Matthew Gunther, Nathan Tran, Katherine Prothro, Boglarka Huddleston, Shixie Jiang
Neurostimulants were associated with short-term improvements in measures of arousal and recovery, although evidence remains heterogeneous and largely observational. Amantadine has the largest ICU evidence base; methylphenidate has been studied as monotherapy and augmentation; modafinil has primarily been evaluated for hypersomnolence. Further placebo-controlled trials are needed to establish efficacy across different causes of DoC; head-to-head studies are needed to clarify comparative effectiveness among available neurostimulants.
BACKGROUND: Disorders of consciousness (DoC; encompassing coma, unresponsive wakefulness syndrome, and minimally conscious state) are sequelae of critical illness that prolong hospitalization and interfere with engagement in care. Due to heterogeneous and incompletely understood pathophysiology, no pharmacologic standard of care has been established. We aimed to systematically examine the efficacy, safety, and dosing of neurostimulants among adult ICU patients with DoC.
METHODS: We conducted a systematic search of PubMed, Embase, CINAHL, and Web of Science from inception to December 2025. Studies that examined the use of neurostimulants for DoC in critically ill adults were included. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and used the Effective Public Health Practice Project framework to appraise bias.
RESULTS: 35 studies met inclusion criteria: 11 randomized controlled trials, 19 observational, and 5 case-based studies. Amantadine was the most studied agent (N = 2743), with several studies reporting improvements in standardized measures of consciousness and earlier transition to rehabilitation. Modafinil (N = 1776) was primarily evaluated for hypersomnolence and demonstrated mixed effects on Glasgow Coma Scale (GCS) scores. Methylphenidate (N = 1044) demonstrated signals of benefit in both randomized studies and augmentation strategies with amantadine. Apomorphine was evaluated in one placebo-controlled ICU trial and carbidopa-levodopa in one case series. Despite inclusion in our search strategy, no studies examined caffeine, amphetamines, or bromocriptine.
CONCLUSIONS: Neurostimulants were associated with short-term improvements in measures of arousal and recovery, although evidence remains heterogeneous and largely observational. Amantadine has the largest ICU evidence base; methylphenidate has been studied as monotherapy and augmentation; modafinil has primarily been evaluated for hypersomnolence. Further placebo-controlled trials are needed to establish efficacy across different causes of DoC; head-to-head studies are needed to clarify comparative effectiveness among available neurostimulants.