Naltrexone/Bupropion/Mirtazapine Triple Therapy for Treatment-Resistant Methamphetamine Use Disorder: A Case Series

Stimulant use disorders (StUDs) remain a growing public health concern in the United States, with no FDA-approved pharmacological treatment available. While medications such as naltrexone (NTX), bupropion (BUP), and mirtazapine (MIRT) have shown modest benefits individually or in combination as BUP/NTX, no prior studies have examined their combined use as a triple therapy. Here, we present a case series of three patients with severe, treatment-resistant methamphetamine use disorder treated with a combination of NTX/BUP/MIRT for 18-24 months. Clinical outcomes such as methamphetamine use via urine drug screening, psychiatric comorbidity symptoms, and quality of life were monitored over time. All three patients experienced clinically meaningful reductions in methamphetamine use following initiation of triple therapy. Improvements were sustained over months and were accompanied by enhanced mood and improved psychosocial functioning. NTX/BUP/MIRT therapy was well-tolerated, with no major adverse events. These cases suggest that NTX/BUP/MIRT triple therapy may offer a promising pharmacologic strategy for patients with refractory StUDs. The complementary pharmacologic profiles of the three agents may produce synergistic benefits by targeting craving, withdrawal, mood instability, and insomnia. While encouraging, these findings require validation in controlled clinical trials.