Dextromethorphan hydrobromide

What it is

Dextromethorphan hydrobromide is the hydrobromide salt of dextromethorphan, a morphinan that has been sold over the counter as a cough suppressant for more than fifty years. Pharmacologically it is not an opioid analgesic: it is an uncompetitive antagonist at the NMDA glutamate receptor and an agonist at the sigma-1 receptor, and it is converted by the liver enzyme CYP2D6 into the active metabolite dextrorphan. Because that conversion is fast in most people, modern prescription products deliberately slow it down by pairing dextromethorphan with a CYP2D6 inhibitor: quinidine for pseudobulbar affect, bupropion for depression and for agitation in Alzheimer's disease.

What the research says

Lead with the awkward part: the use most people know it for is the one with the weakest evidence. Cochrane's review of over-the-counter cough medicines concluded there is no good evidence for or against them, and in children two placebo-controlled trials found dextromethorphan no better than placebo for night-time cough. Where dextromethorphan now has real trial support is in combination products at prescription doses: dextromethorphan-bupropion beat placebo in a phase 3 depression trial and in an agitation trial, and dextromethorphan-quinidine beat placebo for pseudobulbar affect. Against that sit substantial harms: a well-documented abuse and dependence literature, serotonin syndrome when combined with MAO inhibitors or serotonergic antidepressants, wide variation in blood levels depending on CYP2D6 genetics, and paediatric deaths that drove cough-and-cold products off the market for infants.

Evidence grade: Disputed.

How it works

Drug class: Uncompetitive NMDA-receptor antagonist and sigma-1 receptor agonist; morphinan centrally acting antitussive

Dextromethorphan blocks the NMDA receptor, one of the brain's main glutamate receptors, and switches on the sigma-1 receptor. That combination is thought to be behind its effects on mood and on emotional lability, although the manufacturer's own label says the mechanism in depression and in dementia-related agitation is not understood. It is broken down by the liver enzyme CYP2D6 into dextrorphan, which is itself active; prescription combinations add a CYP2D6 inhibitor so that more of the parent drug survives. (Source 1)

Boxed warning

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. AUVELITY is not approved for use in pediatric patients [see Use in Specific Populations (8.4)].

(Source 2)

What it is used for

• This is the oldest and least well supported use. In Cochrane's review of 29 placebo-controlled trials the six adult antitussive trials had variable results and the authors concluded there is no good evidence for or against over-the-counter cough medicines. The drug remains on the market under the over-the-counter monograph for people 12 and over. Evidence: disputed. (Source 3)
• Two placebo-controlled randomised trials found dextromethorphan no better than placebo in children, and Cochrane found the same across three paediatric studies. Insomnia was reported more often with dextromethorphan. Single-ingredient labels now say the product is not intended for children under 12. Evidence: not-supported. (Source 4)
• A 6-week phase 3 trial in 327 adults found a 3.87-point greater fall in the MADRS depression score than placebo, with remission in 39.5% against 17.3%. The difference appeared by week 1. The trial was sponsored by the manufacturer and the absolute MADRS gain is modest against a large placebo response. Evidence: established. (Source 5)
• In a 5-week placebo-controlled trial of 308 patients the Cohen-Mansfield Agitation Inventory fell 3.3 points more than placebo (95% CI -5.8 to -0.8) on a 29-to-203 point scale, and a randomised-withdrawal study showed longer time to relapse. The bupropion-alone arm of the first trial was stopped early for futility. Psychotic symptoms occurred in 3% on drug against 0% on placebo. Evidence: limited. (Source 6)
• A network meta-analysis of five randomised trials in 605 participants found dextromethorphan-quinidine improved the Center for Neurologic Study-Lability Scale by about 2.5 points, with dizziness the only dose-related adverse event reaching significance. Evidence: established. (Source 7)
• A cohort study of two commercial insurance databases found most people filling dextromethorphan-quinidine prescriptions had dementia or Parkinson's disease, populations the approval trials did not study, and 13.3% had heart failure, which the label contraindicates. The study measured prescribing, not benefit, so this off-label use has no efficacy evidence attached to it here. Evidence: unknown. (Source 8)
• This is not a therapeutic use but it is a major part of the drug's real-world profile. Dextromethorphan has long been misused, mainly by adolescents, for the psychoactive effects of its metabolite dextrorphan; dependence and a high relapse rate are documented. Evidence: not-supported. (Source 9)

Interactions

• Monoamine oxidase inhibitors (including linezolid and intravenous methylene blue) (label): This is the headline interaction. Combining dextromethorphan with an MAO inhibitor risks hypertensive crisis and serotonin syndrome, and both the prescription and the over-the-counter labels forbid it, including for 14 days after stopping the MAO inhibitor. (Source 10)
• Over-the-counter cough products containing dextromethorphan, taken alongside a prescription dextromethorphan combination (label): Stacking a cough syrup on top of a prescription dextromethorphan product doubles the same drug. The label tells prescribers to screen for other dextromethorphan-containing products before starting. (Source 11)
• SSRIs and tricyclic antidepressants (serotonergic antidepressants) (case reports): Taken with a serotonergic antidepressant, dextromethorphan can precipitate serotonin syndrome, with altered mental status, hypertension, myoclonus, hyperthermia, sweating, shivering and tremor. There is a published case of this with escitalopram and a dextromethorphan cough syrup. (Source 11)
• Paroxetine (and other strong CYP2D6 inhibitors such as fluoxetine and quinidine) (pharmacokinetic study): Paroxetine blocks the enzyme that clears dextromethorphan, so blood levels of dextromethorphan rise. In a randomised drug-interaction trial, adding paroxetine to dextromethorphan-quinidine raised dextromethorphan exposure by 50%, and adverse events were commoner on the combination. (Source 12)
• Quinidine (deliberate pharmacokinetic interaction) (pharmacokinetic study): Quinidine inhibits CYP2D6 and so raises dextromethorphan levels. This is used on purpose in the pseudobulbar affect product, and the same effect is why any CYP2D6 inhibitor matters. (Source 13)
• Grapefruit juice and Seville (sour) orange juice (pharmacokinetic study): Both juices raised the bioavailability of dextromethorphan in healthy volunteers by inhibiting gut CYP3A and P-glycoprotein, and the effect had still only half washed out after three days. (Source 14)
• St John's wort (pharmacokinetic study): A controlled human study of six botanicals found that St John's wort did not change CYP2D6 activity, so the commonly repeated worry that it will alter dextromethorphan clearance through this enzyme is not supported. Goldenseal, by contrast, halved CYP2D6 activity. (Source 15)
• Goldenseal (Hydrastis canadensis) (pharmacokinetic study): Goldenseal supplementation for 14 days inhibited CYP2D6 activity by about half in healthy volunteers. Because dextromethorphan is cleared by CYP2D6, that would be expected to raise dextromethorphan levels; the study measured the enzyme with debrisoquine, not dextromethorphan itself. (Source 15)
• Alcohol (case reports): Alcohol taken with dextromethorphan can produce dissociation, and a published case in a man with alcohol dependence was hard to tell apart from alcohol withdrawal. The prescription combination's label also advises minimising or avoiding alcohol, there because of its bupropion content. (Source 16)
• Alcohol (label position for the prescription combination) (label): The prescription label's own interaction table says alcohol should be minimised or avoided during treatment, because the bupropion component can increase neuropsychiatric events or reduce alcohol tolerance. (Source 17)
• Drugs cleared by CYP2D6 (the interaction running the other way) (label): The prescription combination raises levels of other CYP2D6 substrates because of its bupropion component, and can make prodrugs that need CYP2D6 activation less effective. (Source 17)

Stopping it

• For dextromethorphan dependence, stopping is the hard part: in a series of 28 patients treated for dependence, 71.43% had relapsed by 6 months and 89.29% within a year, and baseline depression and anxiety predicted who relapsed. (Source 18)
• The prescription label records that the combination contains dextromethorphan and that dextromethorphan abuse cases have been reported, mainly in adolescents, and advises close observation of patients with a history of drug abuse. It reports no systematic study of tolerance or physical dependence. (Source 19)
• When serotonin syndrome is suspected, the label's instruction is immediate discontinuation rather than tapering. There is no taper schedule in the label for ordinary discontinuation of the dextromethorphan component. (Source 11)
• For the over-the-counter cough use, the label frames stopping in terms of symptom duration rather than withdrawal: it tells people to stop and see a doctor if cough lasts more than 7 days, comes back, or comes with fever, rash or persistent headache. (Source 20)

What goes wrong

In the depression trial reported on the label, dextromethorphan-bupropion caused dizziness in 16% against 6% on placebo, and sexual dysfunction and hyperhidrosis in 6% and 5% against 0% on placebo. (Source 21)

• Randomized trial, Moderate certainty.
• Size: 326 patients in the 6-week placebo-controlled study (162 drug, 164 placebo); 2,550 adults exposed in the whole programme.
• Who: adults with major depressive disorder.
• How long: 6 weeks.
• Result: Dizziness 16% versus 6%, nausea 13% versus 9%, headache 8% versus 4%, diarrhoea 7% versus 3%, somnolence 7% versus 3%, dry mouth 6% versus 2%, sexual dysfunction 6% versus 0%, hyperhidrosis 5% versus 0%; 4% on drug and 0% on placebo stopped because of adverse reactions.
• Funding: industry (manufacturer's label)

Limit of this finding: The label's two adverse-reaction tables are headed 'Occurring in ≥2%', but the label's own body text drops the greater-than-or-equal sign and says reactions 'occurred in 2%' and 'incidence 5%'. The figures are thresholds, not exact rates: the table lists reactions at 2 per cent or more. These are rates in one 6-week trial run by the manufacturer, with no comparison against any other antidepressant.

Table 2: Adverse Reactions Occurring in ≥2% of Adult Patients with MDD Treated with AUVELITY and More Frequently than in Patients Treated with Placebo in a 6-Week Placebo-Controlled Study (Study 1) aSexual dysfunction includes orgasm abnormal, erectile dysfunction, libido decreased, anorgasmia bFatigue includes fatigue, lethargy cParaesthesia includes paraesthesia, hypoaesthesia Adverse Reaction AUVELITY (N=162) % Placebo (N=164) % Dizziness 16 6 Nausea 13 9 Headache 8 4 Diarrhea 7 3 Somnolence 7 3 Dry mouth 6 2 Sexual dysfunctiona 6 0 Hyperhidrosis 5 0

In the dementia-agitation trial, psychotic symptoms were reported in 3% of patients on dextromethorphan-bupropion and 0% on placebo. (Source 21)

• Randomized trial, Moderate certainty.
• Size: 317 patients (159 drug, 158 placebo)
• Who: older patients with agitation in Alzheimer's dementia, median age 75.
• How long: 5 weeks.
• Result: Dizziness 9% versus 3%, somnolence 8% versus 4%, dyspepsia 6% versus 1%, constipation 3% versus 0%, psychotic symptom 3% versus 0%, confusional state 3% versus 1%.
• Funding: industry (manufacturer's label)

Limit of this finding: As in the depression table, the caption's threshold is '≥2%' while the label's body text omits the greater-than-or-equal sign; read the numbers as 'at least' this percentage. The percentages are rounded whole numbers in a 5-week trial of about 160 patients per arm, so a 3 against 0 per cent difference rests on about five patients.

Table 3: Adverse Reactions Occurring in ≥2% of Adult Patients with Agitation Associated with Dementia Due to Alzheimer’s Disease Treated with AUVELITY and More Frequently than in Patients Treated with Placebo in a 5-Week Placebo-Controlled Study (Study 3) a Dizziness includes Vertigo, Dizziness postural, Balance disorder. b Somnolence includes Somnolence, Hypersomnia. c Dyspepsia includes Abdominal discomfort, Dyspepsia, Gastritis, Abdominal pain upper, Gastroesophageal reflux disease. d Fatigue includes Asthenia, Lethargy, Fatigue. e Nausea includes Nausea, Vomiting. f Psychotic symptom includes Catatonia, Delusion, Hallucination, Hallucination visual. g Confusional State includes Confusional state, Delirium, Disorientation. h Bacterial infection includes Abscess limb, Staphylococcal infection, Urinary tract infection. Adverse Reaction AUVELITY (N=159) % Placebo (N=158) % Dizzinessa 9 3 Somnolenceb 8 4 Dyspepsiac 6 1 Fatigued 6 3 Nauseae 5 3 Dry Mouth 4 3 Headache 4 3 Constipation 3 0 Psychotic symptomf 3 0

Dextromethorphan has long been misused for the psychoactive effects of its metabolite dextrorphan, and this is the stated reason abuse liability had to be assessed before the depression combination reached wide use. (Source 9)

• Expert review, not systematic, Low certainty.
• Size: not applicable (narrative pharmacological review)
• Who: people using dextromethorphan non-medically, and patients prescribed dextromethorphan-bupropion.
• How long: not applicable.
• Result: no rates reported in the section quoted; the review's stated position is that the combination product carries reduced abuse liability relative to dextromethorphan alone.
• Funding: not stated in the abstract; the senior author group publishes extensively on this drug class.

As DXM/BUP moves closer to widespread clinical use for MDD, examining whether the combination does or does not carry meaningful abuse liability is essential given that DXM alone has long been misused, likely attributed to its metabolism into the psychoactive metabolite DXO.

Among 28 patients treated for dextromethorphan dependence, almost nine in ten had relapsed within a year. (Source 22)

• Case series, Low certainty.
• Size: 28 patients with dextromethorphan dependence (20 male, 8 female)
• Who: patients admitted for dextromethorphan dependence, mean age 25.89 years (SD 7.84), mean duration of abuse 24.96 months (SD 17.40)
• How long: followed to 1 year.
• Result: Relapse rates were 7.14% at 1 month, 25% at 3 months, 71.43% at 6 months and 89.29% at 1 year. Baseline depression and anxiety predicted relapse (r = -.539, P = .006, R2 = 0.290 and r = -.449, P = .024, R2 = 0.202).
• Funding: not stated.

Limit of this finding: A retrospective series of 28 people from one hospital, with no control group. The abstract also describes depression and anxiety as 'positive predictors of relapse' while printing negative correlations (r = -.539 and r = -.449). The sign only makes sense if the outcome is time to relapse rather than relapse itself, which the abstract never says, so this must not be read as 'worse mood meant more relapse'.

The relapse rates at 1 month, 3 months, 6 months, and 1 year were 7.14%, 25%, 71.43%, and 89.29%, respectively.

In a cross-sectional study of opioid-dependent patients on maintenance therapy, hair analysis found dextromethorphan use in 11.5%, almost all of whom had not reported it. (Source 23)

• Survey study, Low certainty.
• Size: 104 opioid-dependent patients in maintenance treatment.
• Who: outpatients at the Psychiatric Hospital, University of Zurich.
• How long: 3-month hair toxicology window.
• Result: 12 of 104 patients (11.5%) had dextromethorphan detected; 11 of those 12 (91.7%) had not reported using it. Dextromethorphan users differed significantly on sexual maltreatment or violence trauma, multiple traumas and harmful hallucinogen use.
• Funding: not stated.

Limit of this finding: A single-centre cross-sectional study of a highly selected population; it cannot be generalised to people taking dextromethorphan for cough.

Dextromethorphan was abused by 12 (11.5%) patients, 11 (91.7%) of whom did not report concomitant abuse of dextromethorphan but were identified through hair analysis.

Medical examiners in two US states attributed the deaths of three infants under 6 months in 2005 to cough and cold medications, in a setting where no dosing recommendations exist for children under 2. (Source 24)

• Case series, Low certainty.
• Size: three infant deaths identified; an estimated 1,519 children aged under 2 treated in US emergency departments during 2004-2005 for adverse events associated with cough and cold medications.
• Who: US infants aged under 12 months.
• How long: calendar year 2005.
• Result: three deaths of infants aged under 6 months in 2005 for which cough and cold medications were determined by medical examiners or coroners to be the underlying cause.
• Funding: not applicable (government surveillance report)

Limit of this finding: This is an agency investigation of combination products, not of dextromethorphan alone, and it is a case series, so it cannot give a rate.

This report describes the results of that investigation, which identified deaths of three infants aged <6 months in 2005, for which cough and cold medications were determined by medical examiners or coroners to be the underlying cause.

In a national surveillance system covering 2009 to 2016, dextromethorphan was involved in nearly a third of the healthcare-facility admissions that followed a reported cough and cold medication exposure in children, and the admitted proportion rose over time. (Source 25)

• Cohort study, Low certainty.
• Size: 4,756 cases judged at least potentially related to an index ingredient.
• Who: children aged under 12 years in the United States exposed to an over-the-counter cough or cold ingredient with at least one significant adverse event.
• How long: 2009 to 2016.
• Result: Accidental unsupervised ingestions were the most common case type; nearly half of adverse-event cases involved children aged 2 to under 4 years. The overall case rate did not change significantly (p = 0.22), but the proportion of cases admitted to a healthcare facility rose from 32.4% in 2009 to 43.4% in 2016 (p < 0.01). Exposures to diphenhydramine (1,305; 67.3%) and/or dextromethorphan (591; 30.5%) were involved in the majority of admissions.
• Funding: not stated in the abstract; the author list includes investigators associated with industry-supported surveillance programmes.

Limit of this finding: The abstract prints 'About 4756 (72.6%) cases' without ever stating the total it is 72.6 per cent of, so the percentage cannot be checked against a denominator from the source; the implied total is roughly 6,500 cases. These are poison-centre reports of exposures, counted after the event, so they show what turned up in the system, not a rate of harm per child who took a cough or cold medicine. The surveillance system records which ingredients were involved in an admission, not which ingredient caused it, so these figures describe an association and not a cause.

Exposures to diphenhydramine (1,305; 67.3%) and/or dextromethorphan (591; 30.5%) were involved in the majority of HCF admissions.

How much dextromethorphan a person is exposed to depends heavily on CYP2D6: in poor metabolisers the parent drug persisted with a half-life of about 29.5 hours, while in normal metabolisers it was undetectable until quinidine was added. (Source 13)

• Blood level study, Moderate certainty.
• Size: 5 extensive metabolisers and 4 poor metabolisers.
• Who: healthy adults phenotyped for CYP2D6, given a single 30 mg oral dose of dextromethorphan hydrobromide.
• How long: single dose, with and without 100 mg quinidine pretreatment.
• Result: In extensive metabolisers dextromethorphan was not detectable in plasma; after quinidine pretreatment it appeared with a half-life of 16.4 hours. In poor metabolisers dextromethorphan was the major plasma component with a half-life of 29.5 hours, and the other metabolites were present at 5- to 10-fold lower concentrations.
• Funding: not stated.

Limit of this finding: Nine people. This is a mechanism study, not a safety outcome study, but it is the reason a standard dose is not a standard exposure.

In poor metabolizers (N = 4) given the same dose, dextromethorphan was the major component in the plasma with a t1/2 of 29.5 hours.

Serotonin syndrome occurred in a woman taking escitalopram after she was prescribed a dextromethorphan-containing cough syrup, and resolved when both were stopped. (Source 26)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: a 63-year-old woman with long-standing depression maintained on escitalopram.
• How long: symptoms after about 2 weeks of cough syrup use; resolution overnight after withdrawal.
• Result: lethargy, obtundation and inducible myoclonus with QTc prolongation on ECG; mental status and QTc both resolved after both drugs were suspended.
• Funding: none declared.

Limit of this finding: A single case report cannot establish a rate; it establishes that the interaction happens.

A 63-year-old woman with a history of long-standing depression, maintained on escitalopram, presented with altered mental status. Patient had recently been prescribed dextromethorphan-promethazine cough syrup 2 weeks prior for an upper respiratory tract infection.

Dextromethorphan overdose causes stupor, coma, respiratory depression, seizures and toxic psychosis, and the risk of serotonin syndrome rises with overdose. (Source 27)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: people who take more dextromethorphan than labelled, alone or with serotonergic drugs.
• How long: not applicable.
• Result: no rates given on the label.
• Funding: not applicable (manufacturer label)

Symptoms of dextromethorphan overdose include nausea, vomiting, stupor, coma, respiratory depression, seizures, tachycardia, hyperexcitability, and toxic psychosis.

The over-the-counter dextromethorphan label tells anyone pregnant or breast-feeding to ask a health professional before using it, and gives the poison-control instruction for overdose. (Source 20)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: adults and children 12 years and over buying the product over the counter, including people who are pregnant or breast-feeding.
• How long: not applicable.
• Result: no rates are given on the label.
• Funding: not applicable (manufacturer label)

If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. (1-800-222-1222)

What the evidence supports

In the GEMINI phase 3 trial, dextromethorphan-bupropion reduced depression scores more than placebo, with remission in about four in ten patients against under two in ten. (Source 5)

• Randomized trial, Moderate certainty.
• Size: 327 adults randomised (163 to dextromethorphan-bupropion, 164 to placebo)
• Who: adults meeting DSM-5 criteria for major depressive disorder, mean baseline MADRS 33.6 and 33.2.
• How long: 6 weeks.
• Result: Least-squares mean change in MADRS total score -15.9 with drug versus -12.0 with placebo; difference -3.87 (95% CI -1.39 to -6.36; P = .002). Remission 39.5% versus 17.3% (treatment difference 22.2; 95% CI 11.7 to 32.7; P < .001); response 54.0% versus 34.0% (difference 20.0%; 95% CI 8.4%, 31.6%; P < .001). Absolute remission difference 22.2 percentage points corresponds to about 5 patients treated for one extra remission.
• Funding: industry-funded; the author list includes employees of the sponsor Axsome Therapeutics.

Limit of this finding: A single 6-week trial against a large placebo response; the MADRS difference of under 4 points on a 0-60 scale is at the low end of what is usually called clinically meaningful. Two confidence intervals are printed backwards in the published paper: the primary endpoint reads '-3.87; 95% CI, -1.39 to -6.36' when a negative difference should run -6.36 to -1.39, and the CGI-S interval reads '-0.48; 95% CI, -0.48 to -0.79', where the point estimate equals one of its own bounds. Treat the bounds as unreliable as printed and do not read precision off them.

The least-squares mean change from baseline to week 6 in MADRS total score was -15.9 points in the dextromethorphan-bupropion group and -12.0 points in the placebo group (least-squares mean difference, -3.87; 95% confidence interval [CI], -1.39 to -6.36

For agitation in Alzheimer's disease, dextromethorphan-bupropion improved the Cohen-Mansfield Agitation Inventory by 3.3 points more than placebo over 5 weeks. (Source 6)

• Randomized trial, Moderate certainty.
• Size: 308 patients in the placebo comparison (152 drug, 156 placebo), plus a bupropion arm of 49 terminated early for futility.
• Who: patients with probable Alzheimer's disease, Mini-Mental State Examination 10 to 24, moderate to severe agitation; median age 75 years.
• How long: 5 weeks.
• Result: Least-squares mean change in CMAI total score -14.9 with drug versus -11.6 with placebo; difference -3.3 (95% CI -5.8 to -0.8) on a scale running from 29 to 203.
• Funding: industry-funded (manufacturer's registration trials reported in the label)

Limit of this finding: A 3.3-point change on a 29-to-203 scale is small, and the bupropion comparator arm was stopped for futility rather than completed, which limits what can be said about the contribution of each component.

Treatment Group Mean Baseline Score (SD) LS Mean Change from Baseline (SE) LS Mean Difference (95% CI) AUVELITY (N=152) 60.8 (17.4) -14.9 (0.9) -3.3a (-5.8, -0.8) Placebo (N=156) 59.3 (15.5) -11.6 (0.9) ---

A network meta-analysis of five randomised trials found dextromethorphan-quinidine improved emotional lability in pseudobulbar affect, with dizziness the only significant dose-related harm. (Source 7)

• Meta-analysis, Moderate certainty.
• Size: 605 participants across five randomised controlled trials.
• Who: people with pseudobulbar affect in neurological disorders including ALS, multiple sclerosis, stroke and traumatic brain injury.
• How long: not stated in the abstract.
• Result: Dextromethorphan-quinidine 20/10 mg and 30/10 mg improved the Center for Neurologic Study-Lability Scale by mean differences of -2.52 and -2.45; 30/30 mg gave larger quality-of-life gains (VAS-QOL mean difference 17.20, VAS-QOR 14.90). Dizziness was the only statistically significant dose-related adverse event.
• Funding: independent (authors declared no conflicts of interest and no financial interests)

Limit of this finding: The authors disclose that generative AI tools were used for language editing. Only five trials, and the dose comparisons are indirect.

DM/Q 20/10 mg and 30/10 mg significantly improved CNS-LS scores (mean difference [MD] - 2.52 and - 2.45, respectively), while DM/Q 30/30 mg produced greater gains in VAS-QOL (MD 17.20) and VAS-QOR (MD 14.90). Dizziness was the only statistically significant, dose-related adverse event.

What the evidence does not support

Cochrane's review of over-the-counter cough medicines concluded there is no good evidence for or against them, and warned about the centrally active antitussives specifically in children. (Source 28)

• Systematic review, Low certainty.
• Size: 29 placebo-controlled randomised trials, 4835 people (3799 adults and 1036 children)
• Who: children and adults with acute cough from upper respiratory tract infection in community settings.
• How long: trials typically a few days.
• Result: No pooled effect estimate was produced; the review authors judged pooling inappropriate because of the small number of trials per category and the differences between them.
• Funding: independent (all three authors declared no conflict of interest)

There is no good evidence for or against the effectiveness of OTC medicines in acute cough. This should be taken into account when considering prescribing antihistamines and centrally active antitussive agents in children; drugs that are known to have the potential to cause serious harm.

In the same review, antitussives in children were no more effective than placebo, while in adults the six antitussive trials gave variable results. (Source 3)

• Systematic review, Low certainty.
• Size: six adult antitussive trials; three paediatric antitussive studies, within 29 trials and 4835 people.
• Who: children and adults with acute cough.
• How long: trials typically a few days.
• Result: variable results in adults; no effect over placebo in children.
• Funding: independent.

In the child studies, antitussives (data from three studies), antihistamines (data from three studies), antihistamine-decongestants (two studies) and antitussive/bronchodilator combinations (one study) were no more effective than placebo.

In a randomised trial of 100 children, dextromethorphan was no better than placebo for night-time cough or sleep, and insomnia was reported more often with it. (Source 4)

• Randomized trial, Moderate certainty.
• Size: 100 children.
• Who: children with upper respiratory infection and night-time cough, with parents reporting outcomes.
• How long: two consecutive nights, one untreated and one treated.
• Result: All outcomes improved on the second night in every group including placebo; neither diphenhydramine nor dextromethorphan was superior to placebo for any outcome. Insomnia was reported more frequently with dextromethorphan; drowsiness more frequently with diphenhydramine.
• Funding: not stated.

Limit of this finding: Outcomes were parent-reported on a non-blinded-to-time two-night design, and the improvement in every arm shows how much of the perceived benefit is natural resolution.

However, neither diphenhydramine nor dextromethorphan produced a superior benefit when compared with placebo for any of the outcomes studied. Insomnia was reported more frequently in those who were given dextromethorphan

The trial's authors stated plainly that dextromethorphan is not superior to placebo for night-time symptom relief in children. (Source 29)

• Randomized trial, Moderate certainty.
• Size: 100 children.
• Who: coughing children with upper respiratory infection and their parents.
• How long: two nights.
• Result: no superiority over placebo for the child's symptoms or for the parents' sleep quality.
• Funding: not stated.

Diphenhydramine and dextromethorphan are not superior to placebo in providing nocturnal symptom relief for children with cough and sleep difficulty as a result of an upper respiratory infection.

A second randomised placebo-controlled trial, in 120 Indian children aged 1 to 12, also found dextromethorphan no better than placebo, with more frequent adverse effects. (Source 30)

• Randomized trial, Low certainty.
• Size: 120 children.
• Who: children aged 1-12 years with upper respiratory infection attending a Delhi hospital outpatient department.
• How long: 3 days.
• Result: The whole cohort improved on all parameters after 3 days, with no superior benefit for dextromethorphan or promethazine over placebo. Adverse effects were more frequent in the dextromethorphan and promethazine groups, though not statistically significantly so.
• Funding: not stated.

Limit of this finding: The outcome scale was described as internally validated and indigenously prepared, so it is not a standard instrument, and the adverse-effect comparison was underpowered.

However, no superior benefit was noted when individual parameters were compared in the promethazine and dextromethorphan groups with the placebo group. Adverse effects were more frequent in the dextromethorphan and promethazine groups although the difference was not statistically significant.

The same authors concluded night-time cough in these infections resolves on its own and that dextromethorphan is not superior to placebo. (Source 31)

• Randomized trial, Low certainty.
• Size: 120 children.
• Who: children aged 1-12 years with upper respiratory infection.
• How long: 3 days.
• Result: no superiority over placebo.
• Funding: not stated.

Nocturnal cough in URI is self-resolving and dextromethorphan and promethazine prescribed for the same are not superior to placebo.

Where the evidence is mixed

A pharmacology review comparing laboratory activity with estimated free brain concentrations suggests dextromethorphan with quinidine also inhibits serotonin and noradrenaline reuptake, which is the likely route to serotonin syndrome. (Source 32)

• Expert review, not systematic, Low certainty.
• Size: not applicable (review of in-vitro functional assays set against estimated brain concentrations)
• Who: not applicable.
• How long: not applicable.
• Result: no clinical effect size; the review infers which of the many receptor and transporter interactions are likely to be reached at clinical doses.
• Funding: not stated in the abstract; the author list includes authors affiliated with the manufacturer of the dextromethorphan-quinidine product.

Limit of this finding: This is an inference from in-vitro potency compared with estimated free brain concentrations, not a measurement in people.

The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors.

Dextromethorphan-quinidine, approved on trials in ALS and multiple sclerosis, is in practice mostly prescribed to people with dementia or Parkinson's disease, and to many with a contraindication. (Source 8)

• Cohort study, Moderate certainty.
• Size: 12,858 patients filling a prescription in two commercial insurance databases, plus Medicare Part D counts.
• Who: US patients prescribed dextromethorphan-quinidine from October 2010 to 2015-2017.
• How long: study period October 2010 to March 2017 (Optum) and December 2015 (Truven)
• Result: Mean age 66.0 years (SD 18.5), 66.7% women, 13.3% with a history of heart failure, which is a contraindication. 8.4% had multiple sclerosis and 6.8% ALS, while 57.0% had dementia and/or Parkinson's disease. Medicare Part D patients rose 15.3-fold from 3296 in 2011 to 50,402 in 2016, with reported spending rising from $3.9 million to $200.4 million.
• Funding: independent; one author reported unrelated FDA grants.

Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD.

Where the research disagrees

Whether the abuse liability of dextromethorphan carries over to the prescription dextromethorphan-bupropion combination

• Zheng and colleagues, pharmacological review, narrative pharmacological review of preclinical, clinical and pharmacovigilance data: We then highlight the abuse potential of DXM when administered alone. Additionally, we present preclinical, clinical, and pharmacovigilance findings that support the reduced abuse liability of DXM/BUP. (Source 33)
• The manufacturer's own label, regulatory label position, August 2026: While clinical studies with AUVELITY did not reveal drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this experience the extent to which AUVELITY will be misused, diverted, and/or abused once marketed. (Source 19)

Whether dextromethorphan helps acute cough at all

• Smith, Schroeder and Fahey, Cochrane review 2014, systematic review of 29 placebo-controlled randomised trials: There is no good evidence for or against the effectiveness of OTC medicines in acute cough. (Source 28)
• The over-the-counter monograph label, effective October 2026, regulatory position under the US over-the-counter monograph: temporarily relieves cough due to minor throat and bronchial irritation as may occur with a cold. (Source 20)

How much

• Reference intake: There is no reference intake for a medicine. For the prescription combination the label's recorded position is one tablet of dextromethorphan hydrobromide 45 mg with bupropion hydrochloride 105 mg once daily in the morning, later increased to one tablet twice daily at least 8 hours apart, with no more than two doses in a day. The day on which the increase happens cannot be stated from this label: the published document carries an uncorrected edit and prints both 'After 3 days' and 'On day 4' in the same sentence. (Source 34)
• Upper limit: The AUVELITY prescription label's ceiling is one tablet twice daily, with the instruction not to exceed two doses within the same day. The over-the-counter cough label's ceiling is 8 softgels in any 24-hour period, which is 120 mg of dextromethorphan hydrobromide. Both are labelled maxima set by the manufacturers, not toxicological limits. (Source 20)
• Studied: The GEMINI phase 3 depression trial gave dextromethorphan-bupropion 45 mg-105 mg once daily for days 1 to 3 and twice daily thereafter for 6 weeks. (Source 5)
• Studied: The pseudobulbar affect network meta-analysis compared dextromethorphan-quinidine 20/10 mg, 30/10 mg and 30/30 mg regimens. (Source 7)
• Studied: The pharmacokinetic study of CYP2D6 phenotype gave a single oral dose of dextromethorphan hydrobromide 30 mg, with or without quinidine 100 mg pretreatment. (Source 13)
• Studied: The paediatric trial by Paul and colleagues gave a single bedtime dose of dextromethorphan, diphenhydramine or placebo to 100 children on one of two consecutive nights. (Source 4)

A common belief, and what the research shows

The belief: Cough syrup with dextromethorphan is a proven way to stop a cough, and it is gentle enough for children.

What the research shows: Cochrane's review of 29 placebo-controlled trials found no good evidence for or against over-the-counter cough medicines, and in children three studies of antitussives found them no more effective than placebo. Two separate randomised trials in children found dextromethorphan no better than placebo for night-time cough, with insomnia reported more often on the drug. Three infant deaths in 2005 were attributed by medical examiners to cough and cold medications, and single-ingredient dextromethorphan labels now say the product is not intended for children under 12.

Questions and answers

What is it?

Dextromethorphan hydrobromide is a manufactured medicine, the hydrobromide salt of dextromethorphan. It has been sold over the counter as a cough suppressant for decades, usually as 15 mg per dose unit. It is chemically related to opioids but acts differently: it blocks the NMDA glutamate receptor and switches on the sigma-1 receptor. Prescription products pair it with a second drug that slows its breakdown. (Source 1)

What does it do in the body?

It suppresses the cough reflex through a central action, and at prescription doses it acts on glutamate signalling in ways that affect mood and emotional control. The label itself admits the mechanism behind its antidepressant and anti-agitation effects is not understood. CYP2D6 converts it to dextrorphan, which is also active and is the part responsible for the dissociative effects people seek when misusing it. (Source 1)

Is it good or bad for you?

Both, depending entirely on the setting. As a cough medicine the evidence does not support it, and in children it has repeatedly failed against placebo while being linked to insomnia, emergency department visits and, in infants, deaths. As a prescription combination it has genuine randomised evidence in depression, in agitation in Alzheimer's disease and in pseudobulbar affect, at the cost of dizziness in about one in six and a boxed warning about suicidal thoughts. At high recreational doses it causes dependence with a very high relapse rate. (Source 28)

How do you get more of it?

This question does not apply as it would to a nutrient; dextromethorphan is not something the body makes or needs. Exposure comes only from medicines: over the counter in cough preparations for people 12 and over, or on prescription in combination with bupropion or quinidine. What changes a person's internal exposure most is not the dose but CYP2D6 genetics and other drugs that block that enzyme, which can raise levels several-fold. (Source 13)

If it is harmful, what reduces it?

The body clears dextromethorphan through CYP2D6, mostly within a day in people with normal enzyme activity, so stopping the product is what reduces it. There is no antidote. In overdose the management recorded on the label is symptomatic and supportive care, and the risk of serotonin syndrome rises if serotonergic drugs are also on board. For dependence, the literature shows stopping is achievable but relapse is common. (Source 27)

Why might someone be low in it or missing it?

Having none is the normal state, so this question is really about why someone cannot or should not take it. The prescription combination is contraindicated in people with a seizure disorder, with current or past bulimia or anorexia nervosa, undergoing abrupt withdrawal from alcohol or benzodiazepines, taking an MAO inhibitor or within 14 days of stopping one, or hypersensitive to either component. The over-the-counter cough product is not for children under 12 and not for anyone on an MAO inhibitor. (Source 10)

Which whole foods contain it or feed it?

No food contains dextromethorphan; it is entirely synthetic. Food does affect it, though, in the opposite direction from the question: grapefruit juice and Seville orange juice significantly increased its bioavailability in healthy volunteers, and the effect had only half washed out three days later, so these juices raise exposure rather than supply the drug. (Source 14)

What happens if you do not have it?

Nothing is lost physiologically by never taking it. For cough, the best evidence says there is no established benefit to forgo, and night-time cough in children resolves on its own. For the prescription uses the picture differs: in the depression trial, 17.3% of people on placebo reached remission against 39.5% on the drug, so for some people not taking it means a lower chance of remission over 6 weeks. (Source 31)

How can you test for it?

There is no test of dextromethorphan status in healthy people. Two kinds of test do exist and matter. CYP2D6 genotyping or phenotyping identifies poor metabolisers, in whom the drug persists far longer, and the prescription label carries separate dosing for known poor metabolisers. For detecting use, hair toxicology found dextromethorphan in 11.5% of opioid-dependent outpatients, 11 of 12 of whom had not reported it, so laboratory detection is more sensitive than asking. (Source 23)

References

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