Amantadine

Template:Short description Template:Distinguish Template:Use American English Template:Use dmy dates Template:Cs1 config Template:Drugbox 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 of widespread drug resistance.<ref name="CDC_2019" /><ref name="WHO_2011" /> It is also used for a variety of other conditions. The drug is taken by mouth.

Amantadine has a mild side-effect profile. Common neurological side effects include drowsiness, lightheadedness, dizziness, and confusion.<ref name="Chang_2020">Template:Cite book</ref> Because of its effects on the central nervous system (CNS), it should be combined cautiously with additional CNS stimulants or anticholinergic drugs. Given that it is cleared by the kidneys, amantadine is contraindicated in persons with end-stage kidney disease.<ref name="Gocovri FDA label2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Due to its anticholinergic effects, it should be taken with caution by those with enlarged prostates or glaucoma.<ref name="FDA_2019">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The pharmacology of amantadine is complex.<ref name="DanyszDekundyScheschonka2021" /><ref name="HuberDietrichEmrich1999" /> It acts as a sigma σ₁ receptor agonist, nicotinic acetylcholine receptor negative allosteric modulator, dopaminergic agent, and weak NMDA receptor antagonist, among other actions.<ref name="DanyszDekundyScheschonka2021" /><ref name="HuberDietrichEmrich1999" /> The precise mechanism of action of its therapeutic effects in the treatment of CNS disorders is unclear.<ref name="DanyszDekundyScheschonka2021" /><ref name="HuberDietrichEmrich1999" /> The antiviral mechanism of action is inhibition of the influenza virus A M2 proton channel, which prevents endosomal escape (i.e., the release of viral genetic material into the host cytoplasm).<ref>Template:Cite book</ref><ref>Template:Cite journal</ref> Amantadine is an adamantane derivative and is related to memantine and rimantadine.<ref name="RagshaniyaKumarTittal2024">Template:Cite journal</ref>

Amantadine was first used for the treatment of influenza A.<ref name="DanyszDekundyScheschonka2021" /> After its antiviral properties were initially reported in 1963, amantadine received approval for prophylaxis against the influenza virus A in 1966.<ref name="DanyszDekundyScheschonka2021" /><ref name="Hubsher_2012">Template:Cite journal</ref> In 1968, its antiparkinsonian effects were serendipitously discovered.<ref name="DanyszDekundyScheschonka2021" /> In 1973, the Food and Drug Administration (FDA) approved amantadine for use in the treatment of Parkinson's disease.<ref name="DanyszDekundyScheschonka2021" /> In 2020, the extended-release formulation was approved for use in the treatment of levodopa-induced dyskinesia.<ref name="DanyszDekundyScheschonka2021" /><ref>Template:Cite journal</ref>

Medical uses

Amantadine was initially developed to prevent replication of the influenza A virus.<ref name="Raupp-BarcaroVitalGalduróz2018" /> Its main clinical use today is treatment of Parkinson's disease.<ref name="Raupp-BarcaroVitalGalduróz2018" /> Other uses include treatment of drug-induced extrapyramidal side effects, motor fluctuations during levodopa therapy in Parkinson's disease, traumatic brain injury, and autistic spectrum disorders.<ref name="Raupp-BarcaroVitalGalduróz2018" />

Parkinson's disease

Amantadine is used to treat Parkinson's disease-related dyskinesia and drug-induced parkinsonism syndromes.<ref name="rascol">Template:Cite journal</ref> Amantadine may be used alone or in combination with another anti-Parkinson's or anticholinergic drug.<ref name="Golan_2017">Template:Cite book</ref> The specific symptoms targeted by amantadine therapy are dyskinesia and rigidity.<ref name=rascol/> The extended release amantadine formulation is commonly used to treat dyskinesias in people receiving levodopa therapy for Parkinson's disease.<ref name=rascol/> A 2003 Cochrane review had concluded evidence was insufficient to prove the safety or efficacy of amantadine to treat dyskinesia.<ref>Template:Cite journal</ref>

In 2008, the World Health Organization (WHO) reported amantadine is not effective as a stand-alone parkinsonian therapy, but recommended it could be used in combination therapy with levodopa.<ref name="WHO Formulary 2008">Template:Cite book</ref>

Influenza A

Amantadine is not recommended for treatment or prophylaxis of influenza A in the United States.<ref name="CDC_2019">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Amantadine has no effect preventing or treating influenza B infections.<ref name="CDC_2019" /> The US Centers for Disease Control and Prevention (CDC) found 100% of seasonal H3N2 and 2009 pandemic flu samples were resistant to adamantanes (amantadine and rimantadine) during the 2008–2009 flu season.<ref name="Golan_2017" /><ref name="cdc weekly report">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The U.S. CDC guidelines recommend only neuraminidase inhibitors for influenza treatment and prophylaxis.Template:Medcn The CDC recommends against amantadine and rimantadine to treat influenza A infections.<ref name="CDC_2019" />

Similarly, the 2011 WHO virology report showed all tested H1N1 influenza A viruses were resistant to amantadine.<ref name="WHO_2011">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> WHO guidelines recommend against use of M2 inhibitors for influenza A.Template:Medcn The continued high rate of resistance observed in laboratory testing of influenza A has reduced the priority of M2 resistance testing.Template:Medcn

A 2014 Cochrane review did not find evidence for efficacy or safety of amantadine used for the prevention or treatment of influenza A.<ref>Template:Cite journal</ref>

Extrapyramidal symptoms

An extended-release formulation of amantadine is used to treat levodopa-induced dyskinesia in patients with Parkinson's disease.<ref name="Gocovri FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The WHO recommends the use of amantadine as a combination therapy to reduce levodopa side effects.<ref name="WHO Formulary 2008" />

Off-label uses

Fatigue in multiple sclerosis

A 2007 Cochrane literature review concluded that no overall evidence supports the use of amantadine in treating fatigue in patients with multiple sclerosis (MS).<ref>Template:Cite journal</ref> A follow-up 2012 Cochrane review stated that some amantadine-induced improvement in fatigue may occur in some people with MS.<ref>Template:Cite journal</ref> Despite multiple control trials that have also demonstrated improvements in subjective and objective ratings of fatigue, no final conclusion has been drawn regarding its effectiveness.<ref>Template:Cite journal</ref>

Consensus guidelines from the German Multiple Sclerosis Society (GMSS) in 2006 state that amantadine produces moderate improvement in subjective fatigue, problem solving, memory, and concentration. Thus, in 2006, GMSS guidelines recommended the use of amantadine in MS-related fatigue.<ref>Template:Cite journal</ref>

In the UK, NICE recommends considering amantadine for MS fatigue.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Disorders of consciousness

Disorders of consciousness (DoC) include coma, vegetative state (VS), and minimally conscious state (MCS). Amantadine has been shown to increase the rate of emergence from a MCS, defined by consistent demonstration of interactive communication and functional objective use. In traumatic brain injury patients in the intensive care unit, amantadine has also been shown in various randomized control trials to increase the rate of functional recovery and arousal, particularly in the time period immediately following an injury.<ref name="Ma_2020">Template:Cite journal</ref> Also, significantly improved consciousness has been reported in patients treated for nontraumatic cases of DoC, such as in the case of a subarachnoid hemorrhage, cerebral hemorrhage, and hypoxic encephalopathy.<ref>Template:Cite journal</ref> In 2018, the American Academy of Neurology updated treatment guidelines on the use of amantadine for patients with prolonged DoC, recommending the use of amantadine (100–200Template:Nbspmg b.i.d.) for adults with DoC 4 to 16 weeks after injury to support early functional recovery and reduce disability.<ref>Template:Cite journal</ref>

Brain injury recovery

In various studies, amantadine and memantine have been shown to accelerate the rate of recovery from a brain injury.<ref name="auto">Template:Cite journal</ref><ref>Template:Cite journal</ref> The time-limited window following a brain injury is characterized by neuroplasticity, or the capacity of neurons in the brain to adapt and compensate after injury. Thus, physiatrists often start patients on amantadine as soon as impairments are recognized. Some case reports also show improved functional recovery with amantadine treatment occurring years after the initial brain injury.<ref name="Ma_2020"/> Evidence is insufficient to determine if the functional gains are a result of effects through the dopamine or norepinephrine pathways. Some patients may benefit from direct dopamine stimulation with amantadine, while others may benefit more from other stimulants that act more on the norepinephrine pathway, such as methylphenidate.<ref name="Ma_2020" /> If treatment with amantadine improves long-term outcomes or simply accelerates recovery is unclear.<ref name="auto"/> Nonetheless, amantadine-induced acceleration of recovery reduces the burden of disability, lessens health-care costs, and minimizes psychosocial stressors in patients.Template:Cn

Contraindications

Amantadine is contraindicated in persons with end-stage kidney disease,<ref name="Gocovri FDA label" /> as the drug is renally cleared.<ref name="TGA" /><ref name="FDA_2019" /><ref name="EndoPharmRXInfo">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Amantadine may have anticholinergic side effects. Thus, patients with an enlarged prostate or glaucoma should use with caution.<ref name="Chang_2020" />

Live attenuated vaccines are contraindicated while taking amantadine.<ref name="Gocovri FDA label" /> Amantadine might inhibit viral replication and reduce the efficacy of administered vaccines. The U.S. Food and Drug Administration recommends avoiding amantadine for two weeks prior to vaccine administration and 48 hours afterward.<ref name="FDA_2019" />

Side effects

Amantadine is generally well tolerated and has a mild side effect profile.<ref>Template:Cite journal</ref>

Neurological

Side effects include drowsiness (especially while driving), lightheadedness, falls, and dizziness.<ref name="Gocovri FDA label" /> Patients on amantadine should avoid combination with other CNS-depressing agents, such as alcohol. Excessive alcohol usage may increase the potential for CNS effects such as dizziness, confusion, and light-headedness.<ref name="Chang_2020" />

Rare severe adverse effects include neuroleptic malignant syndrome, depression, convulsions, psychosis, and suicidal ideation.<ref name="Chang_2020" /> It has also been associated with disinhibited actions (gambling, sexual activity, spending, other addictions) and diminished control over compulsions.<ref name="Gocovri FDA label" />

Amantadine may cause anxiety, feeling overexcited, hallucinations, and nightmares.<ref>Amantadine Hydrochloride package leaflet, Manx Healthcare, 1/24; Common possible side effects (may affect up to one in 10 people)</ref>

Cardiovascular

Amantadine may cause orthostatic hypotension, syncope, and peripheral edema.<ref name="Gocovri FDA label" />

Gastrointestinal

Amantadine has also been associated with dry mouth and constipation.<ref name="Gocovri FDA label" />

Skin

Rare cases of skin rashes, such as Stevens–Johnson syndrome and livedo reticularis have also been reported in patients treated with amantadine.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Kidney

Amantadine inhibits the kidney's active-transport removal and transfer of creatinine from blood to urine, which normally occurs in the proximal tubules of the nephrons. The active-transport removal mechanism accounts for about 15% of creatinine clearance, so amantadine may increase serum creatinine concentrations 15% above normal levels and give the false impression of mild kidney disease in patients whose kidneys are actually undamaged (because kidney function is often assessed by measuring the concentration of creatinine in blood.) Also, if the patient does have kidney disease, amantadine may cause it to appear as much as 15% worse than it actually is.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Pregnancy and lactation

Amantadine is USFDA category C for pregnancy. Teratogenic effects have been observed in humans (case reports) and animal reproduction studies. Amantadine may also be present in breast milk and negatively alter breast milk production or excretion. The decision to breastfeed during amantadine therapy should consider the risk of infant exposure, the benefits of breastfeeding, and the benefits of the drug to the mother.<ref name="Chang_2020" />

Interactions

Amantadine may affect the CNS because of its dopaminergic and anticholinergic properties. The mechanisms of action are not fully known. Because of the CNS effects, caution is required when prescribing additional CNS stimulants or anticholinergic drugs.<ref name="FDA_2019" /> Thus, concurrent use of alcohol with amantadine is not recommended because of enhanced CNS depressant effects.<ref>Gocovri (amantadine) extended-release capsules [prescribing information]. Emeryville, CA: Adamas Pharma, LLC; August 2017</ref> In addition, antidopaminergic drugs such as metoclopramide and typical antipsychotics should be avoided.<ref>Reglan (metoclopramide) [prescribing information]. Baudette, MN: ANI Pharmaceuticals Inc; August 2017</ref><ref>Template:Cite journal</ref> These interactions are likely related to opposing dopaminergic mechanisms of action, which inhibits amantadine's anti-Parkinson effects.Template:Medcn

Pharmacology

Mechanism of action

Central nervous system disorders

The mechanism of action of the antiparkinsonian effects of amantadine is poorly understood.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The effects of amantadine in Parkinson's disease were originally assumed to be anticholinergic or dopaminergic, but the situation soon proved more complicated than this.<ref name="DanyszDekundyScheschonka2021" /><ref name="HuberDietrichEmrich1999" /> The pharmacodynamics of amantadine are complex, and it interacts with many different biological targets at a variety of concentrations and hence potencies.<ref name="DanyszDekundyScheschonka2021" /><ref name="HuberDietrichEmrich1999" />

The drug is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake.<ref name="DanyszDekundyScheschonka2021" /><ref name="HuberDietrichEmrich1999" /><ref name="Austria-Codex">Template:Cite book</ref><ref name="Kornhuber1991">Template:Cite journal</ref><ref name="pmid15800186">Template:Cite journal</ref> It is a negative allosteric modulator of the nicotinic acetylcholine receptors, specifically the α₄β₂ and α₇ nicotinic acetylcholine receptors.<ref name="DanyszDekundyScheschonka2021" />

In 1993, amantadine was found to bind to the sigma σ₁ receptor with relatively high affinity (K_i = 20.25Template:NbspμM).<ref name="DanyszDekundyScheschonka2021" /><ref name="KornhuberSchoppmeyerRiederer1993">Template:Cite journal</ref> In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the sigma σ₁ receptor (K_i = 7.44Template:NbspμM and 2.60Template:NbspμM, respectively) and that activation of the σ₁ receptor is potentially involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations.<ref name="PeetersRomieu2004">Template:Cite journal</ref> σ₁ receptor activation is one of amantadine's more potent actions.<ref name="DanyszDekundyScheschonka2021" /><ref name="PeetersRomieu2004" /> σ₁ receptor agonists enhance tyrosine hydroxylase activity, modulate NMDA-stimulated dopamine release, increase dopamine release in the striatum in vivo, and decrease dopamine reuptake.<ref name="DanyszDekundyScheschonka2021" /> As such, σ₁ receptor activation may be involved in the antiparkinsonian and other central nervous system effects of amantadine.<ref name="DanyszDekundyScheschonka2021" /><ref name="PeetersRomieu2004" />

Binding of amantadine to the NMDA receptor was first reported in 1989, and antagonism of the receptor was first reported in 1991.<ref name="DanyszDekundyScheschonka2021" /> Despite some reports, the NMDA receptor antagonism of amantadine is probably not its primary mechanism of action.<ref name="DanyszDekundyScheschonka2021" /><ref name="HuberDietrichEmrich1999" /> It occurs at relatively high concentrations and many of the effects of amantadine are different from those of NMDA receptor antagonists.<ref name="DanyszDekundyScheschonka2021" /> Some of its effects, such as enhancement of dopamine release in the striatum, are even reversed by NMDA receptor antagonists,<ref name="DanyszDekundyScheschonka2021" /> but NMDA receptor antagonism could still contribute to the effects of amantadine.<ref name="DanyszDekundyScheschonka2021" />

Although some publications have reported that amantadine inhibits monoamine oxidase, the drug probably does not actually inhibit this enzyme.<ref name="DanyszDekundyScheschonka2021" /><ref name="HuberDietrichEmrich1999" /><ref>Template:Cite journal</ref>

Amantadine shows amphetamine-like psychostimulant effects (e.g., stimulation of locomotor activity) in animals at sufficiently high doses.<ref name="HuberDietrichEmrich1999" /><ref name="ShimazuTakahataKatsuki2001">Template:Cite journal</ref> It has been found to inhibit the reuptake of serotonin, norepinephrine, and dopamine and to induce the release of serotonin, norepinephrine, and dopamine.<ref name="HuberDietrichEmrich1999" /><ref name="DanyszDekundyScheschonka2021" /><ref name="WankaIqbalSchreiner2013">Template:Cite journal</ref><ref name="SommerauerRebernikReither2012">Template:Cite journal</ref> The concentrations needed for these effects, though, are very high and may not be therapeutically relevant.<ref name="HuberDietrichEmrich1999" /><ref name="DanyszDekundyScheschonka2021" /> It is about 1/25th to 1/50th as potent as amphetamines.<ref name="HuberDietrichEmrich1999" /> Amantadine has been found to increase dopamine levels in the striatum.<ref name="HuberDietrichEmrich1999" /><ref name="DanyszDekundyScheschonka2021" /> It does not act as a monoaminergic activity enhancer.<ref name="ShimazuTakahataKatsuki2001" /><ref name="YonedaMotoSakae2001">Template:Cite journal</ref><ref name="KnollYonedaKnoll1999">Template:Cite journal</ref>

Amantadine is a phosphodiesterase inhibitor, for example of PDE1.<ref name="DanyszDekundyScheschonka2021" />

Amantadine has been found to increase aromatic amino acid decarboxylase expression.<ref name="DanyszDekundyScheschonka2021" /> This enzyme is responsible for the synthesis of dopamine from L-DOPA.<ref name="DanyszDekundyScheschonka2021" /> An imaging study in humans found that amantadine increased AADC activity in the striatum by up to 27%.<ref name="DanyszDekundyScheschonka2021" />

Various additional actions of amantadine have been described.<ref name="DanyszDekundyScheschonka2021" />

Influenza

File:M2 influenza A proton channel amantadine 3C9J.png

Model of amantadine (red) inhibiting influenza A M2 protein (blue).<ref>Template:Cite journal</ref>

File:Virus Replication.svg

Model of viral replication.

The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated.<ref name="TGA" /><ref name="FDA_2019"/> Amantadine targets the influenza A M2 ion channel protein. The M2 protein's function is to allow the intracellular virus to replicate (M2 also functions as a proton channel for hydrogen ions to cross into the vesicle), and exocytose newly formed viral proteins to the extracellular space (viral shedding). By blocking the M2 channel, the virus is unable to replicate because of impaired replication, protein synthesis, and exocytosis.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Amantadine and rimantadine function in a mechanistically identical fashion, entering the barrel of the tetrameric M2 channel and blocking pore function—i.e., proton translocation.<ref name="Golan_2017" />

Resistance to the drug class is a consequence of mutations to the pore-lining amino acid residues of the channel, preventing both amantadine and rimantadine from binding and inhibiting the channel in their usual way.<ref>Template:Cite journal</ref>

Pharmacokinetics

Amantadine is well-absorbed orally. The onset of action is usually within 48 hours when used for parkinsonian syndromes, including dyskinesia. As plasma concentrations of amantadine increase, the risk for toxicity increases.<ref name="Drugs.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Drugs.com_2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Half-life elimination averages eight days in patients with end-stage kidney disease. Amantadine is only minimally removed by hemodialysis.<ref name="Drugs.com_2" /><ref>Template:Cite journal</ref>

Amantadine is metabolized to a small extent (5–15%) by acetylation. It is mainly excreted (90%) unchanged in urine by kidney excretion.<ref name="Drugs.com" />

Chemistry

Amantadine is the organic compound 1-adamantylamine or 1-aminoadamantane, which consists of an adamantane backbone with an amino group substituted at one of the four tertiary carbons.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Rimantadine is a closely related adamantane derivative with similar biological properties;<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> both target the M2 proton channel of influenza A virus.<ref name="Golan_2017" />

Amantadine (1-aminoadamantane) is structurally related to other adamantanes including adapromine (1-(adamantan-1-yl)propan-1-amine), bromantane (N-(4-bromophenyl)adamantan-2-amine), memantine (1-amino-3,5-dimethyladamantane), and rimantadine (1-(1-aminoethyl)adamantane), among others.Template:Cn

History

Influenza A

Antiviral properties were first reported in 1963 at the University of Illinois Hospital in Chicago. In this amantadine trial study, volunteer college students were exposed to a viral challenge. The group who received amantadine (100 milligrams 18 hours before viral challenge) had less Asia influenza infections than the placebo group.<ref name="Hubsher_2012"/> Amantadine received approval for the treatment of influenza virus A<ref>Template:Cite book</ref><ref>Template:Cite news</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> in adults in 1976.<ref name="Hubsher_2012" /> It was first used in West Germany in 1966. Amantadine was approved by the U.S. Food and Drug Administration in October 1968, as a prophylactic agent against Asian (H2N2) influenza and received approval for prophylactic use for influenza A in 1976.<ref name="Hubsher_2012" /><ref name="Gocovri FDA label2"/><ref>Template:Citation</ref>

During the 1980 influenza A epidemic, the first amantadine-resistance influenza viruses were reported. The frequency of amantadine resistance among influenza A (H3N2) viruses from 1991 and 1995 was as low as 0.8%. In 2004, the resistance frequency increased to 12.3%. A year later, resistance increase significantly to 96%, 72%, and 14.5% in China, South Korea, and the United States, respectively. By 2006, 90.6% of H3N2 strains and 15.6% of H1N1 were amantadine resistant. A majority of the amantadine-resistant H3N2 isolates (98.2%) was found to contain an S31N mutation in the M2 transmembrane domain that confers resistance to amantadine.<ref name=kumar>Template:Cite journal</ref> Currently, adamantane resistance is high among circulating influenza A viruses. Thus, they are no longer recommended for treatment of influenza A.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Parkinson's disease

An incidental finding in 1969 prompted investigations about amantadine's effectiveness for treating symptoms of Parkinson's disease.<ref name="Hubsher_2012" /> A woman with Parkinson's disease was prescribed amantadine to treat her influenza infection and reported her cogwheel rigidity and tremors improved. She also reported that her symptoms worsened after she finished the course of amantadine.<ref name="Hubsher_2012" /> The published case report was not initially corroborated by any other instances by the medical literature or manufacturer data. A team of researchers looked at a group of 10 patients with Parkinson's disease and gave them amantadine. Seven of them showed improvement, which was convincing evidence for the need of a clinical trial, which included 163 patients with Parkinson's disease; 66% experienced subjective or objective reduction of symptoms with a maximum daily dose of 200Template:Nbspmg.<ref name="Hubsher_2012" /><ref>Template:Cite journal</ref> Additional studies followed patients for greater lengths of time and in different combinations of neurological drugs.<ref>Template:Cite journal</ref> It was found to be a safe drug that could be used over long periods of time with few side effects as monotherapy or in combination with L-dopa or anticholinergic drugs.<ref name="Hubsher_2012" /> By April 1973, the U.S. FDA approved amantadine for use in the treatment of Parkinson's disease.<ref name="FDA_2019"/><ref name="Hubsher_2012" />

In 2017, the U.S. FDA approved the use of amantadine in an extended-release formulation for the treatment of dyskinesia, an adverse effect of levodopa in people with Parkinson's disease.<ref name="FDA20172">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Society and culture

Names

Brand names of amantadine include Gocovri, Symadine, and Symmetrel.<ref name="Drugs.com-International">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="TGA" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Recreational use

Recreational use of amantadine 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-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> However, the very long duration of action of amantadine (>40Template:Nbsphours) has likely limited its misuse potential.<ref name="MorrisWallach2014" /> Recreational use of the related drug memantine has similarly been reported.<ref name="MorrisWallach2014" />

Veterinary misuse

In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza.<ref name="WashPostBirdFlu">Template:Cite news</ref> In Western countries and according to international livestock regulations, amantadine is approved only for use in humans. Chickens in China have received an estimated 2.6 billion doses of amantadine.<ref name="WashPostBirdFlu"/> Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine, although strains circulating elsewhere still seem to be sensitive. If amantadine-resistant strains of the virus spread, the drugs of choice in an avian flu outbreak will probably be restricted to neuraminidase inhibitors oseltamivir and zanamivir, which block the action of viral neuraminidase enzyme on the surface of influenza virus particles.<ref name=kumar/> Increasing incidence of oseltamivir resistance in circulating influenza strains (e.g., H1N1) exists, highlighting the need for new anti-influenza therapies.<ref>Template:Cite journal</ref>

In September 2015, the U.S. FDA announced the recall of Dingo Chip Twists "Chicken in the Middle" dog treats because the product has the potential to be contaminated with amantadine.<ref name="LoC">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Research

Depression

Interest in and study of amantadine in the treatment of depression has arisen.<ref name="HuberDietrichEmrich1999">Template:Cite journal</ref><ref name="DeutschenbaurBeckKiyhankhadiv2016">Template:Cite journal</ref><ref name="Raupp-BarcaroVitalGalduróz2018">Template:Cite journal</ref><ref name="DanyszDekundyScheschonka2021">Template:Cite journal</ref><ref name="ShamabadiAhmadzadeAgamolaei2022">Template:Cite journal</ref> A 2017 systematic review of off-label augmentation for treatment of unipolar depression found two open-label studies of amantadine for augmenting imipramine and found that it was effective.<ref name="KleeblattBetzlerKilarski2017">Template:Cite journal</ref> However, the quality of evidence was very low and no conclusions could be drawn about its effectiveness.<ref name="KleeblattBetzlerKilarski2017" /> A 2022 systematic review of randomized controlled trials of glutamatergic agents for treatment-resistant depression identified one clinical trial of amantadine for this use.<ref name="ShamabadiAhmadzadeAgamolaei2022" /> Amantadine was found to be effective in treating depressive symptoms in the trial.<ref name="ShamabadiAhmadzadeAgamolaei2022" /> The mechanism of action of amantadine in the treatment of depression is unclear, but various mechanisms have been postulated.<ref name="Raupp-BarcaroVitalGalduróz2018" /><ref name="DeutschenbaurBeckKiyhankhadiv2016" /> These include dopaminergic actions like indirect enhancement of dopamine release, dopamine reuptake inhibition, and D₂ receptor interactions, noradrenergic actions, glutamatergic actions such as NMDA receptor antagonism, and immunomodulation, among many others.<ref name="Raupp-BarcaroVitalGalduróz2018" /><ref name="DeutschenbaurBeckKiyhankhadiv2016" /><ref name="HuberDietrichEmrich1999" />

Attention deficit hyperactivity disorder

Amantadine has been studied in the treatment of attention-deficit hyperactivity disorder (ADHD).<ref name="PozziBertellaGatti2020">Template:Cite journal</ref> A 2010 randomized clinical trial showed similar improvements in ADHD symptoms in children treated with amantadine as in those treated with methylphenidate, with less frequent side effects.<ref name="MohammadiKazemiZia2010">Template:Cite journal</ref> A 2021 retrospective study showed that amantadine may serve as an effective adjunct to stimulants for ADHD-related symptoms and appears to be a safer alternative to second- or third-generation antipsychotics.<ref>Template:Cite journal</ref>

COVID-19

Amantadine has been studied in the treatment of COVID-19.<ref name="Płusa2021">Template:Cite journal</ref><ref name="MarinescuMarinescuMogoantă2020">Template:Cite journal</ref>

External links

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