Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. It is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. Common

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s include

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

sleepiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

, and

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

. Severe side effects may include

blood clot A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

, and

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

. 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 predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

s, working as a pore blocker of these

ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by Gating (electrophysiol ...

s. Memantine was first discovered in 1963. It was approved for medical use in

Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...

in 1989, in the

European Union The European Union (EU) is a supranational union, supranational political union, political and economic union of Member state of the European Union, member states that are Geography of the European Union, located primarily in Europe. The u ...

in 2002, and in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

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 2022, it was the 150th most commonly prescribed medication in the United States, with more than 3million prescriptions.

Medical uses

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 is 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 type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to ...

in those with moderate-to-severe dementia resulted in "limited improvements" in a 2017 review. The UK

National Institute for Clinical Excellence National may refer to: Common uses * Nation or country ** Nationality – a ''national'' is a person who is subject to a nation, regardless of whether the person has full rights as a citizen Places in the United States * National, Maryland, ce ...

(NICE) issued guidance in 2018 recommending consideration of the combination of memantine with donepezil in those with moderate-to-severe dementia.

Radiation therapy

Memantine has been recommended for use by professional organization consensus to prevent neurocognitive decline after

whole brain radiotherapy Whole brain radiotherapy (WBRT) is a treatment option for patients with brain metastases. In WBRT, radiation therapy is administered broadly, to the whole brain, over multiple treatments. Usage WBRT has been shown to alleviate symptoms, decre ...

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 may result from the combination of two or more drugs. The meaning of this ...

s (≥1% of people) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

, 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 ...

cystitis A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra ( urethritis) while upper urinary tract infections affect the kidney (py ...

, and increased

libido In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...

.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 ...

2006. Adelaide: Australian Medicines Handbook; 2006. Like many other

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

s, memantine behaves as a

dissociative anesthetic Dissociatives, colloquially dissos, are a subclass of hallucinogens that 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 Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...

of memantine is rare due to the drug's long duration and limited availability. Additionally, memantine seems to lack effects such as

euphoria Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and da ...

hallucinations A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

. Memantine appears to be generally well tolerated by children with

autism spectrum disorder Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...

Pharmacology

Pharmacodynamics

Glutamatergic

A dysfunction of

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 ...

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron ...

, manifested as

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

excitotoxicity In excitotoxicity, neuron, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamic acid, glutamate become pathologically high, resulting in excessive stimulation of cell surface recept ...

, is hypothesized to be involved in the

etiology Etiology (; alternatively spelled aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek word ''()'', meaning "giving a reason for" (). More completely, etiology is the study of the causes, origins ...

. Targeting the glutamatergic system, specifically ionotropic glutamate

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 ...

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

. 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; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

following

depolarization In biology, depolarization or hypopolarization is a change within a cell (biology), cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolar ...

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 syste ...

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 disease, although this has been suggested in animal models.

Serotonergic

Memantine acts as a non-competitive antagonist of the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT₃ receptor, with a

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

similar to that for the NMDA receptor. Many 5-HT₃ receptor antagonists function as

antiemetic 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 ...

s, however the clinical significance of this anti-serotonergic activity of memantine in Alzheimer's disease is unknown.

Cholinergic

Memantine acts as a non-competitive antagonist of different neuronal

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

s (nAChRs) at potencies possibly similar to the NMDA receptor and 5-HT₃ receptor, 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 α₇ nAChR, which may contribute to initial worsening of cognitive function during early memantine treatment. α₇ nAChR

upregulate In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as RNA ...

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 receptor Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

s in the brain are reduced in Alzheimer's disease, even in the absence of a general decrease in the number of neurons, and

agonists An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...

are viewed as interesting targets for anti-Alzheimer drugs.

Dopaminergic

Memantine was shown in a study to act as an agonist at the

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

D₂^high receptor with equal or slightly higher affinity than to the NMDA receptors. However, the relevance of this action may be negligible, as studies have shown very low affinity for binding to D₂ receptors in general.

Sigmaergic

Memantine acts as an

agonist 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 R ...

of the

sigma Sigma ( ; uppercase Σ, lowercase σ, lowercase in word-final position ς; ) is the eighteenth letter of the Greek alphabet. In the system of Greek numerals, it has a value of 200. In general mathematics, uppercase Σ is used as an operator ...

σ₁ receptor with low

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

(K_i = 2.6μM). The consequences of this activity are unclear (as the role of sigma receptors in general is currently not very well understood). Due to this low affinity, therapeutic concentrations of memantine are most likely too low to have any sigmaergic 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.

Other actions

Memantine does not appear to inhibit or

induce Induce may refer to: * Induced consumption * Induced innovation * Induced character * Induced coma * Induced menopause * Induced metric * Induced path * Induced topology * Induce (musician), American musician * Labor induction Labor indu ...

several

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s including

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

/ 5,

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

, and

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...

. It also does not inhibit

CYP2A6 Cytochrome P450 2A6 (abbreviated CYP2A6) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine an ...

CYP2E1 Cytochrome P450 2E1 (abbreviated CYP2E1, ) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, inclu ...

. However, it might have a small effect on

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Func ...

Pharmacokinetics

Absorption

The

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of memantine is 100%. Time to peak levels of memantine is 3 to 7hours.

Food Food is any substance consumed by an organism for Nutrient, nutritional support. Food is usually of plant, animal, or Fungus, fungal origin and contains essential nutrients such as carbohydrates, fats, protein (nutrient), proteins, vitamins, ...

has no influence on the rate of

absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which su ...

. Memantine exposure is linear over a dose range of 10 to 40mg.

Peak Peak or The Peak may refer to: Basic meanings Geology * Mountain peak ** Pyramidal peak, a mountaintop that has been sculpted by erosion to form a point Mathematics * Peak hour or rush hour, in traffic congestion * Peak (geometry), an (''n''-3)-d ...

levels after a single 20mg dose were found to be 24 to 29μg/L (0.13–0.16μmol/L or μM). Steady-state levels of memantine with 20mg/day are in the range of 0.5 to 1.0μM.

Distribution

Memantine has a relatively high

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

(V_d) of 9 to 11L/kg. It easily crosses

biological membrane A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of th ...

s, is widely

distributed Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...

throughout the body, and crosses the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

into the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. The drug is

transported ''Transported'' is an Australian convict melodrama film directed by W. J. Lincoln. It is considered a lost film. Plot In England, Jessie Grey is about to marry Leonard Lincoln but the evil Harold Hawk tries to force her to marry him and she ...

across the blood–brain barrier by the organic cation transporter novel 1 (OCTN1). The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of memantine is 45% and is described as very low and not clinically significant. Because of its low plasma protein binding, it is unlikely to interact with other highly protein-bound drugs such as

warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...

Metabolism

Memantine does not undergo extensive

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. It is negligibly

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

by the

s. As a result, it has a decreased potential for

drug interaction In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect ...

Metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s of memantine include memantine glucuronide, 6-hydroxymemantine, and 1-nitrosomemantine, all of which show minimal activity as NMDA receptor antagonists.

Elimination

Memantine is eliminated primarily in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

, with 57 to 82% excreted in urine unchanged. Its

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

is 60 to 80hours. The

renal In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retrop ...

clearance of memantine is dependent on

urinary The human urinary system, also known as the urinary tract or renal system, consists of the kidneys, ureters, bladder, and the urethra. The purpose of the urinary system is to eliminate waste from the body, regulate blood volume and blood pressu ...

pH. More

alkaline In chemistry, an alkali (; from the Arabic word , ) is a basic salt of an alkali metal or an alkaline earth metal. An alkali can also be defined as a base that dissolves in water. A solution of a soluble base has a pH greater than 7.0. The ...

urine slows the elimination of memantine, whereas more

acid An acid is a molecule or ion capable of either donating a proton (i.e. Hydron, hydrogen cation, H+), known as a Brønsted–Lowry acid–base theory, Brønsted–Lowry acid, or forming a covalent bond with an electron pair, known as a Lewis ...

ic urine accelerates its elimination.

Chemistry

Memantine, also known as 3,5-dimethyl-1-aminoadamantane (DMAA), is an

adamantane Adamantane is an organic compound with formula C10H16 or, more descriptively, (CH)4(CH2)6. Adamantane molecules can be described as the fusion of three cyclohexane rings. The molecule is both rigid and virtually stress-free. Adamantane is the mo ...

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

and is closely structurally related to

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 because ...

(1-aminoadamantane) and other adamantane derivatives. The

synthesis Synthesis or synthesize may refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of organi ...

of memantine has been described.

History

Memantine was first synthesized,

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an sufficiency of disclosure, enabling discl ...

ed, and described by

Eli Lilly and Company Eli Lilly and Company, Trade name, doing business as Lilly, is an American multinational Medication, pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 count ...

in 1963 as an anti-diabetic agent, but it was ineffective at lowering

blood sugar The blood sugar level, blood sugar concentration, blood glucose level, or glycemia is the measure of glucose concentrated in the blood. The body tightly regulates blood glucose levels as a part of metabolic homeostasis. For a 70 kg (1 ...

. By 1972, it was discovered to have

(CNS) activity, and was developed by Merz for treatment of

neurological disease Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...

s, such as

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. Memantine was first studied in the treatment of

in 1986. The drug was first marketed for dementia in 1989 in Germany under the name Axura. It was not discovered to act as an

until 1989, after clinical trials had initiated. Prior to this, it was theorized to directly and/or indirectly modulate the

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

, noradrenergic, and serotonergic systems. However, these actions were later realized to occur at 100-fold higher concentrations than those achieved therapeutically and hence are unlikely to be involved in its effects. In the United States, 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 ecosystem characterized by a dense ecological community, community of trees. Hundreds of definitions of forest are used throughout the world, incorporating factors such as tree density, tree height, land use, legal standing, ...

to develop the drug for Alzheimer's disease in the United States under the brand 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. Memantine was approved in the

in 2002 and in the United States in 2003. 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.) is a global pharmaceutical company focused on acquiring, developing, manufacturing and marketing branded pharmaceut ...

, 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 covers the states of Connecticut, New York, and Vermont, and it has appellate jurisdic ...

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

Recreational use Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...

of memantine at supratherapeutic doses has been reported. It is a weak

and is reported to produce

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens that 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 ...

and

phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hall ...

(PCP)-like effects in animals and humans at sufficiently high doses. Even therapeutic doses have been found to produce mild dissociative-like effects in clinical studies. In any case, the very long

duration of action Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

of memantine (>40hours) has likely limited its

misuse potential Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

. Recreational use of the related drug

has similarly been reported. A study examining self-reported use of memantine on the social network

Reddit Reddit ( ) is an American Proprietary software, proprietary social news news aggregator, aggregation and Internet forum, forum Social media, social media platform. Registered users (commonly referred to as "redditors") submit content to the ...

showed that the drug was used both recreationally and as a

nootropic Nootropics ( or ) (colloquially brain supplements, smart drugs, cognitive enhancers, memory enhancers, or brain boosters) are chemical substances which purportedly improve cognitive functions, such as attention, memory, wakefulness, and self ...

, but also that it was misused in various illnesses as

self-medication Self-medication, sometime called do-it-yourself (DIY) medicine, is a human behavior in which an individual uses a substance or any exogenous influence to self-administer treatment for physical or psychological conditions, for example headaches or ...

without strong scientific basis.

Brand names

As of August 2017, memantine is 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, Pertam, Polmatine, Prilben, Pronervon, Ravemantine, Talentum, Timantila, Tingreks, Tonibral, Tormoro, Valcoxia, Vilimen, Vivimex, Witgen, Xapimant, Ymana, Zalatine, Zemertinex, Zenmem, Zenmen, and Zimerz. It is marketed in some countries as a

combination drug A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fix ...

with

( memantine/donepezil) under the brand names Namzaric, Neuroplus Dual, and Tonibral MD.

Research

Psychiatric disorders

Memantine has been studied and used

off-label Off-label use is the use of pharmaceutical drugs for an unapproved indication (medicine), indication or in an unapproved age group, dose (biochemistry), dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) ca ...

in the treatment of a variety of

psychiatric disorder A mental disorder, also referred to as a mental illness, a mental health condition, or a psychiatric disability, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. A mental disorder is ...

s. These include depression,

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

obsessive–compulsive disorder Obsessive–compulsive disorder (OCD) is a mental disorder in which an individual has intrusive thoughts (an ''obsession'') and feels the need to perform certain routines (''Compulsive behavior, compulsions'') repeatedly to relieve the dis ...

(OCD),

substance misuse Substance may refer to: * Matter, anything that has mass and takes up space Chemistry * Chemical substance, a material with a definite chemical composition * Drug A drug is any chemical substance other than a nutrient or an essential dieta ...

pervasive developmental disorder The diagnostic category pervasive developmental disorders (PDD), as opposed to specific developmental disorders (SDD), was a group of disorders characterized by delays in the development of multiple basic functions including socialization and ...

s (PDDs), and

binge eating disorder Binge eating disorder (BED) is an eating disorder characterized by frequent and recurrent binge eating episodes with associated negative psychological and social problems, but without the compensatory behaviors common to bulimia nervosa, OSFE ...

(BED). A 2008

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

concluded that although it was promising for such uses, memantine could not be recommended for such indications due to inadequate data. Memantine does not appear to be effective in the treatment of unipolar major depression or

bipolar depression Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that each last from days to weeks, and in some cases months. If the elevated m ...

on the basis of

s and

meta-analyses Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...

, including a 2021

Cochrane review Cochrane is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes ...

. However, a 2022 systematic review and meta-analysis concluded that memantine was significantly effective in the treatment of depressive symptoms in various psychiatric disorders, although with a very small

effect size In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...

( Hedges' g = -0.17). There are likewise limited data to support memantine in the treatment of

based on systematic reviews and meta-analyses. However, a 2019 systematic review and meta-analysis reported that memantine was effective in the treatment of the negative and cognitive symptoms of schizophrenia with medium to large effect sizes.

Parkinson's disease

Memantine has been studied in the treatment of

since the early 1970s. Whereas the related drug

is approved for the treatment of Parkinson's disease and has been since the early 1970s, memantine is not approved for the treatment of Parkinson's disease as of 2024. However, it has been said that memantine, along with amantadine, has been widely used as an

antiparkinsonian agent In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutr ...

since at least 1994. Although amantadine and memantine have fairly similar

pharmacology Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur betwee ...

, it has been said that memantine does not share the antidyskinetic effects of amantadine. However, findings are conflicting, and some data suggest that memantine may also have antidyskinetic effects. Similarly to amantadine and

dopamine receptor agonist A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like ...

s, memantine reverses

haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...

-induced

catalepsy Catalepsy (from Ancient Greek , , "seizing, grasping") is a neurological condition characterized by muscular rigidity and fixity of posture regardless of external stimuli, as well as decreased sensitivity to pain. Signs and symptoms Sympt ...

and monoamine depletion-induced

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

in animals. Memantine has been found to reduce

bradykinesia Hypokinesia is one of the classifications of movement disorders, and refers to decreased bodily movement. Hypokinesia is characterized by a partial or complete loss of muscle movement due to a disruption in the basal ganglia. Hypokinesia is a sy ...

and resting tremor in people with Parkinson's disease. Memantine and amantadine are said to have moderate anti-akinetic effects in the treatment of Parkinson's disease. The doses of memantine used for Parkinson's disease are about 5- to 10-fold lower than those of amantadine, which has been attributed to greater

of memantine. As of 2022, a phase 3

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

is studying the potential of memantine as

disease-modifying treatment A disease-modifying treatment, disease-modifying drug, or disease-modifying therapy is a treatment that delays, slows or reverses the progression of a disease by targeting its underlying cause. They are distinguished from symptomatic treatments th ...

for Parkinson's disease that might slow progression of the disease. It is specifically theorized to act by inhibiting cell-to-cell transmission of

α-synuclein Alpha-synuclein (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the bra ...

. Besides Parkinson's disease, memantine has been studied in the treatment of

Parkinson's disease dementia Parkinson's disease dementia (PDD) is dementia that is associated with Parkinson's disease (PD). Together with dementia with Lewy bodies (DLB), it is one of the Lewy body dementias characterized by abnormal deposits of Lewy bodies in the brain. ...

(PDD) and

dementia with Lewy bodies Dementia with Lewy bodies (DLB) is a type of dementia characterized by changes in sleep, behavior change (individual), behavior, cognition, movement, and dysautonomia, regulation of automatic bodily functions. Unlike some other dementias, mem ...

(DLB).

Apathy

Apathy is a disorder of diminished motivation characterized by diminished interest and activity.

Systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

s and

published from 2016 to 2022 have found that memantine is not effective in the treatment of

apathy Apathy, also referred to as indifference, is a lack of feeling, emotion, interest, or concern about something. It is a state of indifference, or the suppression of emotions such as concern, excitement, motivation, or passion. An apathetic i ...

in Alzheimer's disease and other

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

s. However, another 2022 review reported that it was effective.

Long COVID

Memantine, along with

, is being studied and used

in the treatment

long COVID Long may refer to: Measurement * Long, characteristic of something of great duration * Long, characteristic of something of great length * Longitude (abbreviation: long.), a geographic coordinate * Longa (music), note value in early music mens ...

Catatonia

Memantine, along with

, has been reported to be effective in the treatment of

catatonia Catatonia is a complex syndrome most commonly seen in people with underlying mood disorders, such as major depressive disorder, or psychotic disorders, such as schizophrenia. People with catatonia exhibit abnormal movement and behaviors, wh ...

case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrenc ...

s and case series.

Autism

Effects in

autism Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing d ...

are unclear.

Medical uses

Alzheimer's disease and dementia

Radiation therapy

Adverse effects

Pharmacology

Pharmacodynamics

Glutamatergic

Serotonergic

Cholinergic

Dopaminergic

Sigmaergic

Other actions

Pharmacokinetics

Absorption

Distribution

Metabolism

Elimination

Chemistry

History

Society and culture

Recreational use

Brand names

Research

Psychiatric disorders

Parkinson's disease

Apathy

Long COVID

Catatonia

Autism

References

Further reading