SUMMARY

• SPRAVATO has not been studied in patients with comorbid substance use disorder (SUD) or alcohol use disorder (AUD).
• The phase 3 SPRAVATO trials excluded patients with a history of moderate or severe SUD or AUD, defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, within 6 months before the start of the screening/observational phase. This exclusion criterion did not apply to nicotine or caffeine.^1-6
  • This includes a history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3,4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder.
• Patients with intermittent use of cannabinoids prior to the start of the screening/prospective observational phase were not excluded from the pivotal SPRAVATO trials, provided they did not meet the criteria for SUD.^1,2,4,5
  • A positive test (urine drug screen) for cannabinoids at the start of the screening/prospective observational phase was not exclusionary.
  • However, patients with a positive test result for cannabinoids predose on day 1 of the induction phase were excluded from the trials.
• In a post hoc subgroup analysis of the REAL-ESK study in patients with treatment-resistant depression (TRD) and comorbid SUD, response and remission were reported in 50% (13/26) and 30.8% (8/26) of patients, respectively, after 3 months of treatment with SPRAVATO.⁷
• A retrospective study showed no significant differences in Patient Health Questionnaire (PHQ-9) scores between cannabis and non-cannabis users treated with flexibly-dosed ketamine/SPRAVATO.⁸ 
• A case report described improvement in depressive symptoms, marked craving reduction, and urine confirmed abstinence from opioids and methamphetamine in an adult with MDD and chronic polysubstance use following adjunctive SPRAVATO.⁹ 
• A case report described the achievement of sustained response after the addition of SPRAVATO to the existing regimen of an adult patient with depression and comorbid psychological disorders and a long history of alcohol and substance abuse.¹⁰
• A case report described the improvement in depressive symptoms and cessation of alcohol use in an adult patient with major depressive disorder (MDD) and severe AUD who was being treated with SPRAVATO.¹¹
• Individuals with a history of drug abuse or dependence may be at greater risk for abuse and misuse of SPRAVATO. Physicians are advised to assess individuals prior to treatment for a history of SUD and to monitor for signs of abuse or dependence.¹²

PRODUCT LABELING

Esketamine hydrochloride is a Schedule III controlled substance (CIII) under the Controlled Substances Act.¹³

clinical studies

Post Hoc Subgroup Analysis of the REAL-ESK Study

Chiappini et al (2023)⁷ conducted a post hoc subgroup analysis of the REAL-ESK,¹⁴ a retrospective, observational study in Italy, to evaluate the effectiveness and safety of SPRAVATO in patients (N=26) with TRD and comorbid SUD.

Study Design/Methods

• Psychometric data were collected at baseline and at 1 and 3 months after treatment initiation.
• Response was defined as an overall reduction of 50% in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline.
• Remission was defined as a MADRS score of <10.

Results

• Twenty-six patients with TRD and comorbid SUD were included in the analysis (age, 48.88 years; male, n=15; baseline MADRS score [SD], 33.7 [±8.3]), including patients with AUD (n=13), benzodiazepine use disorder (n=5), cannabis use disorder (n=4), and cocaine use disorder (n=4).
• The decrease in MADRS scores from baseline to month 1 (t-tests [t], 6.533; degrees of freedom [df], 23; P<0.001) was significant compared with that from month 1 to month 3 (t, 2.029; df, 20; P=0.056).
• Significantly more patients achieved response and remission at month 3 vs month 1.
  • Response: month 1, 27% of patients; month 3, 50% of patients (chi-square test [χ²], 3.962; df, 1; P=0.047)
  • Remission: month 1, 15.4% of patients; month 3, 30.8% of patients (χ², 9.600; df, 1; P=0.002)
• Multivariate analysis reported no statistically significant interaction between each substance group and SPRAVATO use over time.
• Side effects (SEs; ≥1) were reported in 73% of patients. All resolved with time with no significant sequelae.
  • Most frequently reported SEs were dissociative symptoms (38%), sedation (26%), increased blood pressure (11%), hypomanic symptoms (11%), psychomotor agitation (4%), and anxiety (4%).
• No cases of abuse or misuse of SPRAVATO were reported.

Retrospective Study

Shenasa et al (2023)⁸ conducted a retrospective chart review to evaluate the effects of cannabis use on treatment response to flexibly-dosed ketamine/SPRAVATO or repetitive transcranial magnetic stimulation (rTMS) among veterans (N=229).

Study Design/Methods

• Key inclusion criteria were having at least 2 ketamine treatments (n=124) or treatment with rTMS for ≥2 weeks (n=105) and having at least 1 post-treatment PHQ-9 score.
• Cannabis use was confirmed by self-report (with rTMS) or by a positive urinary drug screening over the 8-week treatment session (for ketamine/SPRAVATO).
• Treatment effect was measured using change in PHQ-9 scores and ANOVA F statistic (F).

Results

• There was a reduction in PHQ-9 scores by 4.5 points among non-cannabis users treated with ketamine/SPRAVATO (95% CI, 2.54-6.41), compared to a 4.3-point reduction in cannabis users (95% CI, 0.78-7.92).
• The difference in PHQ-9 scores between groups was not statistically significant (P>0.7).
• ANOVA analysis yielded an F statistic of 0.58 (P=0.45), indicating minimal effect of cannabis use.
• No significant differences were observed in rTMS groups stratified by cannabis use status (P>0.7).

Case Reports

Ali et  al (2025)⁹ presented a case of a 41yearold male with a 15year history of MDD, recurrent admissions for severe depression with suicidal ideation, and polysubstance use characterized by daily prescriptionopioid/morphine intake and intermittent methamphetamine use. The patient had previously received SSRIs, SNRIs, bupropion, mirtazapine, vortioxetine, and antipsychotic augmentation therapy without meaningful improvement, and his baseline PHQ9 score was 24 with a craving intensity of 9/10. SPRAVATO was initiated at 56 mg for the first dose and increased to 84 mg after two days. The patient subsequently received 84 mg twice weekly for four weeks, followed by 84 mg once weekly, while continuing his baseline oral antidepressant.

At one month, the patient’s PHQ‑9 score decreased to 17, and his craving score decreased to 5/10. He also demonstrated improvements in energy and sleep. At two months, his PHQ‑9 score decreased further to 6, and his craving score decreased to 1/10. Urine drug screens confirmed abstinence from opioids and methamphetamine, and the patient became more socially active. By four months, his PHQ‑9 score was 5, the craving score was 0/10, and he continued to maintain abstinence and returned to work. At six months, the patient had a PHQ‑9 score of 4, craving score of 0, and he maintained abstinence with full functional recovery. Treatment with SPRAVATO was generally well tolerated. The patient experienced transient dizziness and mild dissociation, both of which resolved within approximately one hour without further complications.

de Filippis et al (2023)¹⁰ presented a case report of a 39-year-old female patient diagnosed with bipolar I disorder and borderline personality disorder who presented to the hospital after a drug ingestion-related suicide attempt. The patient had a long history of alcohol and drug abuse (cannabis, cocaine, heroin, hallucinogens, and poppers), with prior reports of manic episodes, voluntary and compulsory hospitalizations, drug ingestion-related suicide attempts, and depression. A month after her recent drug ingestion-related suicide attempt, the patient was initiated on SPRAVATO as an adjuvant to the current treatment regimen that included fluoxetine, lithium, lurasidone, and quetiapine. At the time, the patient was in complete remission of her alcohol and drug abuse for over 6 months. She received SPRAVATO 56 mg twice a week for 4 weeks followed by 56 mg once a week.

The patient tested negative for drug tests at baseline and at the 6- and 12-month follow-ups. Additionally, no signs of addiction and tolerance toward SPRAVATO were reported during the treatment phase. After 3 months, clinical response (50% reduction in MADRS score) was reported, and at the 12-month follow-up, clinical remission (MADRS score <10) with improvements in global functioning, sleep cycle, suicidality risk, binge eating, and anxiety symptoms was reported. In the continuation phase, the patient had no clinical relapses or hospitalizations, held a part-time job, and started caring for herself and her daughters.

Faruqui and Kim (2022)¹¹ presented the case of a 61-year-old female patient with recurrent treatment-resistant MDD without psychotic features, and severe AUD who visited the clinic for ketamine. Her medical history included generalized anxiety disorder, essential hypertension, and colon and breast cancer. Her previous treatments with psychotherapy, paroxetine, bupropion, and maybe levomilnacipran did not show any significant improvements.

To date, combined with oral paroxetine 30 mg/day, the patient had completed 20 treatment sessions with SPRAVATO 56 mg administered twice a week, 5 treatment sessions with SPRAVATO 56 mg administered once a week, and 21 treatment sessions with SPRAVATO 84 mg administered once a week, with no signs of tolerance or dependence. SPRAVATO dosage was increased to maintain the therapeutic effect. The patient showed significant improvement in depressive symptoms, as her Patient Health Questionnaire-9 (PHQ-9) scores decreased from 23 to 4 at the start of the 46th session, and Hamilton Depression Rating Scale (HAM-D) scores decreased from 13 to 4 from 15th to 46th session. She also reported improvement in anxiety symptoms, and complete cessation of alcohol use by week 2, except for a single relapse episode while on lower dose of SPRAVATO. The patient did not report any adverse events, except for an incidence of insignificant increase in systolic blood pressure (1015 mmHg) which did not require adjustments in her hypertensive medications. The patient continued treatment with SPRAVATO at current dose and frequency, tapering will be considered if she completes 6-8 months of treatment without relapse of her depressive symptoms.

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 25 December 2025.