Psilocybin, unlike S-ketamine and MK-801, does not induce neuronal damage in the retrosplenial cortex of rats. Both S-ketamine and psilocybin are rapid-acting antidepressants that increase glutamate signalling and cortical hyperexcitation, but S-ketamine is known to cause neurotoxicity (Olney's lesions) in the retrosplenial cortex. Using immunohistochemical whole-brain mapping for heat shock protein 70 (HSP70) in rats, no HSP70-positive neurons were detected in the retrosplenial cortex of psilocybin-treated animals, whereas S-ketamine and MK-801 produced such markers. This suggests psilocybin may be safer for clinical use regarding neuronal damage.
Ketamine is a fast-acting antidepressant but can cause psychosis-like side effects. The nitric oxide donor sodium nitroprusside (SNP) prevents such effects in rats and humans. In mice, pre-treatment with SNP (0.5-1 mg/kg) did not alter the antidepressant effect of ketamine (30 mg/kg) in the Porsolt Forced Swim Test, and SNP alone had no effect. This suggests the nitrinergic system may be differentially involved in ketamine's antidepressant versus psychotomimetic effects, though species differences cannot be ruled out.