Should We Worry About Ileus with Pines and Cobenfy? Reconsidering the Risk

Should We Worry About Ileus with Pines and Cobenfy? Reconsidering the Risk

As the psychiatric community continues to explore Cobenfy (xanomeline/trospium chloride) as a novel option in the treatment of schizophrenia, questions have emerged regarding its safety when used in combination with antipsychotics from the “-pine” family—such as clozapine, olanzapine, and quetiapine. Specifically, there’s been concern among some providers about an elevated risk of ileus due to overlapping anticholinergic effects. But is this a true clinical barrier, or can we rethink the concern in light of emerging data?

Cobenfy’s mechanism is both unique and nuanced. Xanomeline is a centrally acting M1/M4 muscarinic agonist with potential benefits across cognitive, negative, and positive symptom domains. Trospium, on the other hand, is a peripherally acting muscarinic antagonist added to counteract the cholinergic side effects of xanomeline (Brannan et al., 2021; Paul et al., 2022). The clinical concern arises when combining this formulation with other medications known for their anticholinergic burden—namely the pines.

Indeed, pines such as clozapine and olanzapine carry significant anticholinergic properties, and when layered with trospium, the theoretical risk for constipation, urinary retention, and yes, ileus, understandably triggers caution. But real-world experience may be more reassuring than expected.

In a recently published case series exploring outpatient use of Cobenfy, Price and Price (2025) offered critical insights. They reported that, in select cases, taking Cobenfy with food during cross-titration from highly anticholinergic agents such as olanzapine or clozapine may intentionally limit trospium absorption—temporarily allowing for a smoother pharmacologic transition. This approach helped minimize excessive anticholinergic load during overlap periods. As the X/T dose is titrated up, these older anticholinergic agents are ideally tapered off, allowing Cobenfy’s therapeutic benefits to fully emerge without additive peripheral burden (Price & Price, 2025).

Additionally, constipation and reflux—common early side effects—were successfully mitigated in several patients using conservative interventions: dietary adjustments, scheduling Cobenfy doses around meals, using agents like famotidine or senna, and carefully titrating dosages. Notably, ileus did not emerge as a reported complication in any of the 40 outpatient cases reviewed in this early experience (Price & Price, 2025).

As an ACT team, this information is particularly valuable. Our clients are closely monitored through frequent in-person contacts, team-based observation, and interdisciplinary collaboration—affording us the unique ability to detect early warning signs and intervene promptly. This high-touch model may allow us to be slightly more aggressive in initiating or cross-titrating with Cobenfy, even when pines are still on board. However, the risk of underreporting—especially among clients with cognitive impairment, poor insight, or limited expressive communication—remains real. Vigilance for subtle signs of GI distress and proactive screening are critical if we are to safely leverage the benefits of this emerging treatment.

Articles like this are especially helpful because they address a major limitation of the clinical trial data: during the pivotal FDA studies, all subjects underwent a complete washout from previous antipsychotics before starting Cobenfy (Kaul et al., 2024), and in the adjunctive trial, the study did not include clients on pines (Bristol Myers Squibb, 2025). That leaves a significant evidence gap for providers managing real-world complexity, especially in outpatient and community-based settings where complete washouts are often impractical or unsafe.

So what’s the takeaway?

While vigilance is always appropriate—especially with clients on multiple medications that can impair GI motility—it may be time to soften the hard stop on co-prescribing Cobenfy with pines. Thoughtful cross-titration strategies, temporary use of food to modulate trospium absorption, and an individualized approach to side effect management can allow for safe, effective transitions. And for many clients, the benefits of Cobenfy—including its non-dopaminergic mechanism, cognitive support, and improved tolerability—may outweigh the manageable risks (Fabiano et al., 2025).

In a field that often wrestles with the consequences of overgeneralized warnings, this might be a case where nuanced clinical judgment—and not reflexive avoidance—is the best prescription.

References

Brannan, S. K., Sawchak, S., Miller, A. C., Lieberman, J. A., Paul, S. M., & Breier, A. (2021). Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. New England Journal of Medicine, 384(8), 717–726. https://doi.org/10.1056/NEJMoa2017015

Bristol Myers Squibb. (2025, April 22). Bristol Myers Squibb announces topline results from Phase 3 ARISE trial evaluating Cobenfy (xanomeline and trospium chloride) as an adjunctive treatment to atypical antipsychotics in adults with schizophrenia [Press release]. Business Wire.

Fabiano, N., Wong, S., Zhou, C., Correll, C. U., Højlund, M., & Solmi, M. (2025). Efficacy, tolerability, and safety of xanomeline–trospium chloride for schizophrenia: A systematic review and meta-analysis. European Neuropsychopharmacology, 92, 62–73. https://doi.org/10.1016/j.euroneuro.2024.11.013

Kaul, I., Sawchak, S., Correll, C. U., Kakar, R., Breier, A., Zhu, H., et al. (2024). Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: Results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. The Lancet, 403(10395), 160–170. https://doi.org/10.1016/S0140-6736(23)02190-6

Price, M. Z., & Price, R. L. (2025). Early outpatient clinical experience with xanomeline and trospium chloride for schizophrenia: A case report. Frontiers in Psychiatry, 16, 1630574. https://doi.org/10.3389/fpsyt.2025.1630574

Paul, S. M., Yohn, S. E., Popiolek, M., Miller, A. C., & Felder, C. C. (2022). Muscarinic acetylcholine receptor agonists as novel treatments for schizophrenia. American Journal of Psychiatry, 179(9), 611–627. https://doi.org/10.1176/appi.ajp.21101083

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