Ketamine to enhance methadone treatment retention in patients with opioid use disorder and co-morbid depression

<i>Background:</i> Opioid use disorder (OUD) is a chronic relapsing condition with a high mortality rate. While medications such as methadone are valuable first-line therapies, retention is poor, with the highest dropout rates early in a treatment attempt. Poor outcomes are due in part to the very high rates of co-morbid depression in people with OUD, as depression can drive opioid use. Therefore, administering a rapid-acting antidepressant such as ketamine early in a treatment attempt may be an effective strategy to improve outcomes. <i>Objectives:</i> Here, we describe a case series of three patients (two males, one female) diagnosed with OUD initiating methadone treatment and endorsing symptoms of depression, who met criteria for a single-arm open-label feasibility trial (NCT05051449) at an opioid treatment program in Baltimore, Maryland. <i>Methods:</i> Participants underwent a 2-week ketamine regimen (0.5 mg/kg infusion over 40 min, three times per week for 2 weeks). <i>Results:</i> Ketamine was safe and generally well-tolerated. At 10-day follow-up post-ketamine infusions, participant acceptability ratings were mostly favorable. All three patients remained in treatment through the 3-month timepoint with strong treatment adherence. With treatment, self-reported depression symptoms decreased from severe to mild/moderate in two patients, and from moderate to remission in the third. <i>Conclusions:</i> Randomized controlled trials are warranted to test whether ketamine may be a feasible and safe adjunctive treatment for OUD in patients initiating methadone treatment.