Opioid receptor antagonist

Aticaprant is an oral, short-acting antagonist of the kappa-opioid receptor, the receptor for dynorphin, developed for anhedonia and depression. In an 8-week trial in people with anhedonia it raised reward-related activity in the ventral striatum and modestly lowered anhedonia scores, and added to an SSRI or SNRI it lowered depression scores by 2–3 points more than placebo in a 6-week phase 2 trial. Johnson & Johnson then stopped its phase 3 program in March 2025 for insufficient efficacy, without publishing the data.

Low-dose naltrexone (LDN) is naltrexone, an opioid receptor antagonist licensed at 50 mg a day for alcohol and opioid dependence, taken off-label at about 1–5 mg a day for fibromyalgia, Crohn's disease, multiple sclerosis and other chronic conditions. At 2–5 mg it blocks roughly a quarter to a half of the brain's mu-opioid receptors, and it is proposed to calm inflammatory glial cells as well. Small early trials were positive, but the larger placebo-controlled trials in fibromyalgia and Crohn's disease were negative, and long COVID has no published randomized trial.