Experiments performed on dolomite or Mg-calcite gouges at seismic slip rates (v > 1 m/s) and displacements (d > 1 m) show that the frictional coefficient μ decays exponentially from peak values (mp ≈ 0.8, in the Byerlee's range), to extremely low steady-state values (μss ≈ 0.1), attained over a weakening distance Dw. Microstructural observations show that discontinuous patches of nanoparticles of dolomite and its decomposition products (periclase and lime or portlandite) were produced in the slip zone during the transient stage (d < Dw). These observations, integrated with CO2 emissions data recorded during the experiments, suggest that particle interaction in the slip zone produces flash temperatures that are large enough to activate chemical and physical processes, e.g., decarbonation reactions (T = 550 °C). During steady state (d ≥ Dw), shear strength is very low and not dependent upon normal stresses, suggesting that pressurized fluids (CO2) may have been temporarily trapped within the slip zone. At this stage a continuous layer of nanoparticles is developed in the slip zone. For d >> Dw, a slight but abrupt increase in shear strength is observed and interpreted as due to fluids escaping the slip zone. At this stage, dynamic weakening appears to be controlled by velocity dependent properties of nanoparticles developed in the slip zone. Experimentally derived seismic source parameter Wb (i.e., breakdown work, the energy that controls the dynamics of a propagating fracture) (1) matches Wb values obtained from seismological data of the A.D. 1997 M6 Colfiorito (Italy) earthquakes, which nucleated in the same type of rocks tested in this study, and (2) suggests similar earthquake-scaling relationships, as inferred from existing seismological data sets. We conclude that dynamic weakening of experimental faults is controlled by multiple slip weakening mechanisms, which are activated or inhibited by physicochemical reactions in the slip zone.