Memantine

Template:Short description Template:Use dmy dates Template:Cs1 config Template:Drugbox Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease.<ref name=AHFS2019/><ref name=BNF76>Template:Cite book</ref><ref name="AlamLingenfelterBender2017">Template:Cite journal</ref> It is taken by mouth.<ref name=AHFS2019/><ref name="AlamLingenfelterBender2017" />

Common side effects include headache, constipation, sleepiness, and dizziness.<ref name=AHFS2019/><ref name=BNF76/> Severe side effects may include blood clots, psychosis, and heart failure.<ref name=BNF76/> It is believed to work by acting on NMDA receptors, working as a pore blocker of these ion channels.<ref name="AlamLingenfelterBender2017" /><ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Memantine was first discovered in 1963.<ref name="AlamLingenfelterBender2017" /><ref name="Río-Sancho2020">Template:Cite book</ref><ref name="HerrmannLiLanctôt2011">Template:Cite journal</ref> It was approved for medical use in Germany in 1989, in the European Union in 2002, and in the United States in 2003.<ref name="HerrmannLiLanctôt2011" /><ref name=AHFS2019/><ref name="NRDD" /> It is available as a generic medication.<ref name=BNF76/> In 2022, it was the 150th most commonly prescribed medication in the United States, with more than 3Template:Nbspmillion prescriptions.<ref name="Top 300">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name=MountC2006>Template:Cite journal</ref><ref name="NICE Guidelines">NICE review of technology appraisal guidance 111 January 18, 2011 Alzheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination Template:Webarchive</ref> One guideline recommends memantine or an AChE inhibitor be considered in people in the early-to-mid stage of dementia.<ref>Template:Cite journal</ref>

Memantine has been associated with a modest improvement;<ref name="AMH2006" /> with small positive effects on cognition, mood, behavior, and the ability to perform daily activities in moderate-to-severe Alzheimer's disease.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> There does not appear to be any benefit in mild disease.<ref name=Review11>Template:Cite journal</ref>

Memantine when added to donepezil in those with moderate-to-severe dementia resulted in "limited improvements" in a 2017 review.<ref name="Chen2017">Template:Cite journal</ref> The UK National Institute for Clinical Excellence (NICE) issued guidance in 2018 recommending consideration of the combination of memantine with donepezil in those with moderate-to-severe dementia.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Radiation therapy

Memantine has been recommended for use by professional organization consensus to prevent neurocognitive decline after whole brain radiotherapy.<ref>Template:Cite journal</ref>

Adverse effects

Memantine is, in general, well tolerated.<ref name=AMH2006/> Common adverse drug reactions (≥1% of people) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common adverse effects include vomiting, anxiety, hypertonia, cystitis, and increased libido.<ref name=AMH2006>Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.</ref><ref name=BNF47>Template:Cite book</ref>

Like many other NMDA receptor antagonists, memantine behaves as a dissociative anesthetic at supratherapeutic doses.<ref name=Morris>Template:Cite journal</ref> Despite isolated reports, recreational use of memantine is rare due to the drug's long duration and limited availability.<ref name="Morris"/> Additionally, memantine seems to lack effects such as euphoria or hallucinations.<ref>Template:Cite journal</ref>

Memantine appears to be generally well tolerated by children with autism spectrum disorder.<ref name="Elbe 2019 p. ">Template:Cite book</ref>

Pharmacology

Pharmacodynamics

Glutamatergic

A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimer's disease. Targeting the glutamatergic system, specifically ionotropic glutamate NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system.<ref name=Cacabelos1999>Template:Cite journal</ref>

Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors.<ref name=Rogawski2003 >Template:Cite journal</ref><ref name=Robinson>Template:Cite journal</ref> 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 following depolarization of the postsynaptic neuron.<ref>Template:Cite journal</ref><ref name=Parsons2007>Template:Cite journal</ref><ref name=Lipton2007>Template:Cite journal</ref> 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.<ref name=Parsons2007/>

Serotonergic

Memantine acts as a non-competitive antagonist of the serotonin 5-HT₃ receptor, with a potency similar to that for the NMDA receptor.<ref name=Rammes2001>Template:Cite journal</ref> Many 5-HT₃ receptor antagonists function as antiemetics, 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 receptors (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 upregulates quickly in response to antagonism, which could explain the cognitive-enhancing effects of chronic memantine treatment.<ref name=Buisson1998>Template:Cite journal</ref><ref name=Aracava2005>Template:Cite journal</ref> 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 are viewed as interesting targets for anti-Alzheimer drugs.<ref name=Gotti2004>Template:Cite journal</ref>

Dopaminergic

Memantine was shown in a study to act as an agonist at the dopamine D₂^high receptor with equal or slightly higher affinity than to the NMDA receptors.<ref name="SeemanCarusoLasaga2008">Template:Cite journal</ref> However, the relevance of this action may be negligible, as studies have shown very low affinity for binding to D₂ receptors in general.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Sigmaergic

Memantine acts as an agonist of the sigma σ₁ receptor with low affinity (K_i = 2.6Template:NbspμM).<ref name="pmid15090047">Template:Cite journal</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Other actions

Memantine does not appear to inhibit or induce several cytochrome P450 enzymes including CYP3A4/5, CYP1A2, CYP2D6, and CYP2C9.<ref name="AlamLingenfelterBender2017" /> It also does not inhibit CYP2A6 or CYP2E1.<ref name="SchmittRyanCooper2007" /> However, it might have a small effect on CYP2B6.<ref name="AlamLingenfelterBender2017" />

Pharmacokinetics

Absorption

The oral bioavailability of memantine is 100%.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> Time to peak levels of memantine is 3 to 7Template:Nbsphours.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> Food has no influence on the rate of absorption.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> Memantine exposure is linear over a dose range of 10 to 40Template:Nbspmg.<ref name="AlamLingenfelterBender2017" /> Peak levels after a single 20Template:Nbspmg dose were found to be 24 to 29Template:Nbspμg/L (0.13–0.16Template:Nbspμmol/L or μM).<ref name="AlamLingenfelterBender2017" /> Steady-state levels of memantine with 20Template:Nbspmg/day are in the range of 0.5 to 1.0Template:NbspμM.<ref name="SchmittRyanCooper2007" />

Distribution

Memantine has a relatively high volume of distribution (V_d) of 9 to 11Template:NbspL/kg.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> It easily crosses biological membranes, is widely distributed throughout the body, and crosses the blood–brain barrier into the central nervous system.<ref name="SchmittRyanCooper2007" /> The drug is transported across the blood–brain barrier by the organic cation transporter novel 1 (OCTN1).<ref name="AlamLingenfelterBender2017" /> The plasma protein binding of memantine is 45% and is described as very low and not clinically significant.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> Because of its low plasma protein binding, it is unlikely to interact with other highly protein-bound drugs such as warfarin or digoxin.<ref name="SchmittRyanCooper2007" />

Metabolism

Memantine does not undergo extensive metabolism.<ref name="SchmittRyanCooper2007" /> It is negligibly metabolized by the cytochrome P450 enzymes.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> As a result, it has a decreased potential for drug interactions.<ref name="SchmittRyanCooper2007" /> Metabolites of memantine include memantine glucuronide, 6-hydroxymemantine, and 1-nitrosomemantine, all of which show minimal activity as NMDA receptor antagonists.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" />

Elimination

Memantine is eliminated primarily in urine, with 57 to 82% excreted in urine unchanged.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> Its elimination half-life is 60 to 80Template:Nbsphours.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> The renal clearance of memantine is dependent on urinary pH.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" /> More alkaline urine slows the elimination of memantine, whereas more acidic urine accelerates its elimination.<ref name="AlamLingenfelterBender2017" /><ref name="SchmittRyanCooper2007" />

Chemistry

Memantine, also known as 3,5-dimethyl-1-aminoadamantane (DMAA), is an adamantane derivative and is closely structurally related to amantadine (1-aminoadamantane) and other adamantane derivatives.<ref name="AlamLingenfelterBender2017" /><ref name="RagshaniyaKumarTittal2024">Template:Cite journal</ref><ref name="DanyszDekundyScheschonka2021">Template:Cite journal</ref><ref name="MorozovIvanovaLukicheva2001">Template:Cite journal</ref>

The synthesis of memantine has been described.<ref name="AlamLingenfelterBender2017" />

History

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Memantine was first synthesized, patented, and described by Eli Lilly and Company in 1963 as an anti-diabetic agent, but it was ineffective at lowering blood sugar.<ref name="AlamLingenfelterBender2017" /><ref name="Río-Sancho2020" /><ref name="HerrmannLiLanctôt2011" /><ref name="GerzonKrumkalnsBrindle1962">Template:Cite journal</ref><ref name="Elks2014">Template:Cite book</ref> By 1972, it was discovered to have central nervous system (CNS) activity, and was developed by Merz for treatment of neurological diseases, such as Parkinson's disease.<ref name="AlamLingenfelterBender2017" /><ref name="Río-Sancho2020" /> Memantine was first studied in the treatment of Alzheimer's disease in 1986.<ref name="HerrmannLiLanctôt2011" /><ref name="NRDD" /> The drug was first marketed for dementia in 1989 in Germany under the name Axura.<ref name="AlamLingenfelterBender2017" /><ref name="NRDD" /><ref name="Río-Sancho2020" />

It was not discovered to act as an NMDA receptor antagonist until 1989, after clinical trials had initiated.<ref name="AlamLingenfelterBender2017" /><ref name="Río-Sancho2020" /><ref name="Bormann1989">Template:Cite journal</ref> Prior to this, it was theorized to directly and/or indirectly modulate the dopaminergic, noradrenergic, and serotonergic systems.<ref name="Río-Sancho2020" /><ref name="ParsonsSanyszQuack1999">Template:Cite journal</ref><ref name="WesemannSontagMaj1983">Template:Cite journal</ref><ref name="JackischLinkNeufang1992">Template:Cite journal</ref> 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.<ref name="Río-Sancho2020" /><ref name="ParsonsSanyszQuack1999" /><ref name="JackischLinkNeufang1992" />

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.<ref name=10KSB1996>{{#invoke:citation/CS1|citation |CitationClass=web }} NTI-Children's license is included in the filing.</ref> In 1998, NTI amended its agreement with Children's to allow Merz to take over development.<ref name=SVBJ2000>Template:Cite news</ref>

In 2000, Merz partnered with Forest to develop the drug for Alzheimer's disease in the United States under the brand name Namenda.<ref name="AlamLingenfelterBender2017" /><ref name="NRDD">Template:Cite journal</ref> In 2000, Merz partnered with Suntory for the Japanese market and with Lundbeck for other markets including Europe;<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> the drug was originally marketed by Lundbeck under the name Ebixa.<ref name=NRDD/> Memantine was approved in the European Union in 2002 and in the United States in 2003.<ref name="AlamLingenfelterBender2017" /><ref name="HerrmannLiLanctôt2011" />

Sales of the drug reached $1.8 billion for 2014.<ref name="AlamLingenfelterBender2017" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The cost of Namenda was $269 to $489 a month in 2012.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

In February 2014, as the July 2015 patent expiration for memantine neared, Actavis, 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, filed a lawsuit to compel Actavis to keep selling the IR version on the basis of antitrust law.<ref>Template:Cite news</ref><ref name=Capati>Template:Cite journal</ref>

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 upheld the injunction, and in June Actavis asked that its case be heard by the full Second Circuit panel.<ref>Template:Cite news</ref><ref>Template:Cite news</ref> In August 2015, Actavis' request was denied.<ref>Template:Cite news</ref>

Society and culture

Recreational use

Recreational use of memantine at supratherapeutic doses has been reported.<ref name="MorrisWallach2014">Template:Cite journal</ref> It is a weak NMDA receptor antagonist and is reported to produce dissociative and phencyclidine (PCP)-like effects in animals and humans at sufficiently high doses.<ref name="MorrisWallach2014" /><ref name="HealGosdenSmith2018">Template:Cite journal</ref><ref name="NicholsonJonesBalster1998">Template:Cite journal</ref> Even therapeutic doses have been found to produce mild dissociative-like effects in clinical studies.<ref name="MorrisWallach2014" /> In any case, the very long duration of action of memantine (>40Template:Nbsphours) has likely limited its misuse potential.<ref name="MorrisWallach2014" /> Recreational use of the related drug amantadine has similarly been reported.<ref name="MorrisWallach2014" />

A study examining self-reported use of memantine on the social network Reddit showed that the drug was used both recreationally and as a nootropic, but also that it was misused in various illnesses as self-medication without strong scientific basis.<ref name="NatterMichel2020">Template:Cite journal</ref>

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.<ref name="brands">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

It is marketed in some countries as a combination drug with donepezil (memantine/donepezil) under the brand names Namzaric, Neuroplus Dual, and Tonibral MD.<ref name="brands" />

Research

Psychiatric disorders

Memantine has been studied and used off-label in the treatment of a variety of psychiatric disorders.<ref name="ZdanysTampi2008">Template:Cite journal</ref> These include depression, bipolar disorder, schizophrenia, obsessive–compulsive disorder (OCD), substance misuse, pervasive developmental disorders (PDDs), and binge eating disorder (BED).<ref name="ZdanysTampi2008" /> A 2008 systematic review concluded that although it was promising for such uses, memantine could not be recommended for such indications due to inadequate data.<ref name="ZdanysTampi2008" />

Memantine does not appear to be effective in the treatment of unipolar major depression or bipolar depression on the basis of systematic reviews and meta-analyses, including a 2021 Cochrane review.<ref name="DeanHurducasHawton2021">Template:Cite journal</ref><ref name="KleeblattBetzlerKilarski2017">Template:Cite journal</ref><ref name="KishiMatsunagaIwata2017">Template:Cite journal</ref><ref name="VeroneseSolmiLuchini2016">Template:Cite journal</ref><ref name="BartoliCavaleriBachi2021">Template:Cite journal</ref> 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 (Hedges' g = -0.17).<ref name="HsuChuChing2022">Template:Cite journal</ref>

There are likewise limited data to support memantine in the treatment of schizophrenia based on systematic reviews and meta-analyses.<ref name="Andrade2017">Template:Cite journal</ref><ref name="KishiIkutaOya2018">Template:Cite journal</ref> 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.<ref name="ZhengZhuZhang2019">Template:Cite journal</ref>

Parkinson's disease

Memantine has been studied in the treatment of Parkinson's disease since the early 1970s.<ref name="HerrmannLiLanctôt2011" /><ref name="Río-Sancho2020" /><ref name="LangeRiederer1994" /><ref name="FischerJacobiSchneider1977">Template:Cite journal</ref><ref name="SchneiderFischerClemens1984">Template:Cite journal</ref> Whereas the related drug amantadine is approved for the treatment of Parkinson's disease and has been since the early 1970s,<ref name="DanyszDekundyScheschonka2021" /> memantine is not approved for the treatment of Parkinson's disease as of 2024.<ref name="AdisInsight">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> However, it has been said that memantine, along with amantadine, has been widely used as an antiparkinsonian agent since at least 1994.<ref name="LangeRiederer1994">Template:Cite journal</ref>

Although amantadine and memantine have fairly similar pharmacology, it has been said that memantine does not share the antidyskinetic effects of amantadine.<ref name="OlivaresDeshpandeShi2012">Template:Cite journal</ref><ref name="MerelloNouzeillesCammarota1999" /> However, findings are conflicting, and some data suggest that memantine may also have antidyskinetic effects.<ref name="Gonzalez-LatapiGhomwickSaranza2020">Template:Cite journal</ref><ref name="Onofrj_2016">Template:Cite book</ref><ref name="VidalFukushimaValle2013">Template:Cite journal</ref> Similarly to amantadine and dopamine receptor agonists, memantine reverses haloperidol-induced catalepsy and monoamine depletion-induced sedation in animals.<ref name="OlivaresDeshpandeShi2012" /><ref name="DanyszGosselSajaczkowski1994">Template:Cite journal</ref> Memantine has been found to reduce bradykinesia and resting tremor in people with Parkinson's disease.<ref name="OlivaresDeshpandeShi2012" /><ref name="MerelloNouzeillesCammarota1999">Template:Cite journal</ref> Memantine and amantadine are said to have moderate anti-akinetic effects in the treatment of Parkinson's disease.<ref name="LangeRiederer1994" /><ref name="RabeyNissipeanuKorczyn1992">Template:Cite journal</ref> 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 potency of memantine.<ref name="LangeRiederer1994" />

As of 2022, a phase 3 clinical trial is studying the potential of memantine as disease-modifying treatment for Parkinson's disease that might slow progression of the disease.<ref name="GrossoJasutkarOh2022">Template:Cite journal</ref><ref name="McFarthingRafaloffBaptista2022">Template:Cite journal</ref><ref name="NCT03858270">Template:ClinicalTrialsGov</ref> It is specifically theorized to act by inhibiting cell-to-cell transmission of α-synuclein.<ref name="GrossoJasutkarOh2022" /><ref name="McFarthingRafaloffBaptista2022" />

Besides Parkinson's disease, memantine has been studied in the treatment of Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB).<ref name="BallardKahnCorbett2011">Template:Cite journal</ref><ref name="SzetoLewis2016">Template:Cite journal</ref><ref name="WangYuTang2015">Template:Cite journal</ref>

Apathy

Apathy is a disorder of diminished motivation characterized by diminished interest and activity.<ref name="MarinWilkosz2005">Template:Cite journal</ref><ref name="ChongHusain2016">Template:Cite book</ref> Systematic reviews and meta-analyses published from 2016 to 2022 have found that memantine is not effective in the treatment of apathy in Alzheimer's disease and other dementias.<ref name="SepehrySaraiHsiung2017">Template:Cite journal</ref><ref name="HarrisonAertsBrodaty2016">Template:Cite journal</ref><ref name="Andrade2022">Template:Cite journal</ref> However, another 2022 review reported that it was effective.<ref name="AzharKusumoMarotta2022">Template:Cite journal</ref>

Long COVID

Memantine, along with amantadine, is being studied and used off-label in the treatment long COVID.<ref name="MüllerRiedererKuhn2023">Template:Cite journal</ref><ref name="FronteraGuekhtAllegri2023">Template:Cite journal</ref>

Catatonia

Memantine, along with amantadine, has been reported to be effective in the treatment of catatonia in case reports and case series.<ref name="BeachGomez-BernalHuffman2017">Template:Cite journal</ref><ref name="ObregonVelascoWuerz2011">Template:Cite journal</ref><ref name="GrazianeDavidowiczFrancis2020">Template:Cite journal</ref>

Autism

Effects in autism are unclear.<ref name="Parr2010">Template:Cite journal</ref><ref name="Hong Erickson 2019 pp. 709–718">Template:Cite journal</ref>

Further reading

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