Summary: A randomized, double-blind trial suggests the antibiotic doxycycline can weaken the formation of fear-related memories that underlie conditions such as post-traumatic stress disorder (PTSD).

Source: UCL

The common antibiotic doxycycline can reduce formation of negative associations in the brain

Researchers report that a single course of doxycycline, a widely used antibiotic, significantly reduced the strength of experimentally induced fear memories in healthy volunteers. The findings, published in Molecular Psychiatry, come from a pre-registered, placebo-controlled, double-blind randomized trial involving 76 participants and point to a novel pharmacological route for preventing or treating maladaptive fear learning linked to anxiety disorders.

Design and key results

Participants received either doxycycline or an inert placebo before completing a standardized Pavlovian fear-conditioning task. During the initial session, volunteers sat in front of a screen that alternated between two colors; one color was paired with an uncomfortable electric shock on half of the presentations, establishing a learned association between that color and threat.

One week later, participants returned without medication for a follow-up session. The same colored cues were shown, but no shocks were delivered; instead, a loud sound accompanied each cue. Researchers measured fear responses using the startle reflex—tracked by eye-blink magnitude—which provides an instinctive, objective index of defensive reactivity. The magnitude of the fear response to the previously shock-associated color was approximately 60% lower in the group that had received doxycycline during the initial learning session compared with the placebo group. Measures of sensory memory and attention were not significantly affected.

Mechanism and scientific rationale

Lead author Professor Dominik Bach explains that the intervention does not erase factual memory of an event but rather reduces the automatic fearful reaction tied to that memory. The theoretical basis for the experiment rests on growing evidence that synaptic remodeling needed for forming long-term memories requires extracellular enzymes known as matrix metalloproteinases (MMPs). MMP activity contributes to changes in the brain’s extracellular matrix that permit synaptic plasticity.

Doxycycline is known to inhibit matrix metalloproteinases and crosses the blood–brain barrier. Because MMP overactivity is already a drug target in other medical conditions, researchers hypothesized that doxycycline could interfere with the extracellular signaling required to consolidate fear memories. The trial results support this hypothesis by showing a marked attenuation of conditioned fear when doxycycline was present during initial learning.

Implications for PTSD prevention and treatment

Post-traumatic stress disorder develops when a traumatic memory triggers persistent, exaggerated fear responses. The study provides a proof of principle that pharmacological blockade of extracellular enzymes during memory formation can reduce the strength of threat memories. While preventing PTSD in advance would be difficult in many real-world situations because traumatic events are typically unpredictable, the authors note another promising application: targeting memory reconsolidation.

Reconsolidation refers to the process by which a consolidated memory can become labile and susceptible to modification when it is retrieved or reactivated. If doxycycline can weaken fear memory during reconsolidation after a traumatic event, the approach could be translated into interventions that reduce pathological fear responses in clinically relevant settings. The research team plans to test doxycycline’s effect on reconsolidation in future studies and to explore more realistic models of PTSD.

Study methods in more detail

During the acquisition session, the colored cues were presented 160 times in random order, with one color followed by a painful shock on 50% of presentations. This protocol established a robust learned association. Seven days later, in the absence of shocks and without any medication, the same cues were shown and a loud sound played after each cue to elicit startle. Fear memory was quantified as the difference between startle responses to the previously shock-paired cue and startle to the non-shock cue.

Funding and publication

The work was funded by the Swiss National Science Foundation, the University of Zurich and the Wellcome Trust. The trial and its results are reported in the peer-reviewed article “Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline” by D. R. Bach, A. Tzovara and J. Vunder in Molecular Psychiatry (published online April 4, 2017).

Abstract summary

The study tested whether inhibition of matrix metalloproteinases by doxycycline affects human threat learning. In a randomized, double-blind, placebo-controlled design, doxycycline given during initial acquisition reduced fear-potentiated startle at recall seven days later by about 60%. The pattern of results supports the role of extracellular signaling pathways in threat memory formation and suggests potential pharmacological strategies for the prevention and treatment of PTSD.