Olney's lesions
Encyclopedia
Olney's lesions, also known as NMDA receptor antagonist
neurotoxicity
(NAN), are a potential form of brain damage
. They are named after John Olney
, who conducted a study investigating neurotoxicity caused by PCP
and related drugs in 1989.
, MK-801 (dizocilpine) and ketamine
. Examination of neurons in the posterior cingulate and retrosplenial cortices by electron micrograph revealed apparent lytic breakdown of mitochondria in the large vacuoles which had become apparent 2 hours after administration of an NMDA antagonist. After administration of 1.0 (mg/kg sc) MK-801 to rats, these neurotoxic changes became more apparent until about 12 hours post-dose, but the morphology of most cells appeared normal by light microscope about 24 hours post-dose. With 10 (mg/kg sc) doses of MK-801, the vacuolation reaction was still visible by light microscope 48 hours post-dose. After repeated doses of the NMDA antagonists MK-801 and PCP, the vacuolation reaction appeared consistent with the reaction after a single dose, so there was no evidence of a cumulative neurotoxic effect or that the reaction proceeded to an irreversible stage with repeated doses. The lowest doses of ketamine and tiletamine
that produced neurotoxic changes visible by light microscope 4 hours post dose were 40 (mg/kg sc) and 10 (mg/kg sc), respectively. The potency of the drugs in producing these neurotoxic changes corresponded with their potency as NMDA antagonists: i.e. MK-801 > PCP > tiletamine > ketamine.
Researcher Roland N. Auer conducted similar studies to look at the correlation
between age and sex and the development of 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) neuron
s 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 often found in cough medicine
s, has been shown to cause vacuolization in rats' brains when administered at doses of 75 mg/kg. However, oral administration of dextromethorphan hydrobromide (DXM HBr) to female rats in single doses as high as 120 mg/kg did not result in detectable neurotoxic changes at 4-6 hours or 24-26 hours post-dose (female rats are more sensitive to NMDA antagonist neurotoxicity). The same researchers also found no evidence of neurotoxic changes in retrosplenial or cingulate cortices of male rats orally administered up to 400 mg/(kg day) DXM HBr or female rats orally administered 120 mg/(kg day) DXM HBr, both for 30 days. Carliss et al. (2007) also found that rats administered 9 mg/(kg day sc) (+)-MK-801 hydrogen maleate for 30 days did produce detectable vacuolation as expected. When 30 mg/(kg ip) dextrorphan
was administered to male rats, neurotoxic changes were observed only 30 minutes post-dose.
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 tissue, and critics claim that animal testing
is not a reliable predictor of the effects of dissociative substances on humans:
receptor agonists are used to effectively prevent any neurotoxicity
caused by them. Drugs that work to suppress NAN include anticholinergics, benzodiazepines, barbiturates and agonists at the alpha-2 adrenergic receptor
in the brain, such as clonidine
.
Conversely, coadministration of NMDA-antagonists with alpha-2 adrenergic antagonists
, like yohimbine
could theoretically potentiate NAN.
researcher, concluded that Olney's lesions were forming in humans, but retracted his statement in 2004. 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:
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.
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. Tests on rats indicate that 5-HT agonists like LSD
and psilocybin
prevent the neurotoxicity caused by NMDA receptor antagonists.
NMDA receptor antagonist
NMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor . They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia...
neurotoxicity
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
(NAN), are a potential form of brain damage
Brain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...
. They are named after John Olney
John Olney
John Olney is a medical doctor and neuropathologist known for his work on brain damage. He coined the term excitotoxicity in his 1969 paper published in Science. Olney's lesions are named after him. In 1996 he was elected to the Institute of Medicine of the United States National Academy of Sciences...
, who conducted a study investigating neurotoxicity caused by PCP
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
and related drugs in 1989.
History
In 1989, Olney et al. discovered that neuronal vacuolation and other cytotoxic changes ("lesions") occurred in brains of rats administered NMDA antagonists, including PCPPhencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
, MK-801 (dizocilpine) and ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
. Examination of neurons in the posterior cingulate and retrosplenial cortices by electron micrograph revealed apparent lytic breakdown of mitochondria in the large vacuoles which had become apparent 2 hours after administration of an NMDA antagonist. After administration of 1.0 (mg/kg sc) MK-801 to rats, these neurotoxic changes became more apparent until about 12 hours post-dose, but the morphology of most cells appeared normal by light microscope about 24 hours post-dose. With 10 (mg/kg sc) doses of MK-801, the vacuolation reaction was still visible by light microscope 48 hours post-dose. After repeated doses of the NMDA antagonists MK-801 and PCP, the vacuolation reaction appeared consistent with the reaction after a single dose, so there was no evidence of a cumulative neurotoxic effect or that the reaction proceeded to an irreversible stage with repeated doses. The lowest doses of ketamine and tiletamine
Tiletamine
Tiletamine is a dissociative anesthetic and pharmacologically classified as an NMDA receptor antagonist. It is related chemically and pharmacologically to other anesthetics in this family such as ketamine and phencyclidine...
that produced neurotoxic changes visible by light microscope 4 hours post dose were 40 (mg/kg sc) and 10 (mg/kg sc), respectively. The potency of the drugs in producing these neurotoxic changes corresponded with their potency as NMDA antagonists: i.e. MK-801 > PCP > tiletamine > ketamine.
Researcher Roland N. Auer conducted similar studies to look at the correlation
Correlation
In statistics, dependence refers to any statistical relationship between two random variables or two sets of data. Correlation refers to any of a broad class of statistical relationships involving dependence....
between age and sex and the development of NMDA receptor antagonist neurotoxicity in test rats. Older rats experienced a much higher mortality rate
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
after the development of NAN. Female rats were found, at all ages, to have a higher incidence of necrotic (dead) neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s as a result of NAN.
Nitrous oxide
Nitrous oxide
Nitrous oxide, commonly known as laughing gas or sweet air, is a chemical compound with the formula . It is an oxide of nitrogen. At room temperature, it is a colorless non-flammable gas, with a slightly sweet odor and taste. It is used in surgery and dentistry for its anesthetic and analgesic...
, a common anesthetic for humans (especially in dentistry
Dentistry
Dentistry is the branch of medicine that is involved in the study, diagnosis, prevention, and treatment of diseases, disorders and conditions of the oral cavity, maxillofacial area and the adjacent and associated structures and their impact on the human body. Dentistry is widely considered...
), has also been shown to cause vacuolization
Vacuolization
Vacuolization is the formation of vacuoles within or adjacent to cells, and, in dermatopathology, often refers to the basal cell-basement membrane zone area....
in rats' brains, but caused no irreversible lesions.
Dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
, a common antitussive often found in cough medicine
Cough medicine
A cough medicine is a medicinal drug used in an attempt to treat coughing and related conditions. For dry coughs, treatment with cough suppressants may be attempted to suppress the body's urge to cough...
s, has been shown to cause vacuolization in rats' brains when administered at doses of 75 mg/kg. However, oral administration of dextromethorphan hydrobromide (DXM HBr) to female rats in single doses as high as 120 mg/kg did not result in detectable neurotoxic changes at 4-6 hours or 24-26 hours post-dose (female rats are more sensitive to NMDA antagonist neurotoxicity). The same researchers also found no evidence of neurotoxic changes in retrosplenial or cingulate cortices of male rats orally administered up to 400 mg/(kg day) DXM HBr or female rats orally administered 120 mg/(kg day) DXM HBr, both for 30 days. Carliss et al. (2007) also found that rats administered 9 mg/(kg day sc) (+)-MK-801 hydrogen maleate for 30 days did produce detectable vacuolation as expected. When 30 mg/(kg ip) dextrorphan
Dextrorphan
Dextrorphan is a psychoactive drug of the morphinan chemical class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextro-stereoisomer of racemorphan, the levo-half being levorphanol. Dextrorphan is produced by O-demethylation of dextromethorphan by CYP2D6...
was administered to male rats, neurotoxic changes were observed only 30 minutes post-dose.
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 tissue, and critics claim that animal testing
Animal testing
Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals in experiments. Worldwide it is estimated that the number of vertebrate animals—from zebrafish to non-human primates—ranges from the tens of millions to more than 100 million...
is not a reliable predictor of the effects of dissociative substances on humans:
Prevention
In medical settings, NMDA receptor antagonists are used as anesthetics, so GABA-AGabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
receptor agonists are used to effectively prevent any neurotoxicity
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
caused by them. Drugs that work to suppress NAN include anticholinergics, benzodiazepines, barbiturates and agonists at the alpha-2 adrenergic receptor
Alpha-2 adrenergic receptor
The alpha-2 adrenergic receptor is a G protein-coupled receptor associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well...
in the brain, such as clonidine
Clonidine
Clonidine is a sympatholytic medication used to treat medical conditions, such as high blood pressure, some pain conditions, ADHD and anxiety/panic disorder...
.
Conversely, coadministration of NMDA-antagonists with alpha-2 adrenergic antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, like yohimbine
Yohimbine
Yohimbine is an alkaloid with stimulant and aphrodisiac effects found naturally in Pausinystalia yohimbe . It is also found naturally in Rauwolfia serpentina , Alchornea floribunda , along with several other active alkaloids...
could theoretically potentiate NAN.
Controversy
William White, a DXMDextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
researcher, concluded that Olney's lesions were forming in humans, but retracted his statement in 2004. 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
Monkey
A monkey is a primate, either an Old World monkey or a New World monkey. There are about 260 known living species of monkey. Many are arboreal, although there are species that live primarily on the ground, such as baboons. Monkeys are generally considered to be intelligent. Unlike apes, monkeys...
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.[...]
[R]ats have rates of brain metabolismMetabolismMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
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 primatePrimateA primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
s 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.
Serotonergic drugs
Serotonergic psychedelics such as psilocybinPsilocybin
Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...
and LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
activate 5-HT (serotonin)
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
receptors. Studies have shown that the serotonin systems affected by such serotonergic drugs are linked to the NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
/glutamate systems. Tests on rats indicate that 5-HT agonists like LSD
LSD
Lysergic acid diethylamide, abbreviated LSD or LSD-25, also known as lysergide and colloquially as acid, is a semisynthetic psychedelic drug of the ergoline family, well known for its psychological effects which can include altered thinking processes, closed and open eye visuals, synaesthesia, an...
and psilocybin
Psilocybin
Psilocybin is a naturally occurring psychedelic prodrug, with mind-altering effects similar to those of LSD and mescaline, after it is converted to psilocin. The effects can include altered thinking processes, perceptual distortions, an altered sense of time, and spiritual experiences, as well as...
prevent the neurotoxicity caused by NMDA receptor antagonists.
See also
- NMDA receptorNMDA receptorThe NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
- NMDA receptor antagonistNMDA receptor antagonistNMDA receptor antagonists are a class of anesthetics that work to antagonize, or inhibit the action of, the N-methyl d-aspartate receptor . They are used as anesthesia for animals and, less commonly, for humans; the state of anesthesia they induce is referred to as dissociative anesthesia...
- Dissociative
- Neurotoxic drug