Introduction to Intranasal Administration
Intranasal administration — delivering medication through the nasal passages — is an established route for many medications. The nasal mucosa is richly supplied with blood vessels, allowing drugs to be absorbed relatively quickly into the bloodstream. For ketamine, the intranasal route offers a non-invasive alternative to IV infusion while still providing reasonably rapid onset and meaningful bioavailability.
Two distinct forms of intranasal ketamine are in clinical use: FDA-approved esketamine (Spravato) and compounded racemic ketamine nasal sprays. While both deliver ketamine through the nose, they differ significantly in their regulatory status, formulation, clinical evidence, and prescribing framework.
Esketamine (Spravato): The FDA-Approved Option
What Is Esketamine?
Esketamine is the S-enantiomer of ketamine — one of the two mirror-image molecular forms that make up racemic ketamine. Developed by Janssen Pharmaceuticals (a subsidiary of Johnson & Johnson), esketamine received FDA approval in March 2019 under the brand name Spravato for treatment-resistant depression (TRD), and in August 2020 for major depressive disorder (MDD) with acute suicidal ideation or behavior.
Esketamine has approximately twice the binding affinity for the NMDA receptor compared to the R-enantiomer (arketamine), which is one reason it was selected for development. However, whether this translates to superior clinical efficacy compared to racemic ketamine remains a subject of ongoing research and debate.
The REMS Program
Because of concerns about sedation, dissociation, and the potential for abuse, Spravato is available only through a restricted distribution program called the Risk Evaluation and Mitigation Strategy (REMS). Under REMS:
- Spravato must be administered in a certified healthcare setting — it cannot be taken at home
- Patients self-administer the nasal spray under direct observation of a healthcare provider
- Patients must be monitored for at least 2 hours after each dose
- Patients must not drive or operate heavy machinery until the following day after restful sleep
- Healthcare settings must be certified and enrolled in the Spravato REMS program
Dosing Protocol
The standard Spravato dosing schedule is:
Induction phase (Weeks 1-4):
- 56 mg or 84 mg per session
- Administered twice per week
Maintenance phase (Weeks 5-8):
- 56 mg or 84 mg per session
- Administered once per week
Long-term maintenance (Week 9 onward):
- 56 mg or 84 mg per session
- Administered once weekly or once every two weeks
- Dosing frequency based on individual response
Spravato is always used in conjunction with an oral antidepressant, not as monotherapy. The nasal spray device delivers the dose in a series of sprays — two devices for a 56 mg dose and three devices for an 84 mg dose.
Clinical Evidence for Spravato
The FDA approval of Spravato was based on several pivotal clinical trials:
- TRANSFORM trials — Three short-term studies evaluating esketamine plus an oral antidepressant versus placebo plus an oral antidepressant in TRD patients. Results showed statistically significant improvement in depressive symptoms.
- SUSTAIN trials — Long-term studies demonstrating that continued Spravato treatment reduced the risk of relapse compared to discontinuation.
- Studies in suicidal ideation — Trials showing rapid reduction in depressive symptoms in patients with MDD and acute suicidal ideation.
Compounded Intranasal Ketamine
What Is Compounded Nasal Ketamine?
Compounded intranasal ketamine is a preparation of racemic ketamine (containing both S- and R-enantiomers) that is formulated by a compounding pharmacy into a nasal spray. Unlike Spravato, compounded ketamine nasal sprays are not FDA-approved for any specific indication and are prescribed off-label.
Key Differences from Spravato
| Feature | Spravato (Esketamine) | Compounded Nasal Ketamine |
|---|---|---|
| FDA approval | Yes (TRD, MDD with SI) | No (off-label use) |
| Administration setting | Certified healthcare facility only | May be prescribed for home use |
| Monitoring requirement | 2-hour post-dose monitoring | Varies by provider |
| Formulation | Standardized, single-use devices | Variable, pharmacy-dependent |
| Insurance coverage | Often covered with prior authorization | Rarely covered |
| Cost per session | $600-$900 (before insurance) | $50-$150 per month (typical) |
Home Use Considerations
Some clinicians prescribe compounded intranasal ketamine for home use, particularly as a maintenance strategy after an initial series of IV infusions or for patients who cannot regularly access in-office treatment. This approach is more accessible and less expensive but requires:
- Careful patient selection and screening
- Clear instructions on safe use and storage
- Regular follow-up appointments
- Monitoring for signs of misuse or tolerance
- Secure storage, as ketamine is a controlled substance
Bioavailability and Pharmacokinetics
The bioavailability of intranasal ketamine is approximately 25-50%, compared to 100% for IV administration. This means that a higher absolute dose must be given intranasally to achieve comparable blood levels. Onset of action is typically within 10 to 20 minutes, with peak effects at 20 to 40 minutes. The total duration of acute effects is generally 1 to 2 hours.
Side Effects
The side effect profile of intranasal ketamine is generally similar to IV ketamine, though the experience may differ in intensity and timing:
- Dissociation (reported in approximately 60-75% of Spravato sessions)
- Dizziness and vertigo
- Nausea
- Sedation
- Increased blood pressure
- Nasal discomfort (stinging, irritation, or congestion)
- Altered taste
Most side effects resolve within 1.5 to 2 hours after administration.
Choosing Between Intranasal Options
The choice between Spravato and compounded intranasal ketamine depends on several factors, including insurance coverage, access to certified Spravato providers, preference for FDA-approved versus off-label treatment, and whether home-based administration is desired. Patients should discuss these options thoroughly with their healthcare provider. For a detailed comparison, see our article on racemic ketamine vs esketamine. to determine the most appropriate approach for their individual circumstances.
References
- MedlinePlus: Esketamine Nasal Spray — National Library of Medicine drug information on Spravato (esketamine) nasal spray
- FDA: Drug Information — U.S. Food and Drug Administration resource on esketamine approval and REMS program
- StatPearls: Ketamine — Clinical reference covering ketamine pharmacology and intranasal administration
- Ketamine Pharmacology: An Update — NIH review of ketamine pharmacokinetics including intranasal bioavailability
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