Amantadine: reappraisal of the timeless diamond—target updates and novel therapeutic potentials

Abstract

The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson’s disease symptoms and viral infections. Considering amantadine’s affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington’s disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine’s therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.

Neuropsychiatric Drugs Against COVID-19: What is the Clinical Evidence?

“…Amantadine has been introduced many years ago as an antiviral drug to treat influenza A2 but has not been widely used. Besides the antiviral activity, it also possesses a broad spectrum of pharmacological properties 49 including anti-inflammatory effects probably related to its activity as a sigma-1 receptor agonist 49 . The structurally related compound memantine is predominantly an NMDA-receptor antagonist and is used clinically as an antidementia drug 50 .…”

Refractory Methamphetamine-Induced Psychosis: An Emerging Crisis in Rural America and the Role of Amantadine in Therapeutics

“…Amantadine acts via antagonism of the NMDA receptor. It decreases the toxic effects of the glutamatergic neurotransmitter system, which plays an important role in many psychiatric disorders [ 18 ]. There have been many trials involving memantine (NMDA receptor antagonist similar to amantadine) as a drug for adjunctive use with antipsychotics for schizophrenia [ 19 ].…”

“…Amantadine acts via antagonism of the NMDA receptor. It decreases the toxic effects of the glutamatergic neurotransmitter system, which plays an important role in many psychiatric disorders [18].…”

Pharmacologic Therapies to Promote Recovery of Consciousness

“…Amantadine hydrochloride is an antiviral agent approved by the United States Food and Drug Administration (USFDA) in the early 1960s, and soon after was reported to significantly improve symptoms in a patient with Parkinson's disease initiated on amantadine for antiviral purposes. 12 It has since been identified as a dopaminergic agent with added labeled indications for treatment of Parkinson's disease and drug-induced extrapyramidal reactions. 17 For the treatment of DoC, amantadine is typically dosed at 100 to 200 mg enterally twice daily, with dose reductions required in the setting of renal dysfunction due to the high urinary elimination (>90%) as unchanged drug ( Table 1 ).…”