Olney's lesions, also known as

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...

neurotoxicity (NAN), are a form of potential

brain damage Neurotrauma, brain damage or brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating t ...

due to drugs that have been studied experimentally and have produced neuronal damage, yet are administered by doctors to humans in the settings of

pharmacotherapy Pharmacotherapy is therapy using pharmaceutical drugs, as distinguished from therapy using surgery (surgical therapy), radiation (radiation therapy), movement (physical therapy), or other modes. Among physicians, sometimes the term ''medical ther ...

and of

anesthesia Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...

. They are named after

John Olney John Olney (1932 – April 14, 2015) was a medical doctor and a professor of psychiatry, pathology, and immunology at the Washington University School of Medicine. He is known for his work on brain damage. He coined the term excitotoxicity in his 19 ...

, who conducted a study in 1989 to investigate

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...

caused by PCP and related drugs. They are important for two reasons. Firstly,

NMDA receptor antagonists NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...

are physician-prescribed drugs for therapeutic treatment of human diseases such as

memantine Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizziness. Severe side effects may include blood clots ...

for

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...

and

amantadine Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wid ...

for

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

, and also occur as street drugs that are taken recreationally. Secondly in the field of anesthesiology, the

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens which distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

anesthesia of many general anesthetics is due to NMDA receptor antagonist properties. Because the neuronal vacuolation of Olney's lesions evolves into neuronal

necrosis Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated diges ...

or death of neurons, it is important to determine whether Olney's lesions occur in humans, not only in experimental animals. The essential question is whether an

drug is to be considered a human

neurotoxin Neurotoxins are toxins that are destructive to nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insultsSpencer 2000 that can adversely affect function in both developing and mature nerv ...

or not. The

patient safety Patient safety is a discipline that emphasizes safety in health care through the prevention, reduction, reporting and analysis of error and other types of unnecessary harm that often lead to adverse patient events. The frequency and magnitude of ...

implications for

and for

would each be profound, if the answer is affirmative.

History

In 1989, Olney et al. discovered that neuronal

vacuolation A vacuole () is a membrane-bound organelle which is present in plant and fungal cells and some protist, animal, and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic mo ...

and other cytotoxic changes ("lesions") occurred in brains of rats administered NMDA antagonists, including PCP,

MK-801 Dizocilpine ( INN), also known as MK-801, is a pore blocker of the ''N''-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is ...

(dizocilpine) and

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppress ...

. Examination of neurons in the posterior cingulate and retrosplenial cortices by

electron microscopy An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...

revealed apparent lytic breakdown of

mitochondria A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

in the large vacuoles which had become apparent 2 hours after administration of an NMDA antagonist. After administration of 1.0 (mg/kg subcutaneously) 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

and

tiletamine Tiletamine is a dissociative anesthetic and pharmacology, pharmacologically classified as an NMDA receptor antagonist. It is related chemically to ketamine. Tiletamine hydrochloride exists as odorless white crystals. It is used in veterinary me ...

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 In statistics, correlation or dependence is any statistical relationship, whether causal or not, between two random variables or bivariate data. Although in the broadest sense, "correlation" may indicate any type of association, in statistic ...

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, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. Mortality rate is typically expressed in units of d ...

after the development of NAN. Female rats were found, at all ages, to have a higher incidence of

necrotic Necrosis () is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated dige ...

(dead)

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...

s as a result of NAN.

Nitrous oxide Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or nos, is a chemical compound, an oxide of nitrogen with the formula . At room temperature, it is a colourless non-flammable gas, and ha ...

, a common

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two ...

for humans (especially in

dentistry Dentistry, also known as dental medicine and oral medicine, is the branch of medicine focused on the teeth, gums, and mouth. It consists of the study, diagnosis, prevention, management, and treatment of diseases, disorders, and conditions of ...

), has also been shown to cause

vacuolization Vacuolization is the formation of vacuoles or vacuole-like structures, within or adjacent to cells. Perinuclear vacuolization of epidermal keratinocytes is most likely inconsequential when not observed in combination with other pathologic find ...

in rats' brains, but caused no irreversible lesions.

Dextromethorphan Dextromethorphan (DXM) is a medication most often used as a cough suppressant in over-the-counter cold and cough medicines. It is sold in syrup, tablet, spray, and lozenge forms. In 2022, the FDA approved a formulation of it combined with b ...

, a common

antitussive Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including ...

often found in

cough medicine Cold medicines are a group of medications taken individually or in combination as a treatment for the symptoms of the common cold and similar conditions of the upper respiratory tract. The term encompasses a broad array of drugs, including ...

s, has been shown to cause vacuolization in rats' brains when administered at doses of 75 mg/(kg ip). 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 (DXO) is a psychoactive drug of the morphinan class which acts as an antitussive or cough suppressant and dissociative hallucinogen. It is the dextrorotatory enantiomer of racemorphan; the levorotatory enantiomer is levorphanol. D ...

was administered to male rats, neurotoxic changes were observed only 30 minutes post-dose. Even if the hypothesis of gross neural apoptosis proves to be false in humans, NMDA antagonists certainly have potential to permanently alter synaptic structure due to effects upon long term potentiation, a process in which

NMDA receptors The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...

plays a crucial role. Perhaps, with repeated usage, this would manifest, due to tolerance, thus downregulation, of the NMDA receptor system. This could feasibly alter the function/relationship of various structures, specifically the ventral visual stream, perhaps a cause of the anecdotal reports of hallucinogen persisting perception disorder (HPPD) from such chronic users of novel psychoactive substances. In 1999 an autopsy study by

Johannes Kornhuber Johannes Kornhuber (born September 11, 1959) is a German psychiatrist and psychotherapist. Life Kornhuber worked in the Department of Psychiatry at the University of Würzburg, Germany, as Postdoctoral Fellow, Resident and Supervising Physician ...

of 8 patients who had received

therapy looked at the selectively vulnerable brain regions where Olney's lesions occur, the cingulate and retrosplenial cortex, and found no evidence of Olney's lesions. In 2013 a study using magnetic resonance imaging showed brain lesions in ketamine addicts (using from 0.2g twice a week up to 1g daily for 0.5 up to 12 years) with severity depending on the duration of addiction and daily intake of ketamine. Cortical atrophy and holes in superficial white matter are seen early on. After 4 years of addiction lesions spread throughout the brain and damage is evident in the pons and other deeper brain structures.

Prevention

In medical settings, NMDA receptor antagonists are used as anesthetics, so GABA_A receptor positive allosteric modulators are used to effectively prevent any

caused by them. Drugs that work to suppress NAN include

anticholinergics Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous sys ...

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

barbiturates Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...

and

Alpha-adrenergic agonist The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...

s, such as

clonidine Clonidine, sold under the brand name Catapres among others, is an α2-adrenergic agonist medication used to treat high blood pressure, ADHD, drug withdrawal ( alcohol, opioids, or nicotine), menopausal flushing, diarrhea, spasticity, and c ...

. Conversely, coadministration of NMDA-antagonists with alpha-2 adrenergic antagonists, like

yohimbine Yohimbine (), also known as quebrachine, is an indole alkaloid derived from the bark of the African tree '' Pausinystalia johimbe''; also from the bark of the unrelated South American tree ''Aspidosperma quebracho-blanco''. Yohimbine is an α2 ...

, could theoretically potentiate NAN.

Controversy

In Karl L. R. Jansen's book, ''Ketamine: Dreams and Realities'', unpublished studies are cited on

monkey Monkey is a common name that may refer to most mammals of the infraorder Simiiformes, also known as the simians. Traditionally, all animals in the group now known as simians are counted as monkeys except the apes, which constitutes an incomple ...

brains. The opinion that DXM caused Olney's Lesions therefore came under fire. Jansen writes:

References

External links

"Lycaeum" about NAN
{{DEFAULTSORT:Olney's Lesions Neurotrauma Toxicology Lesion de:John W. Olney

History

Prevention

Controversy

See also

References

External links