The acute effect of cannabis on plasma, liver and brain ammonia dynamics, a translational study

Abstract Recent reports of ammonia released during cannabis smoking raise concerns about putative neurotoxic effects. Cannabis (54 mg) was administered in a double-blind, placebo-controlled design to healthy cannabis users ( n =15) 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 90 min from onset of cannabis administration showed significant time ( P =0.016), and treatment ( P =0.0004) effects with robust differences between placebo and edible at 30 ( P =0.002), and 90 min ( P =0.007) and between placebo and vaporized ( P =0.02) and smoking routes ( P =0.01) at 90 min. Furthermore, plasma ammonia positively correlated with blood THC concentrations ( P =0.03). To test the hypothesis that this delayed increase in plasma ammonia originates from the brain we administered THC (3 and 10mg/kg) to mice and measured plasma, liver, and brain ammonia concentrations at 1, 3, 5 and 30 min post-injection. Administration of THC to mice did not cause significant change in plasma ammonia concentrations within the first 5 min, but significantly reduced striatal glutamine-synthetase (GS) activity ( P =0.046) and increased striatal ammonia concentration ( P =0.016). Furthermore, plasma THC correlated positively with striatal ammonia concentration ( P P =0.030). At 30 min, we found marked increase in striatal ammonia ( P P =0.042) 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.