OBJECTIVE. The relationship between metformin accumulation and lactate increase is still debated. This observational case series aims to evaluate the correlation of metformin plasma levels with the pH, lactate and creatinine levels, and with the mortality rate in selected patients with metformin accumulation confirmed through metformin plasma concentration detection at hospital admission. MATERIAL AND METHODS. All cases of lactic acidosis (pH, ≤ 7.35; arterial lactate, ≥ 5 mmol/L) related to metformin accumulation (plasma level ≥ 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. RESULTS. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 ± 0.18; lactate, 14.36 ± 4.90 mmol/L) and acute renal failure (creatinine, 7.24 ± 3.29 mg/dL). The mean metformin plasma concentration was 40.68 ± 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p < 0.0001, R = - 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases). Lactate and metformin concentrations had mean levels not statistically different in surviving and deceased patients. CONCLUSIONS. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission. The correlation between metformin plasma concentrations and creatinine, pH, and lactate levels seems to be related to the mechanism of action (inhibition of complex I of the mitochondrial respiratory chain) and to the kinetic properties (high distribution volume and low protein binding) of the drug. The relevant early mortality seems not correlated with the levels of metformin or lactates: this could be due to the possible role of concurrent illness even if, such as for the relationships with lactate and creatinine, a more proper toxicological evaluation could be obtained by assessing metformin erythrocyte concentrations instead of the plasmatic ones.

Recent data indicate that both availability and consumption of synthetic and natural psychoactive substances, marketed under the name of "legal highs", has increased. Among them, the aminoalkylindole-derivative JWH-018 is widely distributed due to its capability of binding the cannabinoid receptors CB1 and CB2 thereby mimicking the effects of classical drug agonists. To address whether the behavioral effects of the synthetic compound JWH-018 are similar to those induced by classical cannabinoid agonists, we investigated, in outbred CD1 mice, the consequences of its acute and sub-chronic administration (0, 0.03, 0.1, or 0.3 mg/kg, IP) at the level of body temperature, pain perception, general locomotion, and anxiety. In order to address whether the exposure to precocious stressors-modified individual reactivity to this psychoactive substance, we also investigated its effects in adult mice previously exposed to prenatal stress in the form of corticosterone supplementation in the maternal drinking water (33 or 100 mg/L). In the absence of major effects on motor coordination, JWH-018-reduced body temperature, locomotion and pain reactivity, and increased indices of anxiety. Prenatal corticosterone administration-reduced individual sensitivity to the effects of JWH-018 administration in all the aforementioned parameters. This altered response is not due to variations in JWH-018 metabolism. Present data support the hypothesis that precocious stress may affect, in the long-term, the functional status, and reactivity of the endocannabinoid system.

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