Stress axis (HPA)

Ashwagandha (Withania somnifera) extracts have modest human trial evidence for perceived stress and sleep, although pooled results differ by outcome and trial quality is mixed. KSM-66, a root-only extract standardized to at least 5% withanolides, is used in several well-known trials. Extract names and standardization measures matter: their trial results are not automatically interchangeable.

Phosphatidylserine (PS) is a membrane phospholipid sold for memory. The strongest early trial used PS extracted from cow brain, in 494 elderly patients with cognitive decline. Soy-derived PS, developed as an alternative to bovine PS, has smaller trials showing memory gains in older adults with memory complaints. Smaller studies suggest it blunts the cortisol response to stress.

Rhodiola rosea is an Arctic and alpine herb marketed as an adaptogen for stress and fatigue. Some randomized trials report less mental fatigue, but one found it made fatigue worse. Systematic reviews describe the evidence as contradictory and the trials as poorly reported.

Seltorexant (JNJ-42847922, MIN-202) is an investigational selective orexin-2 receptor antagonist from Janssen, developed with Minerva Neurosciences as an add-on treatment for major depression with insomnia symptoms. Unlike the licensed dual orexin antagonists it binds the OX2 receptor about 100 times more tightly than OX1, and its half-life is only 2–3 hours. Added to an antidepressant, 20 mg at bedtime lowered depression scores by about 3 points more than placebo in a phase 2 trial, mostly in people with marked insomnia, and a 586-patient phase 3 trial reported a 2.6-point advantage; a head-to-head phase 3 trial against quetiapine missed its primary endpoint, and as of mid-2026 it was not approved anywhere.