Memantine is a medication used to slow the progression of moderate-to-severe
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, 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 short-term me ...
.
It is taken by mouth.[
Common side effects include headache, constipation, sleepiness, and dizziness.][ Severe side effects may include blood clots, ]psychosis
Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavior ...
, and heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
.[ It is believed to work by acting on ]NMDA receptor
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 rece ...
s, working as pore blockers of these ion channels.
Memantine was approved for medical use in the United States in 2003.[ It is available as a ]generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
.[ In 2020, it was the 152nd most commonly prescribed medication in the United States, with more than 3million prescriptions.
]
Medical use
Alzheimer's disease and dementia
Memantine is used to treat moderate-to-severe Alzheimer's disease, especially for people who are intolerant of or have a contraindication to AChE (acetylcholinesterase) inhibitors.[NICE review of technology appraisal guidance 111 January 18, 201]
Alzheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination
One guideline recommends memantine or an AChE inhibitor be considered in people in the early-to-mid stage of dementia.
Memantine has been associated with a modest improvement; with small positive effects on cognition
Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
, mood, behavior, and the ability to perform daily activities in moderate-to-severe Alzheimer's disease. There does not appear to be any benefit in mild disease.
Memantine when added to donepezil
Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's disease, Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, ha ...
in those with moderate-to-severe dementia resulted in "limited improvements" in a 2017 review. The UK National Institute of Clinical Excellence
The National Institute for Health and Care Excellence (NICE) is an executive non-departmental public body of the Department of Health and Social Care in England that publishes guidelines in four areas:
* the use of health technologies withi ...
(NICE) issued guidance in 2018 recommending consideration of the combination of memantine with donepezil in those with moderate-to-severe dementia.
Psychiatry
Bipolar disorder
Memantine has been investigated as a possible augmentation strategy for depression in bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
but meta-analytic evidence does not support its clinical utility.
Autism
Effects in autism are unclear.
Adverse effects
Memantine is, in general, well tolerated.[ Common ]adverse drug reaction
An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...
s (≥1% of people) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia
Hypertonia is a term sometimes used synonymously with spasticity and rigidity in the literature surrounding damage to the central nervous system, namely upper motor neuron lesions. Impaired ability of damaged motor neurons to regulate descending ...
, cystitis
A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...
, and increased libido
Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...
.[Rossi S, editor. ]Australian Medicines Handbook
Australian Medicines Handbook (AMH) is a peer-reviewed medicines prescribing guide for Australian health professionals. The handbook is available in paper and digital formats and is supplemented by the ''AMH Aged Care Companion'' and the ''AMH C ...
2006. Adelaide: Australian Medicines Handbook; 2006.
Like many other NMDA 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 induc ...
, memantine behaves as a dissociative anesthetic
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 ...
at supratherapeutic doses. Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability. Also memantine seems to lack effects such as euphoria or hallucinations.
Memantine appears to be generally well tolerated by children with autism spectrum disorder
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...
.
Pharmacology
Glutamate
A dysfunction of glutamatergic neurotransmission, manifested as 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. N ...
al excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate re ...
, is hypothesized to be involved in the etiology
Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
of Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, 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 short-term me ...
. Targeting the glutamatergic
Glutamatergic means "related to glutamate". A glutamatergic agent (or drug) is a chemical that directly modulates the excitatory amino acid (glutamate/ aspartate) system in the body or brain. Examples include excitatory amino acid receptor agonist ...
system, specifically NMDA receptor
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 rece ...
s, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic
Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...
system.
Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
following depolarization
In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...
of the postsynaptic
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous sys ...
neuron. The interaction of memantine with NMDA receptors plays a major role in the symptomatic improvement that the drug produces in Alzheimer's disease. However, there is no evidence as yet that the ability of memantine to protect against extrasynaptic NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's, although this has been suggested in animal models.[
Memantine's antagonism on NMDA receptors has aroused interest in repurposing it for mental illnesses such as ]bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
, considering the involvement of the glutamatergic system in the pathophysiology of mood disorders.
Serotonin
Memantine acts as a non-competitive antagonist at the 5-HT3 receptor, with a potency similar to that for the NMDA receptor. Many 5-HT3 antagonists function as antiemetics
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may be ...
, however the clinical significance of this serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...
activity in the treatment of Alzheimer's disease is unknown.
Cholinergic
Memantine acts as a non-competitive antagonist at different neuronal nicotinic acetylcholine receptors (nAChRs) at potencies possibly similar to the NMDA and 5-HT3 receptors, but this is difficult to ascertain with accuracy because of the rapid desensitization of nAChR responses in these experiments. It can be noted that memantine is an antagonist at Alpha-7 nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. Alpha-7 nAChR upregulate
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pro ...
s quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment. It has been shown that the number of nicotinic receptors in the brain are reduced in Alzheimer's disease, even in the absence of a general decrease in the number of neurons, and nicotinic receptor agonists
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an ...
are viewed as interesting targets for anti-Alzheimer drugs.
Dopamine
Memantine was shown in a study to act as an agonist at the dopamine D2HIGH receptor with equal or slightly higher affinity than to the NMDA receptors; however, the relevance of this may be negligible, as studies have shown very low affinity for binding to D2 receptors in general.
Sigmaergic
Memantine acts as an agonist at the σ1 receptor with a low affinity (Ki 2.6 μM). The consequences of this activity are unclear (as the role of sigma receptors in general is not yet that well understood). Due to this low affinity, therapeutic concentrations of memantine are most likely too low to have any sigmaergic
Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...
effect as a typical therapeutic dose is 20 mg, however excessive doses of memantine taken for recreational purposes many times greater than prescribed doses may indeed activate this receptor.
History
Memantine was first synthesized and patented by Eli Lilly and Company in 1968 as an anti-diabetic agent, but it was ineffective at lowering blood sugar. Later it was discovered to have Central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
(CNS) activity, and was developed by Merz Merz may refer to:
* Merz (art style), a synonym for the more common term Dada
* Merz (musician), a British electro-folk singer
* Merz (surname)
* Merz Apothecary, a historic German health care store in Chicago
* Merz & McLellan, a British electric ...
for dementia in Germany; the NMDA activity was discovered after trials had already begun. Memantine was first marketed for dementia in Germany in 1989 under the name Axura.[
In the US, some CNS activities were discovered at Children's Hospital of Boston in 1990, and Children's licensed patents covering uses of memantine outside the field of ophthalmology to Neurobiological Technologies (NTI) in 1995.][ NTI-Children's license is included in the filing.] In 1998 NTI amended its agreement with Children's to allow Merz to take over development.
In 2000, Merz partnered with Forest
A forest is an area of land dominated by trees. Hundreds of definitions of forest are used throughout the world, incorporating factors such as tree density, tree height, land use, legal standing, and ecological function. The United Nations' ...
to develop the drug for Alzheimer's disease in the U.S. under the name Namenda.
In 2000, Merz partnered with Suntory for the Japanese market and with Lundbeck for other markets including Europe; the drug was originally marketed by Lundbeck under the name Ebixa.[
Sales of the drug reached $1.8 billion for 2014. The cost of Namenda was $269 to $489 a month in 2012.
In February 2014, as the July 2015 patent expiration for memantine neared, ]Actavis
Actavis Generics (formerly known as Watson Pharmaceuticals and Actavis plc, prior to the acquisition of Irish-based Allergan, Inc., Allergan Inc) is a global pharmaceutical company focused on acquiring, developing, manufacturing and marketing bran ...
, which had acquired Forest, announced that it was launching an extended release (XR) form of memantine that could be taken once a day instead of twice a day as needed with the then-current "immediate release" (IR) version, and that it intended to stop selling the IR version in August 2014 and withdraw the marketing authorization. This is a tactic to thwart generic competition called " product hopping". However the supply of the XR version ran short, so Actavis extended the deadline until the fall. In September 2014 the attorney general of New York, Eric Schneiderman
Eric Tradd Schneiderman (born December 31, 1954) is an American lawyer and politician who served as the 65th Attorney General of New York from 2011 until his resignation in May 2018. Schneiderman, a member of the Democratic Party, spent ten year ...
, filed a lawsuit to compel Actavis to keep selling the IR version on the basis of antitrust law
Competition law is the field of law that promotes or seeks to maintain market competition by regulating anti-competitive conduct by companies. Competition law is implemented through public and private enforcement. It is also known as antitrust ...
.
In December 2014, a judge granted New York State its request and issued an injunction, preventing Actavis from withdrawing the IR version until generic versions could launch. Actavis appealed and in May a panel of the Second Circuit Court of Appeals
The United States Court of Appeals for the Second Circuit (in case citations, 2d Cir.) is one of the thirteen United States Courts of Appeals. Its territory comprises the states of Connecticut, New York and Vermont. The court has appellate juri ...
upheld the injunction, and in June Actavis asked that its case be heard by the full Second Circuit panel. In August 2015, Actavis' request was denied.
Society and culture
Recreational use
One preclinical study 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 ...
s showed that memantine was capable of inducing a PCP-like intoxication
Intoxication — or poisoning, especially by an alcoholic or narcotic substance — may refer to:
* Substance intoxication:
** Alcohol intoxication
** LSD intoxication
** Toxidrome
** Tobacco intoxication
** Cannabis intoxication
** Cocaine i ...
. Because of its very long biological half-life, memantine was previously thought not to be recreational, although a few cases of sporadic recreational use have been described.
A study examining self-reported use of memantine on the social network Reddit
Reddit (; stylized in all lowercase as reddit) is an American social news aggregation, content rating, and discussion website. Registered users (commonly referred to as "Redditors") submit content to the site such as links, text posts, images ...
showed that the drug was used recreationally and as a nootropic
Nootropics ( , or ) (colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic supplements or drugs and other substances that are claimed to improve cognitive function or to promote re ...
, but also that it was misused in various illnesses as self-medication without strong scientific basis.
Brand names
As of August 2017, memantine was marketed under many brand names worldwide including Abixa, Adaxor, Admed, Akatinol, Alceba, Alios, Almenta, Alois, Alzant, Alzer, Alzia, Alzinex, Alzixa, Alzmenda, Alzmex, Axura, Biomentin, Carrier, Cogito, Cognomem, Conexine, Cordure, Dantex, Demantin, Demax, Dementa, Dementexa, Ebitex, Ebixa, Emantin, Emaxin, Esmirtal, Eutebrol, Evy, Ezemantis, Fentina, Korint, Lemix, Lindex, Lindex, Lucidex, Manotin, Mantine, Mantomed, Marbodin, Mardewel, Marixino, Maruxa, Maxiram, Melanda, Memabix, Memamed, Memando, Memantin, Memantina, Memantine, Mémantine, Memantinol, Memantyn, Memanvitae, Memanxa, Memanzaks, Memary, Memax, Memexa, Memigmin, Memikare, Memogen, Memolan, Memorel, Memorix, Memotec, Memox, Memxa, Mentikline, Mentium, Mentixa, Merandex, Merital, Mexia, Mimetix, Mirvedol, Modualz, Morysa, Namenda, Nemdatine, Nemdatine, Nemedan, Neumantine, Neuro-K, Neuroplus, Noojerone, Polmatine, Prilben, Pronervon, Ravemantine, Talentum, Timantila, Tingreks, Tonibral, Tormoro, Valcoxia, Vilimen, Vivimex, Witgen, Xapimant, Ymana, Zalatine, Zemertinex, Zenmem, Zenmen, and Zimerz.
It was also marketed in some countries as a combination drug
A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for a FDC prod ...
with donepezil
Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's disease, Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, ha ...
under the brands Namzaric, Neuroplus Dual, and Tonibral MD.
Research
Psychiatry
Memantine, in light of its NMDA receptor antagonism, has been repurposed as a possible adjunctive treatment for depressive episodes in subjects with bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
, considering the involvement of the glutamatergic system in the pathophysiology of bipolar illness. However, evidence from meta-analyses showed that memantine was not significantly superior to placebo for bipolar depression.
Parkinson's
A phase III clinical trial
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
is studying the potential of memantine as disease modifying treatment 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 becom ...
, to slow progression of the disease.
References
Further reading
*
External links
*
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