NMDA Side Effects: What the Data Means for Troche Users

What the New Research Says

A review published in Psychiatric Times in April 2026 takes a close look at side effect profiles and discontinuation rates across the class of NMDA receptor antagonists used for treatment-resistant depression (TRD) — a category that includes IV ketamine, compounded oral ketamine troches, and FDA-approved esketamine nasal spray (Spravato). The core message from the clinical authors is pointed: depression care is moving too slowly, and the data exists to move faster. They call on prescribers to optimize doses more aggressively, switch agents sooner when a given formulation isn't working, and track standardized outcome measures like the PHQ-9 consistently to reach remission rather than just partial response.

The review synthesizes discontinuation data across NMDA agents, noting that side effects — not lack of efficacy — remain one of the leading reasons patients stop treatment prematurely. Dissociative symptoms, dizziness, nausea, elevated blood pressure, and sedation are the most commonly cited culprits. Critically, the authors argue that many of these side effects are dose-dependent and manageable with thoughtful titration rather than being fixed properties of the medication class.

Where Troches Sit in This Conversation

For patients using ketamine troches — sublingual or buccal lozenges compounded by specialty pharmacies — this research lands differently than it does for infusion or nasal spray patients, and the differences matter practically.

Troches are absorbed primarily through the mucous membranes of the mouth, with some portion swallowed and absorbed orally. This route produces a more gradual onset and a lower peak plasma concentration than IV infusion, which is one reason the dissociative side effects associated with troches tend to be milder and shorter-lived than what infusion patients experience. The review's finding that side effects are largely dose-dependent actually supports this delivery format: because troche dosing is incremental and self-administered at home, there is more flexibility to titrate than with in-clinic infusions, where the dose is set in advance and administered over a fixed window.

At the same time, the at-home nature of troche use creates a distinct monitoring challenge. In an infusion clinic, a nurse is present during the full dissociative window. With troches, the patient and a designated sitter — if one is being used — are responsible for observing and reporting side effects between sessions. The review's emphasis on systematic outcome tracking via tools like the PHQ-9 is directly relevant here: patients who bring structured symptom data to their follow-up appointments give prescribers the information they need to optimize dosing intelligently rather than guessing.

Nausea is worth singling out. It appears with some regularity in troche users because of the swallowed fraction of the dose reaching the GI tract. Timing troches on an empty or light stomach, avoiding excess saliva swallowing during absorption, and staying still during the active window are all practical steps that can reduce this. Prescribers who are aware of the route-specific nausea mechanism are better positioned to address it — and the new research reinforces that managing it rather than abandoning treatment is the right clinical instinct.

The Practical Case for Switching Sooner

One of the more clinically significant points in the review is the call for earlier switching between NMDA agents when a given protocol isn't producing adequate response. In practice, this means that a patient who has tried a standard troche protocol at an optimized dose for a reasonable duration and isn't reaching remission shouldn't simply continue indefinitely on the same course. Esketamine nasal spray, IV infusion, or an adjusted compounding formulation may achieve a different pharmacokinetic profile that works better for that individual.

Compounded troches offer some flexibility that off-the-shelf formulations don't. Dose strength, base composition, and absorption enhancers can all be adjusted by a compounding pharmacist working with a prescriber. If a patient is tolerating troches well but not responding adequately, the answer may be a compounding adjustment rather than a full switch to a different delivery method — but this requires a prescriber willing to engage with the data and iterate rather than hold the protocol static.

The review's emphasis on PHQ-9 tracking as a decision-making tool underscores something troche patients can act on immediately: showing up to appointments with documented scores over time, rather than relying on a snapshot impression in the office, changes the quality of the clinical conversation. A PHQ-9 completed weekly at home — before and after each troche session if frequency allows — creates a real-world efficacy record that a prescriber can use to make the kind of data-driven adjustments the authors are calling for.

The Bigger Picture for At-Home Ketamine Treatment

The compounded troche model exists at a particular intersection: it offers meaningful flexibility and accessibility compared to in-clinic infusions, but it also places more responsibility on the patient and the prescriber relationship to maintain the kind of close monitoring this research says is necessary. The authors of this review aren't specifically writing about at-home troche use — their frame is the broader NMDA class across treatment settings — but the implications land squarely on troche workflows.

Patients who are serious about getting the most from a troche protocol should treat the side-effect and symptom-tracking piece as non-optional, not as paperwork. The data showing early discontinuation driven by unmanaged side effects is a reminder that troche treatment is not a set-and-forget intervention. It's a titrated, monitored protocol that rewards the patients and providers who stay engaged with the details.

Read the full review at Psychiatric Times.