Dextromethorphan (DM) received FDA approval in 1958 for its use as a cough suppressant. It is one of the most common compounds found in the majority of the over-the-counter antitussives for the past 50 years.[1]

In 2010, the FDA approved the use of DM for pseudobulbar affect (PBA) in combination with quinidine. PBA is a neurologic dysfunction of emotional expression characterized by outbursts of crying or laughing inappropriately and disproportionately to the mood. The pathology of PBA is still incompletely understood, but the leading hypothesis suggests that it is due to a loss of descending cortical control of brainstem motor nuclei and the cerebellum. This loss of control disrupts inhibitory mechanisms for motor control of emotional expression.[2][3]

There are many other potential therapeutic uses for DM that are currently under investigation in clinical studies. Most of these use the property that DM has as a neuroprotective agent. These indications include[4]:

• Depression: DM has a fast-acting antidepressant activity for its similarity to ketamine
• Stroke: Studies have shown that DM has a role in the improvement of some neurological and psychiatric complications, however, not the overall functional outcomes
• Traumatic Brain Injury: Although the studies have shown limited effects, there are proposed mechanisms that confer the benefits of DM in TBI including its activity at NMDA and sigma-1 receptors
• Seizure: Some clinical studies have shown that DM has efficacy in refractory seizures
• Pain: There are studies on the analgesic effects of DM for pain conditions such as cancer-related, post-operative, neuropathic and gastrointestinal pain
• Methotrexate Neurotoxicity: DM showed a complete resolution in neurologic deficits associated with MTX toxicity in 5 cases
• Parkinson's Disease: DM meliorated primary Parkinson's disease in 2 studies
• Autism: contradicting data regarding DM's role in behavioral improvement

Dextromethorphan has multi-faceted pharmacodynamic and pharmacokinetic properties. The drug is a lipophilic molecule with an ionizable amine at one end. It is structurally related to alkaloid opioids such as morphine but does not interact with the mu receptor. It derives from levorphanol, first designed as a morphine alternative. The main mechanism of action for its use in the cough suppressant is not completely understood. One proposed mechanism is that DM works on the nucleus tractus solitarius, the estimated site where the pulmonary vagal afferent fibers synapse in the central nervous system. This site in the brainstem functions as a gate for the cough reflex. DM is known to have many interactions with several different receptor sites.[4][5]

DM is a synthetic analog of codeine and undergoes rapid metabolism upon initial absorption. Its metabolism is via cytochrome P450 2D6 (CYP2D6) into major O-demethylated metabolite, dextrorphan (DX). DX is further glucuronidated by uridine diphosphate-glucuronosyltransferase to form dextrorphan-o-glucuronide, the most prevalent form of DX present in the plasma (98%). Dextrorphan-o-glucuronide is permanently charged and has less permeability to the blood-brain barrier. DM also gets metabolized into 3-methoxymorphinan via cytochrome P450 3A4.[1][4]

DM has low oral bioavailability due to its extensive first-pass metabolism; however, this is also dependent on different metabolizers. People may fall under different metabolic groups: ultrarapid, extensive, intermediate, and poor metabolizers. Most of the population falls under the extensive metabolizer. A single oral dose of 30mg of DM showed a median half-life of 2.4 hours with an oral bioavailability of 1 to 2%. Approximately 9% of the population are poor metabolizers. The median half-life of DM after a single dose orally is 19.1 hours, with an oral bioavailability of 80%. Poor metabolizers have approximately four-fold higher plasma levels of DM.[1][4]

Although structurally similar, DM does not have a direct action on the opioid receptors that produce classic CNS effects of opioid agonists. DM is known for its main site of action at N-methyl-D-aspartate (NMDA) receptors as a non-competitive antagonist. However, studies have found many sites of action with which DM and DX interact.[1][4][5]

Other sites of action include:

• Sigma-1 receptors agonist
• Nicotinic receptors (a3b4, a4b2, a7) antagonists
• Serotonin transporters inhibitor
• Norepinephrine transporters inhibitor
• Voltage-gated calcium channels inhibitor

Dosing and administration of dextromethorphan are mostly via the oral route. There are many formulations for administration:

• Combination liquid cough syrups; the common OTC formulation contains 15 mg/tsp of DM; recommended adult dosing is 2 tsp (10ml) every 4 hours
• Sustained-release cough syrup suspensions; another OTC product contains 30 mg/5mL
• Liquid filled capsules containing 15 or 30 mg of DM
• Oral strips containing 7.5 or 15mg of DM
• Lozenges containing 5, 7.5, 10 mg of DM

The recommended dosing for DM is 0.5 mg/kg up to 30 mg, administered three or four times a day.

Some animal studies have suggested that to reach the potential neuroprotective effects requires the ingestion of doses higher than typically used for antitussive effects (60 to 120 mg/d).[6]

For PBA, the FDA has approved the use of DM in combination with quinidine, a CYP2D6 inhibitor. The approved dose is 20/10mg.[2]

Adverse effects from cough suppressants are rare. The most common are nausea and gastrointestinal discomfort, while drowsiness and dizziness can also occur. One study showed at high doses (greater than 4 mg/kg), up to 64% of patients felt euphoria, and some experienced various CNS effects such as visual hallucinations and persecutory delusions. These episodes were associated with agitation, leading to patient management difficulties. The most common side effects in this study were the sensation of a drunk feeling or a "high" (20%), nausea and vomiting (17%), nystagmus (15%), and dizziness (15%). Most side effects resolved within a day after the final dose, and no cardio-respiratory compromises were noted. Serum levels of DM exceeding 400 ng/ml presented in 87.5% of patients with these side effects. More than 60% of the patients who experienced side effects with DM had serum levels exceeding 120ng/ml and brain levels of 700 ng/g.[7]

Dextromethorphan is contraindicated for patients with known or established hypersensitivity as well as those with an idiosyncratic reaction upon administration of the drug.