No Clinically Significant Interaction Between Spravato and Naltrexone
Based on FDA drug labeling data, Spravato (esketamine) does not have a clinically significant pharmacological interaction with naltrexone. The official prescribing information explicitly states that drug interaction studies demonstrated "none of the drug-drug interactions are clinically significant" 1.
Pharmacological Basis for Lack of Interaction
The absence of interaction is supported by esketamine's metabolic and transporter profile:
- Metabolism: Esketamine is primarily metabolized via CYP2B6 and CYP3A4, with minor contributions from CYP2C9 and CYP2C19 1
- No enzyme inhibition: Esketamine and its metabolites do not inhibit CYPs or UGTs (except weak reversible CYP3A4 inhibition by noresketamine) 1
- No transporter interactions: Esketamine does not interact with P-gp, BCRP, OATP1B1/1B3, MATE1/2-K, OCT2, or OAT1/3 1
Naltrexone, as an opioid receptor antagonist, operates through a completely different mechanism (mu-opioid receptor blockade) and does not share metabolic pathways with esketamine's NMDA receptor antagonism.
Clinical Implications
Safe Co-Administration
- Patients on naltrexone for alcohol use disorder or opioid use disorder can safely receive Spravato treatment
- No dose adjustments are required for either medication when used together
- The standard REMS monitoring protocol for Spravato (2-hour post-administration observation) remains unchanged 2
Important Caveat for Substance Use Disorder Populations
While the pharmacological interaction is absent, patients with comorbid substance use disorders receiving naltrexone represent a clinically complex population. However, real-world evidence is reassuring:
- Long-term studies show no instances of esketamine abuse, misuse, addiction, or withdrawal in patients with substance use disorder or alcohol use disorder 3
- No adverse events related to pharmacological interactions with other substances have been reported 3
- Esketamine has not fostered new-onset substance use in vulnerable populations 3
Monitoring Considerations
Standard Spravato administration protocols apply:
- Mandatory 2-hour post-dose monitoring for dissociation, sedation, and cardiovascular effects
- Blood pressure monitoring (esketamine causes transient increases in heart rate >10 bpm) 1
- Assessment for dissociative symptoms, which are common early in treatment but not predictive of therapeutic response 4
Bottom Line
Naltrexone and Spravato can be safely co-administered without pharmacokinetic or pharmacodynamic interference. The FDA labeling confirms no clinically significant drug-drug interactions 1, and post-marketing surveillance has not identified safety signals in patients with substance use disorders 3. Proceed with standard Spravato protocols regardless of concurrent naltrexone use.