strategic caffeine use.

Future Research and Long-Term Outlook

While the results are promising, the research team emphasized that the four-week trial is only a starting point. The study population consisted of generally healthy adults, and the long-term effects of daily solriamfetol use for shift work disorder require further investigation.

"The improvement we saw is clinically meaningful," Czeisler said. "These workers were able to stay awake and alert throughout a full eight-hour shift, which has real implications for performance, safety, and quality of life."

The team is currently moving forward with a follow-up clinical trial that will evaluate solriamfetol’s efficacy in overnight shift workers. If successful, these combined data sets could lead to a broader FDA approval for solriamfetol, specifically targeting shift work disorder across all non-traditional schedules.

As society continues to move toward a 24-hour operational model, the biological limits of the human worker must be addressed. This study serves as a vital reminder that while we can change our clocks, we cannot easily change our biology—but we can develop the tools to help our brains keep up.

The study was supported by funding from Jazz Pharmaceuticals, Axsome Therapeutics, and the Brigham and Women’s Hospital Center for Clinical Investigation. The research team included Katherine R. Gilmore, Brandon J. Lockyer, Wei Wang, Nicolas C. Issa, Stuart F. Quan, Jonathan S. Williams, and Jeanne F. Duffy, along with Eileen B. Leary. Registration for the trial can be found at ClinicalTrials.gov under the identifier NCT04788953.