A Drug That Helps Extinction Stick and Still Loses to Relapse
- A six-arm, randomized, triple-blind, placebo-controlled trial (N = 180 healthy participants) gave a single dose of sodium butyrate (NaBu), an endogenous HDAC inhibitor, before or after a three-day Pavlovian fear-conditioning and extinction paradigm.
- NaBu facilitated retrieval of the extinction memory seven days later, whether given before or after extinction learning.
- NaBu did not prevent the return of fear during a subsequent reinstatement test.
- The drug's benefit depended on the extinction learning itself being robust: it emerged only in participants who had completed a high number of extinction trials, and no side effects were observed at the dose used.
Extinction-based treatments have two separate failure points: the new, safer memory can fail to stick, and even when it sticks, an unexpected aversive event can still bring the old fear back. This trial targeted the first problem and shows, cleanly, that fixing it does not touch the second.
What the Drug Actually Moved
Participants who received NaBu, an over-the-counter-adjacent short-chain fatty acid already implicated in extinction persistence in rodent models, retrieved their extinction memory better a week later than those on placebo, regardless of whether the dose came before or after the extinction session. That is a real effect on a well-established weak point of exposure-based treatment: the tendency for extinction learning to fade with time.
The Reinstatement Test Told a Different Story
The same participants, tested for reinstatement after an unexpected reminder of the original threat, showed the fear return regardless of whether they had received NaBu. Facilitating retrieval of a learned safety memory and blocking the reappearance of an old fear memory are not the same mechanism, and this trial is a direct demonstration that improving one does not automatically improve the other.
A Precondition, Not a Universal Booster
The facilitation effect only appeared in participants who had been through enough extinction trials to learn well in the first place. A drug that only helps good learning become durable is a narrower tool than a drug that rescues poor learning, and that distinction matters for how NaBu might eventually be tested alongside prolonged exposure therapy.
NaBu facilitated later retrieval of extinction memory after seven days... but it did not prevent return of fear during a subsequent reinstatement test.
The paradigm used healthy volunteers and an aversive-tone conditioning model, not a clinical anxiety sample or a real-world trauma reminder, and a single acute dose was tested rather than a dosing schedule aligned with a course of exposure therapy.