Dextromethorphan hydrobromide with promethazine hydrochloride

What it is

This is a prescription oral liquid containing two drugs: dextromethorphan hydrobromide, a cough suppressant that acts on the brain, and promethazine hydrochloride, a first-generation phenothiazine antihistamine that is also sedating and anti-sick. The U.S. label gives it a single indication, temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold. It carries a boxed warning about fatal respiratory depression and is contraindicated below two years of age.

What the research says

It is sold to quieten a cough and dry up cold and allergy symptoms. The evidence for the cough-suppressing part is weak and, in children, mostly negative: a Cochrane review of 29 placebo-controlled trials concluded there is no good evidence for or against over-the-counter cough medicines, a randomised trial of exactly this pair of drugs in children aged 1 to 12 found neither beat placebo, and a capsaicin-challenge study found dextromethorphan had no antitussive effect at all. One 2023 industry-style trial in children aged 6-11 did find a 21% reduction in 24-hour cough counts against placebo. The promethazine component carries the serious risk: postmarketing reports of fatal respiratory depression in young children, which is why the combination is contraindicated under two years of age.

Evidence grade: Limited evidence.

How it works

Drug class: Fixed combination of a centrally acting non-opioid antitussive (dextromethorphan, a levorphanol-related morphinan and NMDA receptor antagonist) with a first-generation phenothiazine H1-antihistamine (promethazine)

Dextromethorphan damps down the brain's cough reflex rather than acting on the airways; the label notes it can release histamine and says it should be used cautiously in children with allergic tendencies. Promethazine blocks histamine H1 receptors, which reduces runny nose and sneezing, and it strongly depresses the central nervous system, which is why it sedates and why it can slow or stop breathing. Promethazine is also metabolically cleared through the liver enzyme CYP2D6 pathway shared with dextromethorphan; a person who inherits a poorly working copy of that enzyme reaches dextromethorphan blood levels around 150 times higher than a normal metaboliser after the same dose. (Source 1)

Boxed warning

Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression.

(Source 2)

What it is used for

• This is the only approved indication. A Cochrane review of 29 placebo-controlled trials in 4,835 people found results in adults variable and could not pool them, and concluded there is no good evidence for or against over-the-counter cough medicines. Adverse effects were commoner in people taking preparations containing antihistamines and dextromethorphan. Evidence: limited. (Source 3)
• The label gives doses down to two years of age, but the trial evidence in children is largely negative. In a randomised, double-blind, placebo-controlled trial of exactly this pair of drugs in 120 children aged 1 to 12, neither promethazine nor dextromethorphan beat placebo on nocturnal cough, post-tussive vomiting or sleep quality. In the Cochrane review, antitussives, antihistamines and antihistamine-decongestants were no more effective than placebo in children. Evidence: not-supported. (Source 4)
• This is not merely unsupported, it is contraindicated. The boxed warning records postmarketing cases of respiratory depression including fatalities in children under two, and says a wide range of weight-based doses produced respiratory depression in these patients, so there is no dose that is known to be safe. Evidence: not-supported. (Source 2)
• Both components are misused. A systematic review of over-the-counter drug misuse found dextromethorphan the single most reported substance, with adolescents and young adults the vulnerable group, and analysis of the European regulator's adverse-reaction database found 557 promethazine misuse, abuse or dependence reports between 2003 and 2019 of which 310 (55.6%) involved a fatality, most often alongside opioids. Evidence: harm. (Source 5)

Interactions

• Monoamine oxidase inhibitors (case reports): This is the most dangerous documented combination. The label records high fever, low blood pressure and death reported alongside MAO inhibitors with dextromethorphan-containing products, and lists MAO inhibitor use as a contraindication for the dextromethorphan component. (Source 6)
• SSRI antidepressants such as sertraline (case reports): Dextromethorphan has serotonergic activity, and serotonin syndrome has been reported when a dextromethorphan cough syrup was added to an SSRI at ordinary doses. The evidence here is case reports, not trials, so no rate can be given. (Source 7)
• Alcohol (label): Alcohol adds to promethazine's sedative and breathing-slowing effect. The label names alcohol first among the central nervous system depressants whose sedative action promethazine may increase, prolong or intensify, and says such agents should be avoided or given in reduced dose. (Source 6)
• Opioids, barbiturates, general anaesthetics, tricyclic antidepressants and tranquillisers (label): The same additive sedation applies, and the label goes as far as specifying that barbiturate doses should be at least halved and opioid doses reduced by a quarter to a half when given with this product. In the European promethazine misuse data, opioids were the commonest concomitant drug in fatal reports. (Source 6)
• Epinephrine (adrenaline) (label): Promethazine can reverse the blood-pressure-raising action of adrenaline, so the label states explicitly that adrenaline must NOT be used to treat low blood pressure caused by an overdose of this product. (Source 8)
• CYP2D6 inhibitors, including quinidine and many antidepressants (pharmacokinetic study): Dextromethorphan is cleared by the CYP2D6 enzyme. Blocking that enzyme turns a normal metaboliser into a functional poor metaboliser within days and raises dextromethorphan exposure many-fold, which is the same state inherited CYP2D6 poor metabolisers are in permanently. (Source 9)
• Drugs with anticholinergic properties (label): The label says concomitant use of other agents with anticholinergic properties should be undertaken with caution; these add to dry mouth, urinary retention, constipation and confusion. (Source 8)

Stopping it

• The label's own statement on dependence is narrow and dated: it cites the WHO Expert Committee on Drug Dependence to the effect that dextromethorphan could produce very slight psychic dependence but no physical dependence. It says nothing about promethazine dependence, and no tapering schedule exists for this product. (Source 10)
• The pharmacovigilance literature does not agree that dependence is a non-issue. Analysis of the European regulator's database found rising misuse, abuse and dependence reports for promethazine across 2003 to 2019, with dependence among the reported reactions, and recommended that clinicians be warned and remain vigilant. (Source 11)
• Because the cough being treated resolves by itself, stopping costs little. In the randomised trial of this exact pair of drugs in children, the whole cohort improved over three days whether they received promethazine, dextromethorphan or placebo, and the authors concluded nocturnal cough in upper respiratory infection is self-resolving. (Source 4)

What goes wrong

People who inherit a poorly functioning CYP2D6 enzyme reach dextromethorphan blood levels roughly 150 times higher than normal metabolisers after the same 30 mg dose. (Source 9)

• Blood level study, Moderate certainty.
• Size: 12 subjects (6 extensive metabolisers, 6 poor metabolisers)
• Who: healthy volunteers genotype- and phenotype-characterised for CYP2D6.
• How long: single 30 mg doses with sampling over 168 hours.
• Result: dextromethorphan AUC 150-fold greater in poor metabolisers than extensive metabolisers; quinidine raised AUC 43-fold in extensive metabolisers; median half-life 19.1 hours in poor metabolisers versus 2.4 hours in extensive metabolisers; apparent partial clearance 1.2 L/hr versus 970 L/hr.
• Funding: Research Support, Non-U.S. Gov't.

Dextromethorphan area under the plasma concentration-time curve (AUC) was 150-fold greater in the poor metabolizers than in the extensive metabolizers, and quinidine increased the AUC in extensive metabolizers 43-fold. The median dextromethorphan half-life was 19.1 hours in poor metabolizers, 5.6 hours in extensive metabolizers given quinidine, and 2.4 hours in extensive metabolizers.

Blocking CYP2D6 with quinidine converted every extensive metaboliser into a functional poor metaboliser within three days and raised dextromethorphan levels at least 27-fold. (Source 12)

• Blood level study, Moderate certainty.
• Size: study 1 randomised 46 healthy extensive metabolisers; study 3 evaluated 7 extensive and 2 poor metabolisers.
• Who: healthy volunteers phenotyped as extensive or poor CYP2D6 metabolisers.
• How long: 7 to 8 days of twice-daily dosing.
• Result: mean urinary metabolic ratio of dextromethorphan to dextrorphan increased at least 27-fold in extensive metabolisers by day 8; no effect of quinidine on urinary metabolic ratios in poor metabolisers; 100% conversion to the poor metaboliser phenotype by day 3 on 25 mg quinidine.
• Funding: not stated (study of the fixed combination AVP-923, a commercial product)

The mean urinary metabolic ratio (DM/DX) increased at least 27-fold in extensive metabolizers by day 8. There was no effect of Q on urinary metabolic ratios in poor metabolizers.

The boxed warning records postmarketing respiratory depression including deaths in children under two, at a wide range of weight-based doses. (Source 2)

• Official position, Certainty not rated.
• Size: not stated; postmarketing case reports.
• Who: paediatric patients less than 2 years of age.
• How long: not stated.
• Result: no rate given; the label states a wide range of weight-based doses of promethazine have resulted in respiratory depression in these patients.
• Funding: manufacturer's label (position of the sponsor and FDA, SPL effective 2025-08-08)

Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients less than 2 years of age. A wide range of weight-based doses of promethazine have resulted in respiratory depression in these patients.

The label states that promethazine-associated respiratory depression and apnoea in children are not related to weight-based dosing, so no weight-based dose can be assumed safe. (Source 13)

• Official position, Certainty not rated.
• Size: not stated.
• Who: paediatric patients 2 years of age and older.
• How long: not stated.
• Result: no rate given; respiratory depression and apnoea sometimes associated with death strongly associated with promethazine products and not directly related to individualised weight-based dosing.
• Funding: manufacturer's label (position of the sponsor and FDA, SPL effective 2025-08-08)

Respiratory depression and apnea, sometimes associated with death, are strongly associated with promethazine products and are not directly related to individualized weight-based dosing, which might otherwise permit safe administration.

The label states that excessively large doses of antihistamines including promethazine may cause sudden death in children, and that hallucinations and convulsions have occurred at therapeutic doses. (Source 13)

• Official position, Certainty not rated.
• Size: not stated.
• Who: paediatric patients.
• How long: not stated.
• Result: no rate given; the label states only that excessively large dosages may cause sudden death and that hallucinations and convulsions have occurred with therapeutic doses as well as overdoses.
• Funding: manufacturer's label (position of the sponsor and FDA, SPL effective 2025-08-08)

Excessively large dosages of antihistamines, including promethazine, in pediatric patients may cause sudden death (see OVERDOSAGE ). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of Promethazine in pediatric patients.

A systematic review of over-the-counter drug misuse found dextromethorphan the most frequently reported substance, with adolescents and young adults the vulnerable group and true prevalence unknown. (Source 5)

• Systematic review, Very low certainty.
• Size: 92 articles (case reports, surveys and retrospective case series)
• Who: published clinical data on misuse of antihistamines including promethazine, dextromethorphan- and codeine-based cough medicines, and pseudoephedrine.
• How long: literature covering roughly the past 20 years.
• Result: dextromethorphan was the focus of 54 of the 92 articles and diphenhydramine of 12; prevalence figures remain unknown because of a lack of appropriate monitoring systems.
• Funding: not stated.

Most articles focused here on DXM (n = 54) and diphenhydramine (n = 12). When specified, dosages, route(s) of administration, toxicity symptoms (including both physical and psychiatric ones), and outcomes were here reported. Conclusion: Results from the systematic review showed that the OTC misusing issues are both widespread worldwide and popular; vulnerable categories include adolescents and young adults, although real prevalence figures remain unknown, due to a lack of appropriate monitoring systems.

In the European regulator's adverse-reaction database, 557 of 1,543 promethazine reports concerned misuse, abuse or dependence, and 310 of those 557 (55.6%) involved a fatality. (Source 11)

• Survey study, Very low certainty.
• Size: 1,543 adverse drug reaction reports, 557 abuse/misuse/dependence-related.
• Who: spontaneous adverse drug reaction reports to the European Medicines Agency database, 2003-2019.
• How long: 2003 to 2019.
• Result: 557/1,543 abuse, misuse or dependence reports; drug abuse 300/557 (53.8%) and intentional product misuse 117/557 (21.0%); fatalities 310/557 (55.6%), mostly recorded as drug toxicity or drug abuse with opiates or opioids the commonest concomitant drugs.
• Funding: not stated.

Limit of this finding: Two oddities in this passage are the journal’s own and have been kept: it prints "misuse/abuse/ dependence" with a stray space, and a full stop in the middle of a sentence, before the word "being". The paper also writes "European Monitoring Agency" in its text where its own title says "European Medicines Agency". The percentages also do not quite match their own denominators: 300 of 557 is 53.9% and the paper prints 53.8%, 310 of 557 is 55.7% and the paper prints 55.6%. The counts are the reliable part, and they have been kept as printed. More importantly, these are spontaneous adverse-reaction reports, not a survey of users: the percentages describe the reports in the database, so they say nothing about how common abuse is among people prescribed promethazine.

Out of a total number of 1543 cases of adverse drug reactions, the abuse/misuse/dependence-related cases reported were 557, with 'drug abuse' (300/557: 53.8%) and 'intentional product misuse' (117/557: 21.0%). being the most represented adverse drug reactions. A high number of fatalities were described (310/557: 55.6%), mostly recorded as 'drug toxicity/drug abuse' cases, with opiates/opioids having been the most commonly reported concomitant drugs used.

A systematic review of the codeine-and-promethazine cough syrup mixture known as purple drank found its misuse is not confined to the groups popular reporting had identified. (Source 14)

• Systematic review, Very low certainty.
• Size: 7 papers from 138 records.
• Who: published studies of misuse of codeine and promethazine cough syrup, typically mixed with soft drink or alcohol.
• How long: literature from the early 1990s onward.
• Result: risk of bias assessment, where applicable, gave a low level of risk; epidemiological data showed heterogeneous diffusion of misuse not exclusively linked to any one type of user.
• Funding: not stated.

Epidemiological data highlighted a heterogeneous diffusion of the misuse of this mixture, which is not exclusively linked to a specific type of user (African-American teenagers, athletes, and rappers), as previously reported in American newspapers and in the social media.

Serotonin syndrome has been reported at therapeutic doses when a dextromethorphan-containing cough syrup was added to an SSRI. (Source 7)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: a 52-year-old man taking sertraline who started a cough syrup containing brompheniramine, pseudoephedrine and dextromethorphan.
• How long: symptoms three days after starting the cough syrup.
• Result: confusion, dilated pupils, myoclonic foot movements and difficulty with speech, resolving after both drugs were stopped; a single case report, so no rate can be derived.
• Funding: not stated.

Limit of this finding: This is one patient. A single case report can show that something is possible, but it cannot show how often it happens, and nothing here gives a rate, a risk or a dose threshold. The man was taking sertraline and recovered when both drugs were stopped, and he was not re-exposed, so even in this one case the link is probable rather than proven.

We report a case of a 52-year-old male on sertraline who developed SS after taking Bromfed DM, a cough syrup containing brompheniramine, pseudoephedrine, and DM. Three days after starting the medication, he experienced confusion, dilated pupils, myoclonic foot movements, and difficulty with speech. Symptoms improved following the discontinuation of both sertraline and Bromfed DM. This case underscores the importance of recognizing the serotonergic potential of common cold medications and the risk of SS even at therapeutic doses, particularly in patients on selective serotonin reuptake inhibitors (SSRIs).

The label states that promethazine may lead to potentially fatal respiratory depression and that the combination should be avoided in people with compromised respiratory function. (Source 1)

• Official position, Certainty not rated.
• Size: not stated.
• Who: patients with compromised respiratory function, for example COPD or sleep apnoea syndrome.
• How long: not stated.
• Result: no rate given in this section.
• Funding: manufacturer's label (position of the sponsor and FDA, SPL effective 2025-08-08)

Promethazine may lead to potentially fatal respiratory depression. Use of Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution in patients with compromised respiratory function (e.g. COPD, sleep apnea syndrome) should be avoided.

The label records that the sedative impairment caused by promethazine is amplified by alcohol and other central nervous system depressants. (Source 15)

• Official position, Certainty not rated.
• Size: not stated.
• Who: people performing potentially hazardous tasks such as driving or operating machinery.
• How long: not stated.
• Result: no rate given in this section.
• Funding: manufacturer's label (position of the sponsor and FDA, SPL effective 2025-08-08)

Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol

The label records that acutely ill, dehydrated children are more susceptible to dystonias on promethazine. (Source 13)

• Official position, Certainty not rated.
• Size: not applicable - regulatory position.
• Who: acutely ill pediatric patients with dehydration.
• How long: not stated.
• Result: no rate given in this section.
• Funding: not stated.

In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine.

A second manufacturer’s label states flatly that promethazine products are contraindicated under two years of age, and that the fatal respiratory depression risk in children aged two and over is not related to weight-based dosing. (Source 16)

• Official position, Certainty not rated.
• Size: not applicable - regulatory position.
• Who: children under two, and children two years and over.
• How long: not applicable.
• Result: an absolute contraindication under two years of age; no rate given.
• Funding: not stated.

Promethazine products are contraindicated for use in pediatric patients less than two years of age. Caution should be exercised when administering promethazine products to pediatric patients 2 years of age and older because of the potential for fatal respiratory depression. Respiratory depression and apnea, sometimes associated with death, are strongly associated with promethazine products and are not directly related to individualized weight-based dosing, which might otherwise permit safe administration.

The same label directs that the product be avoided in children whose signs may suggest Reye’s syndrome or other liver disease, and states that excessively large doses of antihistamines including promethazine may cause sudden death in children. (Source 16)

• Official position, Certainty not rated.
• Size: not applicable - regulatory position.
• Who: pediatric patients.
• How long: not applicable.
• Result: no rate given in this section.
• Funding: not stated.

The use of promethazine products should be avoided in pediatric patients whose signs and symptoms may suggest Reye’s syndrome or other hepatic diseases. Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death (see OVERDOSAGE ).

The U.S. label contraindicates this product outright in children under two years of age, in comatose states, in anyone hypersensitive to promethazine or another phenothiazine, and for lower respiratory symptoms including asthma. (Source 17)

• Official position, Certainty not rated.
• Size: not applicable - regulatory position.
• Who: children under two; comatose patients; people hypersensitive to phenothiazines; anyone with lower respiratory tract symptoms including asthma.
• How long: not applicable.
• Result: absolute contraindications; no rates are given in this section.
• Funding: not stated.

Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution is contraindicated for use in pediatric patients less than two years of age. Promethazine is contraindicated in comatose states, and in individuals known to be hypersensitive or to have had an idiosyncratic reaction to promethazine or to other phenothiazines. Antihistamines are contraindicated for use in the treatment of lower respiratory tract symptoms, including asthma.

What the evidence supports

A placebo-controlled pilot trial using an objective cough monitor in 128 children aged 6 to 11 found dextromethorphan reduced 24-hour cough counts by 21.0%, but found no effect on night-time cough. (Source 18)

• Randomized trial, Low certainty.
• Size: 128 evaluable subjects (67 dextromethorphan, 61 placebo)
• Who: children aged 6 to 11 years with cough due to the common cold who qualified through a sweet-syrup run-in period.
• How long: multiple doses over 4 days, with coughs recorded during the initial 24 hours.
• Result: total coughs over 24 hours reduced 21.0% and daytime cough frequency 25.5% versus placebo; no effects detected for night-time cough rates or impact of cough on sleep.
• Funding: not stated in the abstract; the trial used a proprietary paediatric formulation and all authors' affiliations are not given in the record (treat as probably industry-sponsored and unconfirmed)

Limit of this finding: The authors describe this as a pilot study, run to work out which endpoints are usable in children rather than to settle whether the drug works, and 128 children is small. Children also had to qualify by coughing enough during a run-in period in which everyone was given sweet syrup, which selects for children whose cough does not settle on a sweet syrup alone. "Statistically significant and medically relevant" is the authors' own judgement of a 21% reduction in counted coughs over one day, and the same trial found nothing at night.

Total coughs over 24-hours (primary endpoint) and cough frequency during daytime were reduced by 21.0% and 25.5%, respectively, with DXM relative to placebo. Also, greater reductions in cough severity and frequency were self-reported with DXM. These findings were statistically significant and medically relevant. No effects were detected between treatments for nighttime cough rates or impact of cough on sleep.

What the evidence does not support

A Cochrane review of placebo-controlled trials of over-the-counter cough medicines found no good evidence either way, and specifically found antitussives and antihistamines no better than placebo in children. (Source 19)

• Systematic review, Very low certainty.
• Size: 29 trials involving 4,835 people (3,799 adults and 1,036 children)
• Who: children and adults with acute cough from upper respiratory tract infection in community settings.
• How long: not stated in the abstract; search to March 2014.
• Result: pooling judged inappropriate; in children, antitussives (3 studies), antihistamines (3 studies), antihistamine-decongestants (2 studies) and antitussive/bronchodilator combinations (1 study) were no more effective than placebo; 21 studies reported adverse effects, with higher numbers in participants taking preparations containing antihistamines and dextromethorphan.
• Funding: Research Support, Non-U.S. Gov't (Cochrane review)

Twenty-one studies reported adverse effects. There was a wide range across studies, with higher numbers of adverse effects in participants taking preparations containing antihistamines and dextromethorphan. AUTHORS' CONCLUSIONS The results of this review have to be interpreted with caution because the number of studies in each category of cough preparations was small. Availability, dosing and duration of use of over-the-counter cough medicines vary significantly in different countries. Many studies were poorly reported making assessment of risk of bias difficult and studies were also very different from each other, making evaluation of overall efficacy difficult. 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 a randomised placebo-controlled trial of this exact drug pair in children aged 1 to 12, neither dextromethorphan nor promethazine was better than placebo for nocturnal cough. (Source 4)

• Randomized trial, Low certainty.
• Size: 120 children.
• Who: children aged 1 to 12 years with upper respiratory tract infection attending a paediatric outpatient department in Delhi.
• How long: 3 days of assigned medication.
• Result: the whole cohort improved on all parameters after 3 days, with no superior benefit for promethazine or dextromethorphan over placebo on nocturnal cough severity, post-tussive vomiting or sleep quality; adverse effects were more frequent on the active drugs but not significantly so.
• Funding: not stated.

Entire cohort improved in all the study parameters after 3 d. 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. CONCLUSIONS Nocturnal cough in URI is self-resolving and dextromethorphan and promethazine prescribed for the same are not superior to placebo.

In a trial whose comparison group received no treatment at all rather than a placebo, honey-flavoured dextromethorphan was no better than no treatment for any parent-rated nocturnal cough outcome in children. (Source 20)

• Randomized trial, Low certainty.
• Size: 105 children aged 2 to 18 years.
• Who: children aged 2 to 18 years with upper respiratory tract infection, nocturnal symptoms and illness of 7 days or less, in a single general paediatric practice.
• How long: a single dose 30 minutes before bedtime, with parent surveys on two consecutive days.
• Result: honey was significantly superior to no treatment for cough frequency and the combined score, but dextromethorphan was not better than no treatment for any outcome; honey versus dextromethorphan showed no significant differences.
• Funding: Research Support, U.S. Gov't, Non-P.H.S.

Limit of this finding: This trial had no placebo arm: the three groups were buckwheat honey, honey-flavoured dextromethorphan and no treatment, and only part of the randomisation was double-blinded, so a child given nothing and a parent who knew it are being compared with a child given a sweet syrup. Everything measured was reported by parents on a survey the morning after a single bedtime dose, in one outpatient general paediatric practice, in 105 children. That makes it weak evidence either way: it cannot show that dextromethorphan is useless, and it cannot show that honey works, because neither comparison is against a dummy treatment. The abstract also says nothing about honey being unsafe for babies under one year old because of the risk of botulism, which is a separate and well-established limit that does not come from this paper.

In paired comparisons, honey was significantly superior to no treatment for cough frequency and the combined score, but DM was not better than no treatment for any outcome. Comparison of honey with DM revealed no significant differences.

In a 12-subject capsaicin cough-challenge model, a single 30 mg dose of dextromethorphan produced no antitussive effect in either normal or poor CYP2D6 metabolisers, and the authors questioned the model itself. (Source 9)

• Blood level study, Low certainty.
• Size: 12 healthy subjects (6 extensive and 6 poor CYP2D6 metabolisers)
• Who: healthy volunteers phenotyped for CYP2D6, given 30 mg dextromethorphan with or without quinidine, or placebo.
• How long: blood and urine over 168 hours, with capsaicin aerosol challenge at each blood sampling time.
• Result: no difference in capsaicin-induced cough frequency between the three conditions; very large intersubject variability in capsaicin responsiveness; the authors conclude capsaicin may not be an ideal agent in experimental cough studies.
• Funding: Research Support, Non-U.S. Gov't.

Limit of this finding: This is not evidence that dextromethorphan does not relieve ordinary cough. Cough was provoked artificially with inhaled capsaicin in 12 healthy volunteers given one 30 mg dose, and the authors themselves end the paper by saying capsaicin may not be a suitable way to study cough. The study was designed to measure blood levels, and the cough measurement was a secondary part of it; no design on this monograph’s list fits the cough arm, so it is recorded here as the closest value, pharmacokinetic. Read it as a null result in a laboratory model, nothing more.

There was very large intersubject variability in responsiveness to capsaicin. There was no difference in the capsaicin-induced cough frequency in the three groups. Dextromethorphan had no antitussive effect in this experimental cough model. CONCLUSION The disposition of dextromethorphan was substantially influenced by CYP2D6 status. Capsaicin may not be an ideal agent in experimental cough studies.

Where the research disagrees

What the boxed warning actually says, and whether a given product carries one at all. Across marketed promethazine-dextromethorphan oral solutions we found two different boxed-warning texts and some products with no boxed-warning coding at all

• ANI Pharmaceuticals and Advagen Pharma SPLs (effective 2025-08-08 and 2026-06-26): boxed warning names the combination product, regulatory position, LOINC 34066-1 boxed warning section: Promethazine Hydrochloride and Dextromethorphan Hydrobromide Oral Solution should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression. (Source 2)
• Cosette Pharmaceuticals, Slate Run and PAI SPLs: boxed warning is in capitals and names promethazine hydrochloride rather than the combination, regulatory position, LOINC 34066-1 boxed warning section: PROMETHAZINE HYDROCHLORIDE SHOULD NOT BE USED IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE BECAUSE OF THE POTENTIAL FOR FATAL RESPIRATORY DEPRESSION. (Source 21)
• Amneal Pharmaceuticals SPL (effective 2024-10-30) and Camber Pharmaceuticals SPL (effective 2026-06-09): the same warning text appears, but inside the ordinary WARNINGS section with no boxed-warning coding, so an automated check of LOINC 34066-1 alone would report no boxed warning for these products, regulatory position recorded under LOINC 34071-1 (WARNINGS), not 34066-1: WARNING: Promethazine hydrochloride should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression. (Source 22)

Whether dextromethorphan suppresses cough in children at all

• Bhattacharya and colleagues, randomised placebo-controlled trial of promethazine, dextromethorphan and placebo, 2013, randomised double-blind placebo-controlled trial, 120 children aged 1-12: However, no superior benefit was noted when individual parameters were compared in the promethazine and dextromethorphan groups with the placebo group. (Source 4)
• Meeves and colleagues, placebo-controlled trial with objective cough monitoring, 2023, multiple-dose double-blind placebo-controlled pilot trial with a cough monitor, 128 children aged 6-11: Total coughs over 24-hours (primary endpoint) and cough frequency during daytime were reduced by 21.0% and 25.5%, respectively, with DXM relative to placebo. (Source 18)
• Smith and colleagues, Cochrane review, 2014, systematic review of 29 placebo-controlled randomised trials in 4,835 people: There is no good evidence for or against the effectiveness of OTC medicines in acute cough. (Source 19)

How much

• Reference intake: There is no reference intake for a drug. Dosing is set by the prescriber. As a position, the manufacturer's label (SPL effective 2025-08-08) first states that the product is CONTRAINDICATED for children under 2 years of age, then gives an average effective adult dose of 5 mL every 4 to 6 hours, 2.5 to 5.0 mL for children 6 to under 12, and 1.25 to 2.5 mL for children 2 to under 6. The label also warns that a household teaspoon is not an accurate measuring device. (Source 23)
• Upper limit: The label's stated 24-hour ceilings, as a position of the sponsor and FDA (SPL effective 2025-08-08), are 30.0 mL for adults, 20.0 mL for children 6 to under 12 years, and 10.0 mL for children 2 to under 6 years; below 2 years of age there is no permitted dose at all, because the product is contraindicated and the boxed warning records fatal respiratory depression across a wide range of weight-based doses. (Source 23)
• Studied: The Delhi randomised trial compared promethazine, dextromethorphan and placebo over 3 days in 120 children aged 1 to 12 years with upper respiratory infection. (Source 4)
• Studied: The paediatric cough-monitor trial gave multiple doses of dextromethorphan hydrobromide or placebo over 4 days to children aged 6 to 11 years. (Source 18)
• Studied: The CYP2D6 disposition study gave healthy volunteers single 30 mg doses of dextromethorphan, with or without 50 mg quinidine. (Source 9)
• Studied: Paul and colleagues gave a single nocturnal dose of honey-flavoured dextromethorphan, buckwheat honey, or no treatment 30 minutes before bedtime to children aged 2 to 18 years. (Source 20)

A common belief, and what the research shows

The belief: A prescription cough syrup is stronger than the shop-bought kind, so it must work better, and the paediatric dose on the bottle means it is safe for small children.

What the research shows: Neither half holds. On effectiveness, the Cochrane review of 29 placebo-controlled trials concluded "There is no good evidence for or against the effectiveness of OTC medicines in acute cough.", and a trial of this exact drug pair in children aged 1 to 12 concluded "dextromethorphan and promethazine prescribed for the same are not superior to placebo.". On safety, the paediatric doses printed on the label begin with a contraindication, not a permission: the label states the product "is CONTRAINDICATED for children under 2 years of age", and the boxed warning explains why in a way that defeats the idea of a cautious small dose - "A wide range of weight-based doses of promethazine have resulted in respiratory depression in these patients." The label adds that respiratory depression and apnoea "are not directly related to individualized weight-based dosing, which might otherwise permit safe administration."

Questions and answers

What is it?

It is a prescription oral liquid combining two drugs: dextromethorphan hydrobromide, a cough suppressant acting on the brain, and promethazine hydrochloride, a sedating first-generation antihistamine. The U.S. label gives it one indication, temporary relief of coughs and upper respiratory symptoms with allergy or the common cold. It is not an over-the-counter product in the United States. (Source 3)

What does it do in the body?

Dextromethorphan damps the cough reflex in the brain rather than acting on the airways. Promethazine blocks histamine, which eases runny nose and sneezing, and it strongly sedates, which is why it also slows breathing. The label warns that promethazine may lead to potentially fatal respiratory depression and that the product should be avoided when breathing is already compromised. (Source 1)

Is it good or bad for you?

On the evidence, the benefit is small or absent and the harm is real. The Cochrane review found no good evidence for or against over-the-counter cough medicines and noted more adverse effects with antihistamine- and dextromethorphan-containing preparations. In children the trials are mostly negative. The promethazine component has caused fatal respiratory depression in young children, which is why the product is contraindicated under two years of age. (Source 19)

How do you get more of it?

This is a prescription medicine, so the amount is set by a prescriber, and this monograph gives no dose for a reader to act on. As a position the label records an average effective adult dose of 5 mL every 4 to 6 hours with a 30 mL ceiling in 24 hours, and warns that a household teaspoon is not an accurate measuring device and could lead to overdose. The same section states the product is contraindicated under two years of age. (Source 23)

If it is harmful, what reduces it?

There is no antidote to reverse it and no way to clear it faster. The label's position is avoidance rather than rescue: it is contraindicated below two years, should be avoided when breathing is compromised, and other respiratory depressants should be avoided alongside it. One rescue measure is explicitly ruled out, because promethazine reverses adrenaline's effect on blood pressure, so adrenaline must not be used for hypotension in overdose. (Source 8)

Why might someone be low in it or missing it?

Nobody is naturally short of these drugs. What varies between people is how fast dextromethorphan is broken down. People who inherit a poorly working CYP2D6 enzyme reach about 150 times the blood level of a normal metaboliser from the same dose, and a drug that blocks CYP2D6 produces the same state artificially. Conversely a normal metaboliser clears the drug within hours. (Source 9)

Which whole foods contain it or feed it?

No whole food contains either drug; both are manufactured. The food that appears in this literature is a comparator rather than a source: in a randomised trial in children, buckwheat honey beat no treatment for cough frequency while honey-flavoured dextromethorphan did not, and honey and dextromethorphan did not differ significantly from each other. (Source 20)

What happens if you do not have it?

Nothing is lost by not taking it, because the condition it treats resolves on its own. In the randomised trial of this exact drug pair, the entire cohort of children improved over three days regardless of which arm they were in, and the authors concluded that nocturnal cough in upper respiratory infection is self-resolving. (Source 4)

How can you test for it?

There is no routine clinical test for this syrup. The one test with established relevance is CYP2D6 genotyping or phenotyping, which predicts dextromethorphan exposure: in the Capon study prestudy urinary metabolic ratios correlated strongly with the clearance of dextromethorphan to dextrorphan, r squared of 0.82. That test is not part of ordinary prescribing of a cough syrup, and no test predicts who will suffer respiratory depression. (Source 9)

References

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2. DailyMed (U.S. National Library of Medicine), Structured Product Label. PROMETHAZINE HYDROCHLORIDE AND DEXTROMETHORPHAN HYDROBROMIDE SOLUTION [ANI PHARMACEUTICALS, INC.], SPL effective 2025-08-08 - BOXED WARNING SECTION (LOINC 34066-1). 2025. Read the source
3. DailyMed (U.S. National Library of Medicine), Structured Product Label. PROMETHAZINE HYDROCHLORIDE AND DEXTROMETHORPHAN HYDROBROMIDE SOLUTION [ANI PHARMACEUTICALS, INC.], SPL effective 2025-08-08 - INDICATIONS AND USAGE. 2025. Read the source
4. Indian J Pediatr. To compare the effect of dextromethorphan, promethazine and placebo on nocturnal cough in children aged 1-12 y with upper respiratory infections: a randomized controlled trial.. 2013. PMID 23592248, DOI 10.1007/s12098-013-1002-2. Read the source
5. Front Psychiatry. Focus on Over-the-Counter Drugs' Misuse: A Systematic Review on Antihistamines, Cough Medicines, and Decongestants.. 2021. PMID 34025478, DOI 10.3389/fpsyt.2021.657397. Read the source
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18. Pediatr Pulmonol. Objective and self-reported evidence of dextromethorphan antitussive efficacy in children, aged 6-11 years, with acute cough due to the common cold.. 2023. PMID 37232330, DOI 10.1002/ppul.26416. Read the source
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20. Arch Pediatr Adolesc Med. Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents.. 2007. PMID 18056558, DOI 10.1001/archpedi.161.12.1140. Read the source
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