Apart from medical uses, this compound is useful as a building block, allowing the insertion of an adamantyl group.
According to the US Centers for Disease Control and Prevention, 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza in the United States. Additionally, its effectiveness as an antiparkinsonian drug is undetermined, with a 2003 Cochrane Review concluding that there was insufficient evidence in support or against its efficacy and safety.
Despite a 2003 Cochrane review of the scientific literature concluding that there is inadequate evidence to support the use of amantadine for Parkinson's, the drug continues to be prescribed for this indication.
Amantadine is no longer recommended for treatment of influenza A infection.
Some open-label uncontrolled studies have found it to possess value as an adjunct to antidepressant therapy.
Amantadine has been associated with several central nervous system (CNS) side effects, likely due to amantadine's dopaminergic and adrenergic activity, and to a lesser extent, its activity as an anticholinergic. CNS side effects include nervousness, anxiety, agitation, insomnia, difficulty in concentrating, and exacerbations of pre-existing seizure disorders and psychiatric symptoms in patients with schizophrenia or Parkinson's disease. The usefulness of amantadine as an anti-parkinsonian drug is somewhat limited by the need to screen patients for a history of seizures and psychiatric symptoms.
A starting dose is often 100 mg once daily. All influenza B strains, many influenza A strains (and virtually all H1N1 "swine flu" strains) are resistant to amantadine, so a failure at this dose is likely due to resistance and not underdosing. For its anti-Parkinsonian effects, a starting dose of 300 mg once daily is normal, but can be increased to a limit of about 400 mg.
The mechanisms for amantadine's antiviral and antiparkinsonian effects appear to be unrelated.
The mechanism of Amantadine's antiviral activity involves interference with a viral protein, M2 (an ion channel), which is required for the viral particle to become "uncoated" once taken inside a cell by endocytosis.
Amantadine appears to act through several pharmacological mechanisms, but no dominant mechanism of action has been identified. It is a dopaminergic, noradrenergic and serotonergic substance, blocks monoamine oxidase A and NMDA receptors, and seems to raise beta-endorphin/beta-lipotropin levels.
Research in brain injury
In a 2012 study, 184 patients with severe traumatic brain injury were treated with amantadine or placebo for four weeks. In this study, the drug accelerated functional brain recovery during treatment. However, the placebo group had improved just as much as the amantadine group at six weeks - two weeks after the drug administration ended.
In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza. 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. 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 the scarcer and costlier oseltamivir and zanamivir, which work by a different mechanism and are less likely to trigger resistance.
^Stryjer, R; Strous RD, Shaked G, Bar F, Feldman B, Kotler M, Polak L, Rosenzcwaig S, Weizman A (2003). "Amantadine as augmentation therapy in the management of treatment-resistant depression.". International Journal of Psychopharmacology18 (2): 93–96. PMID12598820.
^K C Singhal & S Z Rahman, Stevens Johnson Syndrome induced by Amantadine, Rational Drug Bulletin, 2002, Vol. 12, No. 1: 6
^Wang C, Takeuchi K, Pinto LH, Lamb RA (1993). "Ion channel activity of influenza A virus M2 protein: characterization of the amantadine block". Journal of Virology67 (9): 5585–94. PMC237962. PMID7688826.
^Jing X, Ma C, Ohigashi Y, et al. (2008). "Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel". Proc. Natl. Acad. Sci. U.S.A.105 (31): 10967–72. doi:10.1073/pnas.0804958105. PMC2492755. PMID18669647.
^Kornhuber J, Bormann J, Hübers M, Rusche K, Riederer P (1991) "Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study." Eur.J.Pharmacol.Mol.Pharmacol.Sect. 206:297-300.
^Giacino, J. T.; Whyte, J.; Bagiella, E.; Kalmar, K.; Childs, N.; Khademi, A.; Eifert, B.; Long, D.; Katz, D. I.; Cho, S.; Yablon, S. A.; Luther, M.; Hammond, F. M.; Nordenbo, A.; Novak, P.; Mercer, W.; Maurer-Karattup, P.; Sherer, M. (2012). "Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury". New England Journal of Medicine366 (9): 819–826. doi:10.1056/NEJMoa1102609. PMID22375973. edit