Memantine is a medication used to treat moderate to severe Alzheimer's disease. Memantine is used as a second-line treatment after acetylcholinesterase inhibitors such as donepezil. Treatment should only be continued if positive effects are seen. The medication is taken by mouth. Common side effects include headache, constipation, drowsiness, and dizziness. Severe side effects may include blood clots, psychosis, and heart failure. It is thought to work by blocking NMDA receptors. Memantine was approved for medical use in the United States in 2003. A monthly supply in the United Kingdom costs the National Health Service about £1.60 per person as of 2019. In the United States, the wholesale cost of this amount is about US$5.50. Memantine was the 147th most prescribed drug in the United States in 2016, with more than 4 million prescriptions. Memantine is used to treat moderate to severe Alzheimer's disease, especially in people who cannot tolerate or are contraindicated in taking acetylcholinesterase inhibitors. One guideline recommends that memantine or an acetylcholinesterase inhibitor be considered in people with early to moderate dementia. Memantine has been associated with moderate improvement with little positive effect on cognition, mood, behavior, and ability to perform daily activities in moderate to severe Alzheimer's disease. There has been no evidence of improvement in mild cases of the disease. Memantine is generally well tolerated. Common adverse drug reactions include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. Less common side effects include vomiting, anxiety, hypertonia, cystitis, and increased libido. Like other N-methyl-D-aspartate receptor antagonists, memantine acts as a dissociative agent when used in supra-therapeutic doses. Memantine also appears to lack most of the psychoactive effects that recreational users typically seek, such as euphoria or hallucinations. Dysfunction of glutamate neurotransmission, manifested by excitotoxicity, is hypothesized to be one of the etiologies of Alzheimer's disease. Targeting the glutamic acid pathway, particularly N-methyl-D-aspartate (NMDA) receptors, offers a new approach to treatment in light of the limited efficacy of existing drugs targeting the acetylcholine system. Memantine is a low-affinity, non-competitive antagonist. With a higher affinity for Mg2+ ions, memantine is unable to suppress the influx of Ca2+ ions for a long time, especially from extrasynaptic receptors, which form the basis of excitatory activity in synapses. However, the low affinity, non-competitive nature, and rapid kinetics of memantine at the level of NMDA receptors preserve the function of the receptors in synapses, where they can still be activated by the physiological release of glutamic acid after depolarization of postsynaptic neurons. The interaction of memantine with NMDA receptors plays a key role in the symptomatic improvement produced by the drug in Alzheimer's disease. However, there is no evidence to date that memantine's ability to protect against NMDA receptor-mediated excitotoxicity has a disease-modifying effect in Alzheimer's disease, although this has been suggested in animal models. Memantine acts as a non-competitive antagonist at serotonin 5-HT3 receptors, with potency similar to that of NMDA receptors. Many serotonin antagonists act as antiemetics, but the clinical significance of this serotonergic activity in the treatment of Alzheimer's disease remains unknown. Memantine acts as a non-competitive antagonist at various acetylcholine receptors in a mode of action that may be similar to that at NMDA and serotonin receptors, but its accuracy is difficult to ascertain due to the rapid sensitivity of acetylcholine receptor responses in these experiments. It should be noted that memantine is an antagonist at the alpha7 acetylcholine receptor, which may contribute to the initial worsening of cognitive function during memantine treatment in the first treatment. The alpha7 acetylcholine receptor rapidly responds to competitive stimuli, which may explain the cognitive-enhancing effect of chronic memantine treatment. The number of nicotinic receptors in the brain has also been shown to decrease in Alzheimer's disease, even in the absence of a general decline in the number of neurons, and nicotinic receptor agonists are seen as interesting targets for anti-Alzheimer's drugs. Memantine acts as a dopamine receptor agonist with an affinity equal to or slightly higher than that of NMDA receptors. Memantine was first manufactured and patented by Eli Lilly and Company in 1968 as a diabetes drug, but was ineffective at lowering blood sugar. Memantine was later discovered to have a central nervous system effect, and was produced by Merz for the treatment of dementia in Germany; NMDA receptors were discovered after trials had already begun. The drug was first marketed as a dementia treatment in Germany in 1989 under the name Axura. Some effects on the central nervous system were discovered at Children's Hospital in Boston in the United States in 1995. In 2000, Mrs. entered into a partnership with Forest to develop an Alzheimer's drug in the United States under the name Namenda. In 2000, Mrs. entered into a partnership with Suntory for the Japanese market and with Lundbeck for other markets including Europe; the drug was originally marketed by Lundbeck under the name Ebixa. Sales of the drug reached $1.8 billion in 2014. Namenda cost $269 to $489 per month in 2012. In February 2014, with the July 2015 patent expiration of memantine, Actavis, which acquired Forest, announced that it was launching an extended-release form of memantine that could be taken once daily instead of twice daily as needed, and that it intended to stop selling the short-acting IR version in August 2014 and withdraw its marketing authorization. This was a mechanism to thwart generic competition called "product hopping." However, the supply of the XR version ran out, so Actavis extended the deadline until it was gone from the market. In September 2014, New York Attorney General Eric Schneiderman filed a lawsuit to force Actavis to continue selling the IR version on antitrust grounds. In December 2014, a New York judge granted his request and issued an injunction, preventing Actavis from withdrawing the short-acting IR version until generic versions could be launched. Actavis appealed the ruling, and in May a panel of the Second Circuit Court of Appeals upheld the appeal, and in June Actavis asked to have its case heard by a full Second Circuit panel. Actavis’s request was denied in August 2015. There is research into the use of memantine in the treatment of attention deficit hyperactivity disorder, but the evidence is not yet conclusive. There is also research into its use in the treatment of migraines.