Concomitant Use of SPRAVATO with Cannabis

SUMMARY

• 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 substance use disorder (SUD).^1-4
  • 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.
• Closely monitor for sedation with concomitant use of SPRAVATO with CNS depressants.^5,6 
• Closely monitor blood pressure with concomitant use of SPRAVATO and cannabis since both agents may affect blood pressure.^5,7
• In a post hoc subgroup analysis of the REAL-ESK study in patients with treatment-resistant depression (TRD) and comorbid cannabis use disorder (n=4), Montgomery-Åsberg Depression Rating Scale (MADRS) scores at baseline, 1 month, and 3 months, were 36.3, 18.5, and 11.5, respectively.⁸
• 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.⁹ 
• 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 substance abuse disorder and to monitor for signs of abuse or dependence.¹⁰

PRODUCT LABELING

Esketamine hydrochloride is a Schedule III controlled substance (CIII) under the Controlled Substances Act.⁵

clinical studies

Post Hoc Subgroup Analysis of the REAL-ESK Study

Chiappini et al (2023)⁸ conducted a post hoc subgroup analysis of the REAL-ESK,¹¹ 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 cannabis 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).
• In patients with TRD and cannabis use disorder, MADRS scores (SD) at baseline, 1 month and 3 months were 36.3 (7.9), 18.5 (16.4), and 11.5 (7.9), respectively.
• Overall, 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 use group and SPRAVATO use over time, showing no between group variation.
• Side effects (SEs; ≥1) were reported in 73% of all 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)⁹ 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).

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.