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Olney's lesions, also known as NMDA receptor antagonist neurotoxicity (NAN), are a form of brain damage caused by high doses of dissociative anaesthetics, particularly those referred to as "noncompetitive NMDA-channel-blockers" such as ketamine, phencyclidine (PCP), and dextromethorphan (DXM).
Additional recommended knowledge
In 1989, John W. Olney et. al conducted tests wherein high doses of the experimental dissociative MK-801 (Dizocilpine) were injected into rats. Shortly after dosage, the rats' brains were examined.
Evidence from these tests seemed to show the post-dissociative development of tiny holes, or vacuoles, primarily in the posterior cingulate cortex and retrosplenial cortex regions of the brain. These vacuoles would lead to a concentration of microglia and Heat-Shock Protein 70 (HSP70), which would form irreversible lesions. The dissociatives also seemed to form antecedents of other forms of brain damage in the test subjects.
Researcher Roland N. Auer conducted similar studies to look at the correlation between age and sex and the development of NAN (NMDA receptor antagonist neurotoxicity) in test rats. Older rats suffered a much higher mortality rate after the development of NAN. Female rats were found, at all ages, to have a higher incidence of necrotic (dead) neurons as a result of NAN.
Nitrous oxide, a common anesthetic for humans (especially in dentistry), has also been shown to cause vacuolization in rats' brains, but caused no irreversible lesions.
Dextromethorphan, a common antitussive found in cough medicines, has been shown to cause vacuolization in rats' brains. However, oral administration of dextromethorphan does not cause vacuolization in rats' brains.
However, Olney's Lesions have not yet been proven or disproven to manifest in humans. No tests on humans have ever been conducted to test the validity of post-dissociative development of vacuolization in brain cells. Therefore, critics claim that this kind of animal testing is not reliable. However, J.W. Olney stated in January 2002:
The evidence is that ketamine and many other NMDA-receptor antagonists that have been tested in humans, cause an acute disturbance in neural circuitry that leads to psychotic manifestations. These same drugs cause the same disturbance in neural circuitry in rats and when we look at their brains we see evidence for physical neuronal injury. Since no one has looked at the brains of humans immediately after administering these drugs, we do not know whether the physical neuronal injury occurs.
In medical settings, NMDA receptor antagonists are used as anesthetics, so GABA-A receptor agonists are used to effectively prevent any neurotoxicity caused by NMDA receptor antagonists. Drugs that work to suppress NAN include anticholinergics, diazepam, and barbiturates.
William White, a DXM researcher, concluded that Olney's lesions were forming in humans. In 2003, Cliff Anderson, a researcher and critic, wrote an article that illustrated that the tests conducted by Olney and Farber did not provide any conclusive evidence that lesions develop in human brains after exposure to dissociatives. Anderson quoted Karl L. R. Jansen's book, Ketamine: Dreams and Realities, which cited unpublished studies on monkey brains. White's opinion that DXM caused Olney's Lesions therefore came under fire. From Ketamine: Dreams and Realities:
Roland Auer injected monkeys with MK801 and was unable to produce any vacuoles.[...]
White therefore concluded that based on some fundamental differences between rat biology and human biology and because there have only been very few studies done on the occurrence of Olney's lesions, no connection can currently be proved or disproved.
Serotonergic psychedelics such as psilocybin and LSD agonize 5-HT (serotonin) receptors. Studies have shown that the serotonin systems affected by such serotonergic drugs are linked to the NMDA/glutamate systems. Tests on rats indicate that 5-HT agonists like LSD and psilocybin prevent the neurotoxicity caused by NMDA receptor antagonists.
NMDA Receptor Antagonists
Common NMDA Receptor Antagonists include:
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Olney's_lesions". A list of authors is available in Wikipedia.|