Abstract:

Background: While stimulant medications remain the first-line treatment for adult ADHD, a subset of patients exhibit poor tolerance, inadequate response, or logistical barriers to traditional options. Modafinil, a wakefulness-promoting agent with a favorable side-effect and abuse potential profile, has emerged as a potential off-label alternative. However, real-world data on its use in complex, treatment-refractory ADHD populations remain limited.

Methods: This ongoing case series explores the clinical trajectories of six adults with ADHD who were initiated on modafinil after inadequate response or contraindication to first- and second-line therapies. Clinic data was extracted from the earliest patient visit (2023) up until January 2025. Treatment outcomes were assessed through longitudinal chart review, focusing on tolerability, functional gains, adherence patterns, and co-management strategies.Common comorbidities assessed in addition to ADHD included major depressive disorder (MDD), generalized anxiety disorder (GAD), and substance use (notably THC). 

Results: All patients had persistent executive dysfunction despite prior trials of antidepressants and/or stimulants. Modafinil (initiated at 100–200 mg QAM) was generally well-tolerated, with no serious adverse effects reported. Subjective improvements in focus, task initiation, and productivity were noted across cases, particularly when dosing was consistent. However, adherence was frequently impacted by financial constraints, substance use, and sleep-wake dysregulation. In one case, modafinil was discontinued due to suspected exacerbation of anxiety symptoms. In another, it successfully replaced Adderall during a national shortage, maintaining equivalent symptom control. Outcomes were most favorable in patients with stable psychiatric comorbidity and consistent routines.

Conclusion: Modafinil was generally well-tolerated and associated with meaningful subjective improvements in attention, task initiation, and daytime productivity across cases—particularly in patients with stimulant intolerance or residual ADHD symptoms despite adequate mood stabilization. Its favorable side-effect profile, low abuse potential, and compatibility with co-administered antidepressants made it a valuable adjunct in complex treatment regimens. However, real-world effectiveness was moderated by factors such as inconsistent adherence, sleep-wake disruption, and comorbid substance use. These early findings highlight modafinil’s promise as an off-label option in select ADHD populations and underscore the need for integrated, flexible care models and further research on its comparative efficacy and optimal use conditions.