The acute effect of cannabis on plasma, liver and brain ammonia dynamics, a translational study.
Recent reports of ammonia released during cannabis smoking raise concerns about putative neurotoxic effects. Cannabis (54mg) was administered in a double-blind, placebo-controlled design to healthy cannabis users (n15) either orally, or through smoking (6.9%THC cigarette) or inhalation of vaporized cannabis (Volcano®). Serial assay of plasma ammonia concentrations at 0, 2, 4, 6, 8, 10, 15, 30, and 90min from onset of cannabis administration showed significant time (P0.016), and treatment (P0.0004) effects with robust differences between placebo and edible at 30 (P0.002), and 90min (P0.007) and between placebo and vaporized (P0.02) and smoking routes (P0.01) at 90min. Furthermore, plasma ammonia positively correlated with blood THC concentrations (P0.03). To test the hypothesis that this delayed increase in plasma ammonia originates from the brain we administered THC (3 and 10mgkg) to mice and measured plasma, liver, and brain ammonia concentrations at 1, 3, 5 and 30min post-injection. Administration of THC to mice did not cause significant change in plasma ammonia concentrations within the first 5min, but significantly reduced striatal glutamine-synthetase (GS) activity (P0.046) and increased striatal ammonia concentration (P0.016). Furthermore, plasma THC correlated positively with striatal ammonia concentration (P<0.001) and negatively with striatal GS activity (P0.030). At 30min, we found marked increase in striatal ammonia (P<0.0001) associated with significant increase in plasma ammonia (P0.042) concentration. In conclusion, the results of these studies demonstrate that cannabis intake caused time and route-dependent increases in plasma ammonia concentrations in human cannabis users and reduced brain GS activity and increased brain and plasma ammonia concentrations in mice.