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NMDA Antagonist Neurotoxicity

Introduction

NMDA Antagonist Neurotoxicity (also known as NAN or Olney’s Lesions) are a form of brain damage occurring in rats, caused by the administration of high doses of dissociative drugs, particularly noncompetitive NMDA channel blockers (DXM, ketamine, nitrous oxide, phencyclidine, etc.). NAN has been discovered by John W. Olney.

Action

NAN consists of the formation of vacuoles (tiny pores) in the posterior cingulate cortex and retrosplenial cortex. These lead to a higher concentration of microglia and Heat Shock Protein 70, causing irreversible brain damage. In other clinical trials, it was shown that other dissociative drugs (PCP, ketamine, dextrorphan) also cause NAN. In the case of nitrous oxide, although vacuolization has been recorded, it did not cause any further brain damage.

Further studies have shown that females and older individuals are more susceptible to NAN, young individuals being less susceptible. The brain damage resulted in permanently weakened learning abilities in test animals.

History

In 1989, the psychiatrist John W. Olney conducted a study in which high doses of the potent NMDA receptor antagonist dizocilpine (MK-801) have been injected into rats. A few hours after injection, the rats were killed and their brains examined. This and further studies (in which other dissociative drugs and possible neuroprotective drugs have been tested) have proven that high doses of NMDA receptor antagonists cause irreversible lesions in the brain. These were called Olney’s Lesions, after their discoverer.

In 1998, the DXM researcher William White, known for his DXM FAQ, published a paper (“This is your brain on dissociatives - The bad news is finally in”) in which he presented his idea that dissociative drugs produce NAN in humans. The correlation (heavy users of NMDA antagonists present cognitive impairment) was presented as a causation (dissociatives cause NAN in humans), based on the fact that most symptoms of the often reported dissociative induced cognitive impairment coincide with the brain areas damaged in rats after administration of high doses of dissociatives.

In 2003, Cliff Anderson published a paper titled “The bad news isn’t in” in which White’s paper was heavily criticized. Anderson argued that White’s ideas were almost completely unfounded from a scientific point of view and tried to find other explanations for the dissociative induced cognitive impairment. As a response, William White retracted his original paper in 2004.

Controversy

It has been strongly argued whether NAN occurs not only in rats, but also in humans.

Arguments for NAN in humans

William White’s sole logical argument for NAN in humans is the fact that some heavy users of dissociatives have reported symptoms coinciding with some of the functions of the brain areas damaged in rats after high-dose dissociative administration (these symptoms include impaired memory, language skills and ability to understand methaphors).

Arguments against NAN in humans

In monkeys, dizocilpine (MK-801) and ketamine have been tested, and both have been found not to cause NAN.

Although ketamine has been proven to cause NAN in rats, most ketamine users have not shown permanent brain damage, even with heavy use over an extended time period, suggesting that NAN does not occur in humans.

In rats, anticholinergics (particularly scopolamine) have successfully prevented NAN. If NAN would occur in humans, the same would take place, for instance with Coricidin HBP Cough & Cold, which contains DXM and chlorpheniramine (an anticholinergic). But Coricidin was never reported to cause less cognitive impairment than DXM alone.

Although it was neither proved nor disproved that NAN can occur in humans, most circumstantial and anecdotal evidence suggests that the damage done by heavy dissociative use is almost completely reversible, by abstaining from dissociative drugs. Considering that NAN means permanent, irreversible brain damage, the dissociative induced cognitive impairment is probably a result of another mechanism or more than one mechanisms. Another possibility is that phenomena similar to NAN can occur in humans, only not causing massive neuron death like in rats. This could possibly explain the irreversible cognitive impairment reported by a small number of heavy DXM users.
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