Low-Dose Naltrexone as an Adjunct in Treatment-Resistant ADHD: A Case Report of Next-Day Improvement in Fatigue and Cognitive Function

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This case report describes the use of low-dose naltrexone (LDN) as an adjunctive treatment in an adult patient with treatment-resistant attention-deficit/hyperactivity disorder (ADHD) and comorbid fatigue. Despite ongoing treatment with high-dose modafinil (400 mg daily) and methylphenidate (18 mg daily), the patient continued to experience significant cognitive impairment and fatigue, with a baseline Modified Fatigue Impact Scale (MFIS) score of 70.

Following initiation of LDN, the patient reported rapid improvement in fatigue and cognitive function within 24–48 hours. Sustained improvement was observed over an 8-week follow-up period, with no significant adverse effects.

Two mechanisms are proposed to explain the observed effect: a rebound increase in endogenous opioid activity following short-term receptor blockade, and reduced neuroinflammation through microglial modulation and TLR4 pathway inhibition. These mechanisms may enhance dopaminergic signaling and reduce cytokine-mediated cognitive dysfunction.

To our knowledge, this is the first published report describing LDN as an adjunct to stimulant and modafinil therapy in ADHD. The findings suggest a potential role for LDN in neuroinflammation-related symptomatology in treatment-resistant ADHD, warranting further controlled investigation.