Olney's lesions
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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).[1]
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[edit] History
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.[1] The dissociatives also seemed to form antecedents of other forms of brain damage in the test subjects.[1]
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 experienced 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.[2]
Nitrous oxide, a common anesthetic for humans (especially in dentistry), also has been shown to cause vacuolization in rats' brains, but caused no irreversible lesions.[3]
Dextromethorphan, a common antitussive often found in cough medicines, has been shown to cause vacuolization in rats' brains.[4] However, oral administration of dextromethorphan does not cause vacuolization in rats' brains.[5]
However, Olney's Lesions have not yet been proven or disproven to manifest in humans. No tests have been conducted to test the validity of post-dissociative development of vacuolization in human brain cells, and critics claim that animal testing is not a reliable predictor of the effects of dissociative substances on humans. 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.[6]
[edit] Prevention
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.[7] Drugs that work to suppress NAN include anticholinergics, diazepam, and barbiturates.[8]
[edit] Controversy
William White, a DXM researcher, concluded that Olney's lesions were forming in humans, but retracted his statement in 2004.[9] 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.[6] 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:[10]
Roland Auer injected monkeys with MK801 and was unable to produce any vacuoles.[...]
[R]ats have rates of brain metabolism that are almost twice as high as those in humans to start with. It is because of this higher base rate of metabolism that ketamine causes over-excitement in rats at doses below those at which it activates shutdown systems.
Frank Sharp also works in this area. I discussed with Sharp how this issue stood in 1998. His view was that reversible toxic changes in the rat started to appear at 40mg/kg and reached a level at which no further changes occurred (a plateau) at 100mg/kg, when a little cell death could be seen - but matters would not progress beyond this point. Extensive attempts to produce toxic changes in monkeys had been a total failure at doses up to 10mg/kg i.m. These monkey studies are unpublished.
I sought the view of Olney's colleague, Nuri Farber. The work of his team indicated that N-P receptors must be blocked for at least 2 hours to cause reversible changes, and at least 24 hours to produce some cell death, in rats. [...][H]e thought that the methods used in monkey studies so far were unsatisfactory, because the animals were probably too young. Only adult rats show the toxic changes. He was not prepared to accept a clean bill of health for the drug in primates until this work with older monkeys had been done, and until the drug companies published their monkey studies to support their claims of harmlessness.
There is thus no published evidence at this time (January 2000) that ketamine can produce toxic cell changes in monkeys. The unpublished monkey data that we know about, that of Frank Sharp, actually shows that there is no damage at doses up to 10mg/kg.
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.[11]
[edit] Serotonergic drugs
Serotonergic psychedelics such as psilocybin and LSD activate 5-HT (serotonin) receptors. Studies have shown that the serotonin systems affected by such serotonergic drugs are linked to the NMDA/glutamate systems.[12] Tests on rats indicate that 5-HT agonists like LSD and psilocybin prevent the neurotoxicity caused by NMDA receptor antagonists.[13]
[edit] NMDA receptor antagonists
Common NMDA Receptor Antagonists include:
[edit] See also
[edit] References
- ^ a b c Olney J, Labruyere J, Price M (1989). "Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs". Science 244 (4910): 1360-2. doi:. PMID 2660263.
- ^ Auer R (1996). "Effect of age and sex on N-methyl-D-aspartate antagonist-induced neuronal necrosis in rats". Stroke 27 (4): 743-6. PMID 8614941.
- ^ Jevtovic-Todorovic V, Beals J, Benshoff N, Olney J (2003). "Prolonged exposure to inhalational anesthetic nitrous oxide kills neurons in adult rat brain". Neuroscience 122 (3): 609-16. doi:. PMID 14622904.
- ^ Hashimoto, K; Tomitaka, S; Narita, N; Minabe, Y; Iyo, M; Fukui, S (1996). "Induction of heat shock protein Hsp70 in rat retrosplenial cortex following administration of dextromethorphan". Environmental Toxicology and Pharmacology 1 (4): 235-239. doi:.
- ^ Carliss RD, Radovsky A, Chengelis CP, O'neill TP, Shuey DL (2007). "Oral administration of dextromethorphan does not produce neuronal vacuolation in the rat brain". NeuroToxicology 28: 813. doi:. PMID 17573115.
- ^ a b Erowid DXM Vaults : Health : The Bad News Isn't In : A Look at Dissociative-Induced Brain Damage, by Anderson C
- ^ Nakao S, Nagata A, Masuzawa M, Miyamoto E, Yamada M, Nishizawa N, Shingu K (2003). "[NMDA receptor antagonist neurotoxicity and psychotomimetic activity]". Masui 52 (6): 594-602. PMID 12854473.
- ^ Olney J, Labruyere J, Wang G, Wozniak D, Price M, Sesma M (1991). "NMDA antagonist neurotoxicity: mechanism and prevention". Science 254 (5037): 1515-8. doi:. PMID 1835799.
- ^ Erowid DXM Vault : Health : This is your brain on dissociatives: the Bad News is Finally In, 1998, William E White
- ^ Jansen, Karl. Ketamine: Dreams and Realities. MAPS, 2004. ISBN 0966001974
- ^ Erowid DXM Vault : Response to "The Bad News Isn't In": Please Pass The Crow, by William E. White
- ^ Arvanov V, Liang X, Russo A, Wang R (1999). "LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex". Eur J Neurosci 11 (9): 3064-72. doi:. PMID 10510170.
- ^ Farber N, Hanslick J, Kirby C, McWilliams L, Olney J (1998). "Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity". Neuropsychopharmacology 18 (1): 57-62. doi:. PMID 9408919.
- ^ "Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy", University Health Network, Toronto, September 2005
- ^ Popik P, Layer R, Skolnick P (1994). "The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex". Psychopharmacology (Berl) 114 (4): 672-4. doi:. PMID 7531855.
