Three months of methoxetamine administration is associated with significant bladder and renal toxicity in mice

UNLABELLED: CONTEXT.: Methoxetamine is a ketamine analogue that has recently emerged as a novel psychoactive substance. Chronic ketamine use is associated with significant bladder and renal toxicity. Methoxetamine has been marketed as "bladder friendly", but there is no data to be able to substantiate this claim.

Objective: To characterise the patterns of bladder and renal toxicity associated with 3 months of methoxetamine administration in an animal model.

Materials and Methods: Two-month-old Institute of Cancer Research mice were administered 30 mg/kg methoxetamine intraperitoneally (n = 5) or saline (n = 3 control) for 3 months. The animals were then sacrificed and histological examination, immuno-cytochemistry using polyclonal anti-CD4 antibodies and sirius-red staining for collagen were performed.

Results: The kidneys of methoxetamine-treated animals showed inflammatory cell infiltration, tubular cell necrosis and glomerular damage (1.9 ± 0.3% shrunken glomeruli in control, 9.8 ± 0.8% in methoxetamine-treated mice (p < 0.0001); 2.9 ± 0.3% tubular cell degeneration in control, 20.4 ± 1.1% in methoxetamine-treated mice (p < 0.0001)). There was a greater density of mononuclear cells in the bladder lamina propria and submucosa in methoxetamine-treated mice (43.0 ± 2.1 per 250 × 250 μm) than controls (7.1 ± 1.2 per 250 × 250 μm), p < 0.001. CD4-positive staining was seen in the bladder submucosa and lamina propria of all methoxetamine-treated mice and muscle-layer of two methoxetamine-treated mice; these changes were not seen in the control mice. There was an increase in sirius-red collagen in the bladder sub-mucosa and muscle-layer in the methoxetamine-treated mice compared with control mice.

Discussion: This study has shown that 3 months of daily 30 mg/kg intra-peritoneal methoxetamine results in significant bladder and renal toxicity in mice. Changes in the bladder included inflammatory changes with subsequent fibrosis and changes in the kidney were seen at both a tubular and glomerular level. These changes are similar to those seen in comparable animal models of chronic ketamine administration. Further work is required to determine the time course of the onset of these effects and whether the effects are reversible with methoxetamine cessation.