D-serine and sarcosine

What they are

The NMDA receptor, which is thought to work too weakly in schizophrenia, needs a second substance, glycine or D-serine, bound alongside glutamate before it can work. D-serine is that second substance itself. Sarcosine, a natural amino acid, blocks the pump that clears glycine away, so more glycine stays near the receptor.^1,2 The reasoning is explained in Beyond dopamine (opens in a new tab).

How well they work

The first trial of D-serine, in Taiwan, added it to antipsychotics in 31 people for six weeks, and symptoms improved.¹ A trial in Israel found the same in 39 people.³ The largest trial, of 195 people over 16 weeks, did not: negative symptoms improved by 11.4% on D-serine and 14.8% on placebo.⁴ That trial used a low dose; an open study had found larger effects at doses about three times as high.⁵ In 44 young people at high risk of psychosis, a higher dose improved negative symptoms.⁶

Sarcosine improved symptoms in two trials in Taiwan, with 38 and 65 people.^2,7 In Poland, 60 people with mainly negative symptoms took sarcosine or a placebo for six months, and their symptoms improved more on sarcosine.⁸ Pooled analyses disagree: one found a benefit,⁹ another found none overall, only in people with long-standing illness who were not taking clozapine.¹⁰

Side effects

D-serine damages the kidney in rats. Across human studies, one person had abnormal kidney values, which returned to normal.¹¹ Sarcosine’s side effects were generally mild, though one person developed a manic episode when it was added to an antidepressant.¹²

Alternatives

Medicines that aim to raise glycine more strongly, glycine transporter inhibitors (opens in a new tab), failed in large trials. Sodium benzoate (opens in a new tab) raises D-serine indirectly.

What we don’t know yet

• Whether higher doses of D-serine help in large trials.
• Which people, if any, benefit from sarcosine.