- Dextromethorphan (DXM) is commonly found in over the counter cough remedies.
- The drug's antitussive effects are mediated by sigma-1 and serotonin 5-HT1A receptors; at therapeutically relevant concentrations, DXM is likely to cause the activation of 5-HT1A receptors indirectly via the inhibition of serotonin reuptake.
- DXM exhibits relatively high affinity binding activity as a sigma-1 receptor agonist and serotonin reuptake inhibitor. DXM is also a noncompetitive NMDA receptor antagonist. The drug is four times more potent at NR1A/NR2A subunit-containing NMDA receptors than at NR1A/NR2B NMDA receptors. Furthermore, DXM exhibits a higher potency at NR1/NR2C receptors than at NR1/NR2A receptors. The active metabolite of DXM, dextrorphan, is a more potent noncompetitive NMDA antagonist and sigma-1 agonist than DXM. Dextrorphan and DXM also bind with low affinity to sigma-2 receptors. DXM and dextrorphan noncompetitively block alpha3beta4 neuronal nicotinic acetylcholine receptors; other nicotinic receptor subtypes may also be affected by these drugs.
Effects on ALS
Dextromethorphan (DM) is a dextrorotary morphinan and a widely used component of cough medicine. Relatively high doses of DM in combination with quinidine are used for the treatment of mood disorders for patients with multiple sclerosis (MS). However, at lower doses, morphinans exert anti-inflammatory activities through the inhibition of NOX2-dependent superoxide production in activated microglia. 
Dextromethorphan is quickly metabolized and the resulting dextrorphan is unable to pass the blood brain barrier and enter the CNS. Adding the heart medicine quinidine 50 % of the weight of dextromethorphan will slow down the decay and significantly improve bioavailability. [source needed]
CONCLUSIONS: These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech. 
May cause dizziness or drowsiness. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Avoid alcoholic beverages. MAO inhibitors may cause a serious (possibly fatal) drug interaction. Avoid taking isocarboxazid, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, selegiline, or tranylcypromine with dextromethorphan. MAO inhibitors should also not be taken for two weeks before. Other interactions are possible. (Source: WebMD)
Where to get it
- Chechneva et al.: Low dose dextromethorphan attenuates moderate experimental autoimmune encephalomyelitis by inhibiting NOX2 and reducing peripheral immune cells infiltration in the spinal cord. Neurobiol. Dis. 2011;44:63-72. PMID: 21704706. DOI. Dextromethorphan (DM) is a dextrorotary morphinan and a widely used component of cough medicine. Relatively high doses of DM in combination with quinidine are used for the treatment of mood disorders for patients with multiple sclerosis (MS). However, at lower doses, morphinans exert anti-inflammatory activities through the inhibition of NOX2-dependent superoxide production in activated microglia. Here we investigated the effects of high (10 mg/kg, i.p., "DM-10") and low (0.1 mg/kg, i.p., "DM-0.1") doses of DM on the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We found no protection by high dose DM treatment. Interestingly, a minor late attenuation by low dose DM treatment was seen in severe EAE that was characterized by a chronic disease course and a massive spinal cord infiltration of CD45(+) cells including T-lymphocytes, macrophages and neutrophils. Furthermore, in a less severe form of EAE, where lower levels of CD4(+) and CD8(+) T-cells, Iba1(+) microglia/macrophages and no significant infiltration of neutrophils were seen in the spinal cord, the treatment with DM-0.1 was remarkably more beneficial. The effect was the most significant at the peak of disease and was associated with an inhibition of NOX2 expression and a decrease in infiltration of monocytes and lymphocytes into the spinal cord. In addition, chronic treatment with low dose DM resulted in decreased demyelination and reduced axonal loss in the lumbar spinal cord. Our study is the first report to show that low dose DM is effective in treating EAE of moderate severity. Our findings reveal that low dose morphinan DM treatment may represent a new promising protective strategy for treating MS.
- Green et al.: Additional evidence for a therapeutic effect of dextromethorphan/quinidine on bulbar motor function in patients with amyotrophic lateral sclerosis: A quantitative speech analysis. Br J Clin Pharmacol 2018;. PMID: 30152872. DOI. AIMS: A recent double-blind placebo-controlled crossover 70-day trial demonstrated that a fixed combination of dextromethorphan and quinidine (DM/Q) improves speech and swallowing function in most patients with amyotrophic lateral sclerosis. In this study, a subset of participants, many of whom did not substantially improve while on DM/Q, were re-evaluated using computer-based speech analyses and expert clinician ratings of the overall severity of speech impairment. METHODS: Speech samples were recorded from the subset of 10 patients at four visits made at approximately 30-day intervals. The recordings were analysed by automated computer-based analysis of speech pausing patterns. Severity of speech impairment was rated by three experienced speech-language pathologists using direct magnitude estimation. Scores on patient-reported and clinician-administered scales of bulbar motor involvement were obtained at each visit. RESULTS: The effects of DM/Q were detected on several of the objective speech measures, including total pause duration (s) (Cohen's d = 0.73, 95% confidence interval (CI) -1.70, 0.24), pause time (%) (d = 0.77, 95% CI -1.75, 0.21), and mean speech event duration (s) (d = 0.52, 95% CI -0.44, 1.47), but not on clinician ratings of speech or the speech components of the self-report or clinician-administered scales. CONCLUSIONS: These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech.