SUMMARY  

• Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO. Careful consideration is advised prior to treatment of individuals with a history of substance use disorder.¹
• The phase 3 SPRAVATO trials excluded patients with a history of moderate or severe substance or alcohol use disorder, defined by DSM-5 criteria, within 6 months before the start of the screening/observational phase.^2-8
• The concomitant use of SPRAVATO and treatments for opioid dependence, such as methadone, buprenorphine, buprenorphine/naloxone, or naltrexone, were not studied in the clinical trial program for SPRAVATO.
• Esketamine (ESK), the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. However, the precise mechanism of action of ESK in major depressive disorder (MDD) is unknown. The antidepressant pharmacologic action of ESK is thought to be similar to ketamine.^9-13
• At the doses used in clinical practice, ESK’s primary antidepressant activity is not believed to directly involve mu-opioid receptor (MOR) stimulation,^14-17 nor is it believed to directly involve inhibition of serotonin, norepinephrine, or dopamine reuptake.^9-11
• A literature search did not yield data with SPRAVATO; however, there was limited information found for ketamine. Results from these studies may not be generalizable to SPRAVATO.
  • Two studies in patients with major depressive disorder (MDD) or treatment-resistant disorder (TRD) suggested that ketamine's acute antidepressant effect may require opioid system activation since pretreatment with naltrexone was found to reduce its effect.^18,19
    • Two studies in patients with alcohol use disorder (AUD) reported that naltrexone pretreatment did not interfere with the antidepressant effects of ketamine.^17,20
    • Another demonstrated that in patients receiving intravenous ketamine treatment, the antidepressant effect was similar between those who were receiving MOR agonists (buprenorphine, methadone) and those who were not receiving opioidergic drugs.²¹
  • A case series evaluating adjunctive IV ketamine during methadone initiation in patients with opioid use disorder and comorbid depression found marked reductions in depressive symptoms, opioid craving, and sleep problems.²² 

Clinical data

Ketamine Data

Randomized Trials

Yoon et al (2025)²⁰ reported results from a 4-week, randomized, double-blind trial (N=58) that compared intravenous (IV) ketamine (0.5 mg/kg weekly × 4 infusions) plus intramuscular (IM) naltrexone (380 mg before the first infusion; n=20), ketamine (0.5 mg/kg) plus saline (n=19), and midazolam (0.045 mg/kg; active control for ketamine) plus saline (n=19) in patients with MDD and AUD. All patients received standard of care regimens in addition to these treatments. Clinical response and alcohol abstinence rates were co-primary endpoints.

Clinical response, defined as a ≥50% reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) score at 240 minutes post-final infusion, was observed to be high across groups: ketamine+naltrexone (93.8%), ketamine+saline (81.8%), and midazolam+saline (86.7%). Remission (MADRS <10) rates were similarly high, at 87.5%, 81.8%, and 73.3%, respectively. One-week post-treatment, MADRS scores remained significantly lower in both ketamine groups versus midazolam. Alcohol abstinence rates throughout the 4-week treatment period were not significantly different (40.9%, 63.5%, and 38.5% respectively). Adverse events were observed in 14 patients (73.7%) in the midazolam-saline group, 14 patients (70.0%) in the ketamine-naltrexone group, and 11 patients (57.9%) in the ketamine-saline group. No study-related serious adverse events occurred; most adverse events were mild to moderate. Limitations include small sample size; weekly infusion schedule and limited assessment timepoints may underestimate peak ketamine effects; findings may not be generalized to a population of patients with MDD alone and did not adjust for multiplicity. The authors stated that although findings appeared to question the role of opioid receptors in the antidepressant effects of ketamine, the results should be interpreted with caution as there was a lack of separation from the control group in the co-primary endpoints.

Jelen et al (2025)¹⁹ conducted a randomized, double-blind, placebo-controlled crossover study (N=26) in adults with MDD to assess the impact of opioid receptor antagonism on ketamine response. Participants received oral naltrexone (50 mg) or placebo (ascorbic acid 50 mg) prior to IV ketamine (0.5 mg/kg over 40 min), with a 2–4 week washout between sessions. Usual psychotropic medications were received during the study.

Based on proton magnetic resonance spectroscopy (¹H-MRS) of 24 patients, naltrexone pretreatment significantly attenuated ketamine-induced glutamatergic activity in the anterior cingulate cortex, as measured by the ratio of glutamate and glutamine to the total N-acetylaspartate (Glx/tNAA: F₁,₂₅₃=4.83, P=0.029) and reduced the antidepressant effect as measured by MADRS at day 1 (mean difference vs placebo=4.15; F₁,₇₄=5.39, P=0.023; Cohen’s d=0.60). No significant differences were observed for Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR), Maudsley 3-item Depression Visual Analogue Scale (M3VAS), or anhedonia scales (Snaith-Hamilton Pleasure Scale [SHAPS], Temporal Experience of Pleasure Scale, [TEPS]) across the two treatment groups at day 1. Dissociation and psychotomimetic effects were similar (Clinician-Administered Dissociative States Scale [CADSS]: F₁,₂₅=0.003, P=0.959). There were no significant differences in adverse event (AE) rates between the two groups, with the most commonly reports AEs (≥10% in either arm) being dissociation, headache, dizziness, nausea, vomiting, and lethargy. No serious adverse events were reported. Limitations include small sample size and short follow-up; no placebo-infusion arm and possible carryover effects; results may not generalize beyond racemic ketamine or a more treatment resistant patient population; using ¹H-fMRS with 3 Tesla may not reliably differentiate glutamate and glutamine.^19,23 

Williams et al (2018 and 2019)^18,24 reported interim results of an analysis in 12 patients with treatment-resistant depression (TRD) who completed a randomized, double-blind, crossover study that evaluated whether opioid receptors play a role in the antidepressant effect of ketamine. Patients received oral naltrexone 50 mg or placebo 45 minutes prior to IV ketamine 0.5 mg/kg over 40 minutes. In the seven patients who met the prespecified response criterion (defined as a ≥50% reduction in the 17-item Hamilton Depression Rating Scale (HAM-D) score from baseline to day 1 with ketamine + placebo), reductions in the 17-item HAM-D score were significantly attenuated in the ketamine + naltrexone arms compared with the ketamine + placebo arm on day 1 (primary endpoint) and day 3, but not at days 5, 7, or 14.¹⁸ In a secondary endpoint analysis, the authors found that changes in suicidality, based on item 3 of the HAM-D, item 10 of the MADRS, and the Columbia Suicide Severity Rating Scale, were also significantly attenuated with the addition of naltrexone.²⁴ The authors suggested that ketamine’s acute antidepressant effect requires opioid system activation.^18,24

The interpretability of these findings is limited by the study design, including a lack of a control arm necessary to assess the effects of naltrexone alone or placebo alone (which is considered relevant since endogenous opioid peptide signaling of MOR have been associated with positive mood responses to placebo),²⁵ possible carryover effects resulting from the crossover design, and a small final sample size due to early termination of the study resulting from ineffectiveness and “noxious” side effects (severe nausea and vomiting) for many patients receiving ketamine + naltrexone. In addition, the study did not specifically recruit for suicidal patients. The authors acknowledged a need to replicate the findings.^18,24

Open-Label Study

Yoon et al (2019)¹⁷ evaluated the use of naltrexone pretreatment with ketamine in patients with MDD and alcohol use disorder. This 8-week, open-label, pilot study included 5 patients who received injectable naltrexone (380 mg once as an extended-release formulation, 2-6 days prior to the first ketamine infusion) and repeated intravenous ketamine infusions (0.5 mg/kg once a week for 4 weeks for a total of 4 treatments). Clinical response, defined as a ≥50% improvement in the MADRS scores from baseline to 4 hours post-infusion, was met by 60% of patients after the initial ketamine dose and by 100% by the fourth dose. No serious side effects were reported. The authors concluded that naltrexone pretreatment does not appear to interfere with the antidepressant effects of ketamine.

Retrospective Study

Marton et al (2019)²¹ conducted a retrospective analysis of treatment outcome data of 40 veterans with TRD who were treated with up to 6 infusions of ketamine (0.5 mg/kg over 40 minutes) twice weekly for 3 weeks. During the treatment period, 7 patients received MOR agonists (buprenorphine [n=5], methadone [n=2]) for >12 months, 1 patient received long-acting injectable naltrexone, and 27 patients were not on opioidergic drugs. While the results demonstrated significant reductions (P<0.001) in Beck Depression Inventory-II scores over the 6 infusions of ketamine treatment, no difference was found between the MOR agonist and non-MOR agonist groups pre- and post-treatment. A similar antidepressant response was seen in the one patient receiving naltrexone.

Case Series

Manza et al (2025)²² presented a case series (N=3) as a feasibility study in patients with severe, chronic opioid use disorder (OUD) and comorbid depression initiating methadone treatment. Within one month of methadone initiation, participants received six IV ketamine infusions (0.5 mg/kg over 40 minutes) administered thrice a week for two weeks.

All three patients completed the ketamine regimen and remained in methadone treatment at 3-month follow-up. Methadone dosing records showed two patients achieved 100% adherence and one achieved 81% (73 of 90 doses). Depression symptoms decreased by >12 points on MADRS in all cases. Self-reported depression symptoms decreased in 2 patients from severe to mild/moderate, and one from moderate to remission. two shifted from severe to mild/moderate, and one from moderate to remission. All participants reported reductions in opioid craving and improvements in sleep quality; two reported fewer life problems related to drug use. Adverse events were mild or moderate, most commonly transient hypertension during infusions; no serious adverse events occurred. Dissociative effects were minimal, though each patient reported at least one session with moderate ratings of “wanting more” ketamine.

Literature SearcH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 09 October 2025.