Xanomeline–trospium

What it is

Xanomeline–trospium is a capsule that combines two drugs. It is the first medicine for schizophrenia that works without blocking dopamine D2 receptors, the target of every antipsychotic approved before it.^1,2 It is sold in the United States as Cobenfy.

How it works

Xanomeline switches on two muscarinic receptors for acetylcholine, M1 and M4, which influence dopamine signalling indirectly. On its own, it also stimulates the same receptors in the rest of the body, causing nausea and other digestive complaints. Trospium blocks those receptors outside the brain and barely enters it, so it eases these side effects without cancelling xanomeline’s effect.¹ Why acetylcholine matters in schizophrenia is explained in Beyond dopamine (opens in a new tab).

History

Xanomeline was first tested in the 1990s in Alzheimer’s disease, where it reduced suspiciousness, delusions and hallucinations, but more than half of those on the highest dose stopped taking it because of digestive and other side effects.³ In 2008, a four-week pilot study in 20 people with schizophrenia found it better than placebo.⁴ Combined with trospium, it was approved in the United States in September 2024.²

How well it works

Three trials, each in about 180 to 260 adults admitted to hospital with a worsening of psychosis, compared it with a placebo for five weeks. Symptoms improved by 8 to 12 points more than on placebo, on the 30-to-210-point PANSS scale.^5,1,6 What the second trial found is explained in detail in A new kind of antipsychotic (opens in a new tab).

In two open-label studies lasting a year, symptoms continued to improve, without weight gain or movement side effects; but in the larger study, fewer than half completed the year.^7,8

Added to another antipsychotic in 396 people whose symptoms had not responded well enough, it did not do clearly better than placebo after six weeks.⁹

Side effects

Outcome	Xanomeline–trospium	Placebo
Nausea	19	4
Indigestion	18	5
Constipation	17	7
Vomiting	15	1
High blood pressure	11	2

Weight gain, stiffness, restlessness and sleepiness, common with dopamine-blocking antipsychotics, were about as frequent as on placebo.¹

Contraindications and cautions

It is not used in people who cannot empty the bladder or the stomach properly, who have moderate or severe liver disease, or who have untreated narrow-angle glaucoma. In long-term studies, 3.5 in 100 people had difficulty passing urine, more often men and older people. It can also raise the heart rate and liver enzymes, and has been linked to swelling of the face and throat (angioedema).¹⁰

In Europe

Xanomeline–trospium is not approved in the European Union. As of October 2026, no application for approval was under evaluation by the European Medicines Agency.¹¹ Its maker plans to launch it in the United Kingdom first,¹² and NICE expects to publish its appraisal in July 2027.¹³

Two trials in Europe are under way. One, testing whether it prevents relapse in adults, was authorised in October 2026 in Bulgaria, Denmark, Poland, Romania and Spain.¹⁴ The other, in teenagers aged 13 to 17, is recruiting in Romania.¹⁵

Alternatives

Other medicines acting on muscarinic receptors are in trials: direclidine (opens in a new tab), emraclidine (opens in a new tab), and MapLight’s combination of betovumeline with fesoterodine, which improved symptoms by 4.5 points more than placebo in a phase 2 trial in 2026.¹⁶

What we don’t know yet

• How well it works over years, against other antipsychotics.
• Whether it helps people whose illness has not responded to other medicines, including clozapine.