Diphenhydramine citrate

What it is

Diphenhydramine citrate is the citrate salt of diphenhydramine, a first-generation sedating H1-antihistamine of the ethanolamine chemical class. It is the salt used in night-time analgesic combinations and some cough-cold products, rather than the hydrochloride that is in most stand-alone diphenhydramine products. Because the citrate molecule is larger, a milligram of citrate carries less diphenhydramine than a milligram of hydrochloride: the US over-the-counter antihistamine monograph sets 38 to 76 mg for the citrate where it sets 25 to 50 mg for the hydrochloride, and the nighttime sleep-aid monograph sets 76 mg against 50 mg. The best-known product is a bilayer tablet of ibuprofen 200 mg plus diphenhydramine citrate 38 mg.

What the research says

The evidence for what this drug does is lopsided: the efficacy base is old and small, and the harm base is recent and large. A 2015 systematic review of randomised placebo-controlled trials concluded that diphenhydramine lacks robust evidence of efficacy for occasional disturbed sleep, and the largest placebo-controlled trial with polysomnography found a diary-reported gain in sleep efficiency but no change in any objectively measured sleep-continuity variable. For colds, Cochrane found a small effect on overall symptom severity on days one and two that had gone by day three, with no clinically significant effect on individual symptoms and no evidence of effectiveness in children. The harm side is better evidenced: a driving-simulator trial found a single 50 mg dose impaired driving more than alcohol at about 0.1% blood alcohol concentration, a prospective hospital cohort linked it to delirium symptoms with a dose-response, and a meta-analysis of observational studies tied first-generation antihistamines to roughly double the odds of injurious falls or fracture in older people. Tolerance to its sedating effect was complete within three days in a crossover trial, which undercuts its use as a nightly sleep aid.

Evidence grade: Limited evidence.

How it works

Drug class: First-generation (sedating) H1-antihistamine, ethanolamine class; the citrate salt of diphenhydramine. In the US over-the-counter system it is listed as an antihistamine active ingredient, as an oral antitussive active ingredient, and as a nighttime sleep-aid active ingredient.

Diphenhydramine occupies the histamine H1 receptor. Modern pharmacology describes drugs of this class as inverse agonists rather than simple blockers: they hold the receptor in its inactive shape, which damps the vasodilation, leaky capillaries, itch and mucus that released histamine drives. Because diphenhydramine is highly fat-soluble it also crosses into the brain, where the same H1 action produces sedation, and it blocks muscarinic acetylcholine receptors, which is the source of dry mouth, blurred vision, constipation, difficulty passing urine and confusion. It is cleared by liver cytochrome P450 enzymes, CYP2D6 among them, and the antihistamine effect of drugs in this class lasts up to about six hours. (Source 1)

What it is used for

• The US OTC nighttime sleep-aid monograph lists diphenhydramine citrate as an active ingredient at 76 mg at bedtime. The trial evidence behind that position is thin: a 2015 systematic review found diphenhydramine lacked robust evidence of efficacy, and the largest placebo-controlled trial with polysomnography found a diary-reported gain in sleep efficiency but no change in any objectively measured sleep-continuity variable. Tolerance to the sedating effect was complete within three days in a separate crossover trial. Evidence: limited. (Source 2)
• This is the licensed indication of the ibuprofen 200 mg plus diphenhydramine citrate 38 mg bilayer tablet. We found no placebo-controlled outcome trial of that particular 38 mg citrate dose; the published work we could reach on the combination is formulation and bioequivalence modelling rather than an efficacy trial. Evidence: unknown. (Source 3)
• Diphenhydramine citrate is a listed OTC antihistamine active ingredient at 38 to 76 mg every 4 to 6 hours. We did not find a modern placebo-controlled allergic rhinitis trial of the citrate salt itself; the class evidence for first-generation antihistamines in allergic rhinitis is old and the comparative trials we found used brompheniramine or chlorpheniramine rather than diphenhydramine. Evidence: limited. (Source 4)
• Diphenhydramine citrate is listed as an oral antitussive active ingredient in the US OTC monograph and the same ingredient may serve as both the antihistamine and the antitussive in a product. We found no outcome trial of diphenhydramine citrate as a cough suppressant that we could read. Evidence: unknown. (Source 4)
• Cochrane found antihistamine monotherapy gave a small benefit on overall cold symptom severity on days one and two only, with no clinically significant effect on nasal obstruction, runny nose or sneezing, and no evidence of effectiveness in children. Antihistamine-containing combination products showed some global benefit in adults and older children but with more adverse effects, and Cochrane rated the combination data scarce. Evidence: not-supported. (Source 5)
• Using a sedating antihistamine for sleep in older people is where the harm evidence is strongest. A prospective hospital cohort linked diphenhydramine to delirium symptoms with a dose-response, a meta-analysis of observational studies linked first-generation antihistamines to about double the odds of injurious falls or fracture, and a long-running cohort linked cumulative strong anticholinergic exposure to incident dementia. Evidence: not-supported. (Source 6)

Interactions

• Alcohol (clinical trial): Diphenhydramine and alcohol together impair central nervous system performance more than either alone. In a crossover trial in healthy volunteers, the diphenhydramine-plus-alcohol combination impaired more tests and impaired them more severely than a second-generation antihistamine with alcohol. (Source 7)
• Alcohol and other central nervous system depressants (hypnotics, sedatives, tranquillisers) (label): The label records an additive sedative effect, and the OTC monograph requires products containing diphenhydramine citrate to carry a marked-drowsiness warning naming alcohol, sedatives and tranquillisers. (Source 8)
• Sedatives, tranquillisers and other sleep aids (label): The OTC monograph warning for diphenhydramine citrate products tells people not to take the product with sedatives or tranquillisers without consulting a doctor, and names a marked rather than a mild drowsiness effect. Limit: This is the wording the US over-the-counter monograph requires on the label, not a measured effect, and no rates are given. One oddity in the regulation itself: it prints its instruction not to use the product with any other product containing diphenhydramine, even one used on the skin, twice over, at (c)(6)(iv) and again at (c)(7). That is the regulation duplicating one rule, not two different rules. (Source 9)
• Metoprolol and other CYP2D6 substrates (pharmacokinetic study): Diphenhydramine inhibits the liver enzyme CYP2D6. In a randomised study in healthy men, steady-state diphenhydramine halved metoprolol clearance in people with normal CYP2D6 activity and prolonged metoprolol's slowing effect on the heart. (Source 10)
• Other drugs cleared by CYP2D6, particularly narrow therapeutic index drugs (pharmacokinetic study): The authors of that study generalised the finding: because diphenhydramine is available without prescription, it can be taken alongside prescription drugs that share the same enzyme, and the result can be drug accumulation. (Source 10)
• Monoamine oxidase inhibitors (label): The label states that MAO inhibitors lengthen and intensify the drying anticholinergic effects of antihistamines. (Source 8)
• Other products containing diphenhydramine, including topical ones (label): Because diphenhydramine appears in many OTC products under different salts and names, the monograph requires a warning against doubling up, explicitly including creams and lotions used on the skin. (Source 11)
• Valerian and hops extracts (clinical trial): No study we found gave diphenhydramine and valerian together. The one randomised trial that tested both compared them as separate arms against placebo, so the literature is silent on whether combining them adds sedation. (Source 12)
• Other anticholinergic medicines (pharmacokinetic study): Sedating antihistamines add to the anticholinergic load of other drugs. A cohort study found first-generation antihistamines were one of the three commonest strong anticholinergic classes taken by older adults, and cumulative use of the class as a whole tracked with incident dementia. Limit: This is cohort evidence about a drug class, not a measured pharmacokinetic interaction between two named drugs. The design value closest to it on the brief's list is cohort; we have recorded the evidence kind as the study it rests on rather than inventing a category. (Source 13)

Stopping it

• In the one randomised trial we found that looked for it, stopping diphenhydramine 50 mg after 14 nights produced no rebound insomnia and no residual effects. (Source 12)
• The trial's conclusion repeats the point about discontinuation, though it covers only 184 people over 28 days and so cannot speak to long-term nightly use. (Source 14)
• The sedating effect itself fades quickly, which bears on stopping: tolerance to the sedation was complete after three days of twice-daily dosing in healthy men, so someone taking it nightly may be continuing a drug that has stopped doing the thing they take it for. (Source 15)
• A systematic review of the related salt dimenhydrinate, which is diphenhydramine combined with 8-chlorotheophylline, reports withdrawal alongside intoxication and dependence in heavy long-term users, on low-quality evidence. We found no comparable literature for the citrate salt itself. (Source 16)

What goes wrong

In a driving simulator trial, a single 50 mg dose of diphenhydramine impaired driving more than alcohol at roughly 0.1% blood alcohol concentration. (Source 17)

• Randomized trial, Certainty not rated.
• Size: 40 licensed drivers aged 25 to 44.
• Who: Licensed drivers with seasonal allergic rhinitis.
• How long: Four weekly single-dose treatment periods, one hour of driving each.
• Result: Lane keeping, measured as steering instability and crossing the centre line, was impaired after both alcohol and diphenhydramine relative to fexofenadine; overall driving performance was poorest after diphenhydramine.
• Funding: Research Support, Non-U.S. Gov't and Research Support, U.S. Gov't, P.H.S. per the PubMed record; no commercial sponsor stated in the abstract.

Lane keeping (steering instability and crossing the center line) was impaired after alcohol and diphenhydramine use compared with fexofenadine use.

The same trial found that people could not tell from their own drowsiness that they were impaired. (Source 18)

• Randomized trial, Certainty not rated.
• Size: 40 licensed drivers.
• Who: Licensed drivers with seasonal allergic rhinitis.
• How long: Single doses, four weekly periods.
• Result: Self-reported drowsiness did not predict lack of coherence and was only weakly associated with minimum following distance, steering instability and left-lane excursion.
• Funding: not stated in the abstract.

Drowsiness ratings were not a good predictor of impairment, suggesting that drivers cannot use drowsiness to indicate when they should not drive.

In hospitalised patients aged 70 and over, diphenhydramine exposure was associated with delirium symptoms in a dose-related way. (Source 6)

• Cohort study, Certainty not rated.
• Size: 426 hospitalised medical patients, 114 (27%) exposed to diphenhydramine.
• Who: Hospitalised medical patients aged 70 years or older in a university hospital.
• How long: Length of the hospital admission; median stay 7 days exposed versus 6 days unexposed.
• Result: Any delirium symptoms RR 1.7 (95% CI 1.3-2.3); inattention RR 3.0 (1.5-5.9); disorganised speech RR 5.5 (1.0-29.8); altered consciousness RR 3.1 (1.6-6.1); urinary catheter placement RR 2.5 (1.0-6.0)
• Funding: Research Support, U.S. Gov't, P.H.S. per the PubMed record.

Limit of this finding: This is an observational cohort. It shows association, not cause, and sicker patients may have been more likely to be given diphenhydramine even though the authors report similar baseline delirium risk.

The diphenhydramine-exposed group was at an increased risk for any delirium symptoms (relative risk [RR], 1.7; 95% confidence interval [CI], 1.3-2.3)

A meta-analysis of observational studies linked first-generation antihistamine use to about double the odds of injurious falls or fracture in older people. (Source 19)

• Meta-analysis, Low certainty.
• Size: Five studies (three case-control, one cohort, one case-crossover) out of 473 screened.
• Who: Elderly patients, in community and hospital settings.
• How long: Databases searched to November 2016.
• Result: First-generation antihistamine use OR 2.03, 95% CI 1.49-2.76, heterogeneity p = 0.41, I2 = 0%; all-generation or unspecified studies of in-hospital falls OR 2.89, 95% CI 1.71-4.89.
• Funding: not stated in the abstract.

Limit of this finding: The authors themselves limit how far this can be read: only five studies were pooled and some results were unadjusted.

First-generation antihistamine use showed significantly increased risk of injurious falls or fracture (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.49-2.76

The authors of that meta-analysis flag their own limitations. (Source 19)

• Meta-analysis, Low certainty.
• Size: Five observational studies.
• Who: Elderly patients.
• How long: Databases searched to November 2016.
• Result: No pooled adjusted estimate was possible for the subgroups.
• Funding: not stated in the abstract.

Due to the small number of studies included and unadjusted results, meaningful interpretation based on subgroup analysis was limited.

A prospective cohort found a dose-response relationship between cumulative strong anticholinergic use, of which first-generation antihistamines were one of the three commonest classes, and incident dementia. (Source 13)

• Cohort study, Certainty not rated.
• Size: 3434 participants aged 65 or older with no dementia at entry; 797 (23.2%) developed dementia.
• Who: Members of an integrated health care system in Seattle, Washington, followed every two years.
• How long: Mean follow-up 7.3 years; cumulative exposure measured over the preceding 10 years.
• Result: Adjusted hazard ratio for dementia 1.54 (95% CI 1.21-1.96) at more than 1095 total standardized daily doses versus non-use, with a significant trend (P < .001); 0.92 (0.74-1.16) at 1 to 90 TSDDs.
• Funding: Research Support, N.I.H., Extramural and Research Support, Non-U.S. Gov't per the PubMed record.

Limit of this finding: Observational. The exposure is all strong anticholinergics pooled, not diphenhydramine alone, so the dementia hazard ratios cannot be read as a diphenhydramine-specific risk.

For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095.

In overdose, diphenhydramine can block cardiac sodium channels and produce a wide-complex dysrhythmia. (Source 20)

• Case series, Very low certainty.
• Size: Three cases.
• Who: Patients presenting after diphenhydramine overdose.
• How long: Single acute overdose episodes.
• Result: All three cases of diphenhydramine-induced cardiac toxicity responded to hypertonic sodium bicarbonate.
• Funding: not stated.

However, because diphenhydramine also exhibits type IA sodium channel blockade, cardiac toxicity is also possible.

Diphenhydramine is one of the antihistamines most often reported in the clinical literature on over-the-counter drug misuse. (Source 21)

• Systematic review, Very low certainty.
• Size: 92 articles, of which 12 concerned diphenhydramine.
• Who: People misusing over-the-counter medicines, reported in case reports, surveys and retrospective case series.
• How long: Literature to the 2021 search date.
• Result: No rates are given; the included designs were case reports, surveys and retrospective case series.
• Funding: not stated in the abstract.

Most articles focused here on DXM (n = 54) and diphenhydramine (n = 12).

Diphenhydramine is among the four medicines accounting for most emergency department visits for unsupervised swallowing of over-the-counter liquids by children under six. (Source 22)

• Survey study, Certainty not rated.
• Size: 13,268 surveillance cases representing an estimated 640,161 emergency department visits.
• Who: Children aged under 6 years in the United States.
• How long: 2004 to 2013, with medicine detail for 2010 to 2013.
• Result: Four medicines were implicated in 91.2% of OTC liquid exposure visits: acetaminophen 32.9%, cough and cold remedies 27.5%, ibuprofen 15.7%, diphenhydramine 15.6%.
• Funding: not stated in the abstract.

Limit of this finding: The review's own arithmetic does not quite close here: the four percentages it lists add up to 91.7%, not the 91.2% the sentence states. We quote the figure as the paper prints it and have not recomputed it. The gap is small and most likely comes from separately weighted national estimates and from visits involving more than one of the four medicines, but a reader should treat 91.2% as the source's own rounded total rather than a sum of the four numbers beside it.

Four medications were implicated in 91.2% of OTC liquid exposure visits: acetaminophen (32.9%), cough and cold remedies (27.5%), ibuprofen (15.7%), and diphenhydramine (15.6%).

The label's own nervous-system adverse-reaction list for diphenhydramine runs from sedation through to convulsions, with no incidence figures attached anywhere in the section. Of that list the label marks only sedation, sleepiness, dizziness and disturbed coordination as being among its most frequent reactions. (Source 23)

• Official position, Certainty not rated.
• Size: Not applicable - a regulatory label listing, not a study.
• Who: Patients given diphenhydramine hydrochloride by injection.
• How long: Not applicable.
• Result: No incidence figures are attached to the list. The label marks its most frequent reactions by italicising them, and in the nervous-system list only sedation, sleepiness, dizziness and disturbed coordination carry that mark.
• Funding: Not applicable.

Limit of this finding: The label flags its most frequent reactions by printing them in italics, and italics cannot survive a plain-text copy, so the asterisks in the quotation stand in for the label's italics. Across the whole ADVERSE REACTIONS section the label marks exactly six items as its most frequent: sedation, sleepiness, dizziness and disturbed coordination in the nervous-system list, epigastric distress in the gastrointestinal list, and thickening of bronchial secretions in the respiratory list. Everything else in these lists, including anaphylactic shock, haemolytic anaemia, thrombocytopenia, agranulocytosis and convulsions, is not marked as frequent; the lists are everything that has been reported, in no order of likelihood, and must not be read as a list of common effects. The label is also for the hydrochloride given by injection, not the oral citrate.

Sedation, sleepiness, dizziness, disturbed coordination, fatigue, confusion, restlessness, excitation, nervousness, tremor, irritability, insomnia, euphoria, paresthesia, blurred vision, diplopia, vertigo, tinnitus, acute labyrinthitis, neuritis, convulsions.

A pharmacology review of the classic H1 antagonists identifies CYP2D6 as contributing to diphenhydramine's metabolism and warns that over-the-counter access makes co-administration with other CYP2D6 drugs easy. (Source 24)

• Expert review, not systematic, Certainty not rated.
• Size: Not applicable - a review with no stated search method.
• Who: Humans, drawn from the published pharmacokinetic literature.
• How long: Not applicable.
• Result: No pooled estimate; the review notes the classic antihistamines produce up to 7% N-glucuronides, that antihistaminic effects last up to 6 hours, and that diphenhydramine inhibited CYP2D6 with a clinically significant interaction with metoprolol.
• Funding: not stated.

The prescription-free access to most classic antihistamines can easily lead to their co-administration with other drugs metabolized by the same enzyme system thereby leading to drug accumulation and adverse effects.

The authors of the hospital delirium cohort concluded that diphenhydramine use in older inpatients is associated with cognitive decline in a dose-related way. (Source 25)

• Cohort study, Certainty not rated.
• Size: 426 hospitalised patients aged 70 or older.
• Who: Hospitalised medical patients aged 70+.
• How long: Length of admission.
• Result: A dose-response relationship was demonstrated for most adverse outcomes.
• Funding: Research Support, U.S. Gov't, P.H.S. per the PubMed record.

Limit of this finding: Observational. Association, not cause.

Diphenhydramine administration in older hospitalized patients is associated with an increased risk of cognitive decline and other adverse effects with a dose-response relationship.

A systematic review of the related diphenhydramine salt dimenhydrinate found reports of seizures, psychosis and withdrawal in heavy users, on low-quality evidence. (Source 26)

• Systematic review, Very low certainty.
• Size: 24 studies, mostly case reports and reviews.
• Who: People using dimenhydrinate, often heavily and often with concurrent psychiatric disorders.
• How long: Databases searched from inception to July 2019.
• Result: No rates could be pooled; the reported sequelae were seizures, psychosis, depression, intoxication resembling anticholinergic syndrome and withdrawal.
• Funding: not stated in the abstract.

Limit of this finding: Dimenhydrinate is diphenhydramine combined with 8-chlorotheophylline, a different salt from the citrate. The diphenhydramine moiety is the same but the dose and the evidence are not interchangeable, and the review itself rates the study quality as low.

We identified 24 studies, which described a range of neuropsychiatric sequelae related to DMH consumption, including seizures, psychosis, depression, intoxication (resembling anticholinergic syndrome) and withdrawal.

The Drug Facts label of the night-time product that carries diphenhydramine citrate also carries a stomach-bleeding warning, which belongs to the ibuprofen in the same tablet rather than to the antihistamine. (Source 27)

• Official position, Certainty not rated.
• Size: Not applicable - label text.
• Who: Adults and children 12 years and over, the labelled population.
• How long: Not applicable.
• Result: The label lists six circumstances that raise the risk: age 60 or older, previous stomach ulcers or bleeding problems, a blood thinner or steroid drug, other NSAIDs, three or more alcoholic drinks a day, and taking more or for longer than directed.
• Funding: not stated.

Limit of this finding: This warning is about ibuprofen, the other active ingredient in the combination tablet. It is recorded here because it is on the label of the main product in which diphenhydramine citrate is sold, not because diphenhydramine causes stomach bleeding.

This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you

The same label carries the standard NSAID heart attack and stroke warning, again for its ibuprofen component. (Source 28)

• Official position, Certainty not rated.
• Size: Not applicable - label text.
• Who: Adults and children 12 years and over, the labelled population.
• How long: Not applicable.
• Result: No risk figures are given on the label; the warning states the risk is higher with more than the directed dose or duration.
• Funding: not stated.

Limit of this finding: This warning belongs to the ibuprofen in the combination tablet, not to diphenhydramine citrate.

NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke. These can be fatal.

The same label carries a pregnancy warning that singles out 20 weeks of pregnancy as the point after which its ibuprofen component should not be used unless a doctor directs it. (Source 29)

• Official position, Certainty not rated.
• Size: Not applicable - label text.
• Who: People who are pregnant or breast-feeding.
• How long: Not applicable.
• Result: No figures are given; the stated concerns are problems in the unborn child and complications during delivery.
• Funding: not stated.

Limit of this finding: The 20-week warning is about ibuprofen. The label gives no separate pregnancy statement for diphenhydramine citrate beyond asking a health professional first.

ask a health professional before use. It is especially important not to use ibuprofen at 20 weeks or later in pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery.

The same label tells people to stop and ask a doctor if sleeplessness lasts more than two weeks, because persistent insomnia can be a symptom of something else. (Source 30)

• Official position, Certainty not rated.
• Size: Not applicable - label text.
• Who: Adults and children 12 years and over, the labelled population.
• How long: More than 2 weeks of continuous sleeplessness.
• Result: No figures; the label frames continuing insomnia as a reason to stop self-treating.
• Funding: not stated.

sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of a serious underlying medical illness.

In overdose the label records that antihistamine effects can go either way, from central nervous system depression to stimulation, and that stimulation is the more likely direction in children. (Source 31)

• Official position, Certainty not rated.
• Size: Not applicable - label text.
• Who: People who have taken an overdose, children specifically named.
• How long: Not applicable.
• Result: The label also lists atropine-like signs: dry mouth; fixed, dilated pupils; flushing, and gastrointestinal symptoms.
• Funding: not stated.

Limit of this finding: This is the label for diphenhydramine hydrochloride given by injection, not the oral citrate. Note also that the label's own text prints one sentence of this section with its spaces missing, as 'Stimulantsshould notbe used.', because the label italicises 'Stimulants' and prints 'not' in bold and leaves no space outside either; the words the labeller intended are 'Stimulants should not be used.' We have left the published text alone, and the emphasis the label puts on 'not' is the point of the sentence.

Antihistamine overdosage reactions may vary from central nervous system depression to stimulation. Stimulation is particularly likely in pediatric patients.

What the evidence supports

A Cochrane review of antihistamine monotherapy for the common cold found a small benefit on overall symptom severity on the first one or two days of treatment only. (Source 5)

• Systematic review, Certainty not rated.
• Size: 18 RCTs, 4342 participants (212 of them children)
• Who: Adults and children with naturally occurring or experimentally induced common cold.
• How long: One to ten days.
• Result: 45% had a beneficial effect with antihistamines versus 38% with placebo on day one or two; OR 0.74, 95% CI 0.60 to 0.92.
• Funding: not stated in the abstract.

In adults there was a short-term beneficial effect of antihistamines on severity of overall symptoms: on day one or two of treatment 45% had a beneficial effect with antihistamines versus 38% with placebo (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.60 to 0.92).

What the evidence does not support

The same Cochrane review found no difference from placebo beyond the first two days. (Source 5)

• Systematic review, Certainty not rated.
• Size: 18 RCTs, 4342 participants.
• Who: Adults and children with the common cold.
• How long: Three to ten days.
• Result: No difference between antihistamines and placebo at three to four days or at six to ten days.
• Funding: not stated in the abstract.

However, there was no difference between antihistamines and placebo in the mid term (three to four days) to long term (six to 10 days).

Cochrane judged the effect of sedating antihistamines on individual cold symptoms to be statistically detectable but not clinically meaningful. (Source 32)

• Systematic review, Certainty not rated.
• Size: 18 RCTs, 4342 participants.
• Who: Adults with the common cold.
• How long: Up to ten days.
• Result: Rhinorrhoea day three mean difference -0.23, 95% CI -0.39 to -0.06 on a four- or five-point scale; sneezing day three MD -0.35, 95% CI -0.49 to -0.20 on a four-point scale, described by the reviewers as clinically non-significant.
• Funding: not stated in the abstract.

There is no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing.

Cochrane found no evidence that antihistamines work for colds in children. (Source 32)

• Systematic review, Certainty not rated.
• Size: Two of the 18 trials included children; 212 children in total.
• Who: Children with the common cold.
• How long: Up to ten days.
• Result: Results of the two paediatric trials were conflicting.
• Funding: not stated in the abstract.

There is no evidence of effectiveness of antihistamines in children.

A systematic review of randomised placebo-controlled trials of over-the-counter sleep aids concluded that diphenhydramine lacks robust evidence of efficacy and safety. (Source 2)

• Systematic review, Certainty not rated.
• Size: Three diphenhydramine studies among 18 trials of OTC agents.
• Who: Healthy adults with or without occasional disturbed sleep, and adults with diagnosed insomnia.
• How long: Trials published 2003 to July 2014.
• Result: Diphenhydramine, immediate-release melatonin and valerian all showed only limited beneficial effects.
• Funding: not stated in the abstract.

In contrast, the clinical trial data for diphenhydramine, immediate-release melatonin, and valerian suggested limited beneficial effects.

The same review's conclusion names diphenhydramine specifically as lacking robust evidence. (Source 33)

• Systematic review, Certainty not rated.
• Size: 18 trials of OTC agents, three with diphenhydramine.
• Who: Adults with occasional disturbed sleep or insomnia.
• How long: Trials from 2003 to 2014.
• Result: No quantitative pooled estimate was given; the conclusion is qualitative.
• Funding: not stated in the abstract.

Limit of this finding: The published conclusion misspells the drug as 'diphenhydamine'. We have quoted it as printed rather than silently correcting it.

A review of randomized controlled studies over the past 12 years suggests commonly used OTC sleep-aid agents, especially diphenhydamine and valerian, lack robust clinical evidence supporting efficacy and safety.

Where the evidence is mixed

In a placebo-controlled trial with polysomnography, diphenhydramine improved sleep efficiency by diary but changed nothing that the sleep laboratory measured. (Source 12)

• Randomized trial, Certainty not rated.
• Size: 184 adults (110 women, 74 men), 60 of them randomised to diphenhydramine.
• Who: Adults with mild insomnia recruited at nine US sleep disorders centres.
• How long: Diphenhydramine 50 mg nightly for 14 days followed by placebo for 14 days.
• Result: Significantly greater increases in sleep efficiency and a trend for increased total sleep time versus placebo over the first 14 days, but no significant group difference on any polysomnographic sleep-continuity variable.
• Funding: not stated in the abstract.

There was no significant group difference on any of the sleep continuity variables measured by polysomnography.

Tolerance to the sedating effect of diphenhydramine was complete within three days of twice-daily dosing. (Source 15)

• Randomized trial, Certainty not rated.
• Size: 15 healthy men aged 18 to 50.
• Who: Healthy men.
• How long: Diphenhydramine 50 mg or placebo twice a day for 4 days, randomised double-blind crossover.
• Result: Objective and subjective sleepiness were significantly higher than placebo on day 1; by day 4 they were indistinguishable from placebo, and the performance impairment was completely reversed.
• Funding: Research Support, Non-U.S. Gov't per the PubMed record.

Limit of this finding: This cuts both ways. It is reassuring about next-day impairment on repeated dosing and discouraging about the drug continuing to work as a sleep aid.

By day 4, however, levels of sleepiness on diphenhydramine were indistinguishable from placebo.

A poison-centre case series found serious effects uncommon after unintentional diphenhydramine ingestion by young children below about 7.5 mg/kg. (Source 34)

• Case series, Low certainty.
• Size: 305 of 928 identified cases met inclusion criteria.
• Who: Children under 6 years with acute single unintentional diphenhydramine ingestion, Texas Poison Center Network.
• How long: Cases from 2000 to 2006.
• Result: Of those ingesting less than 7.5 mg/kg, 99.7% (299/300) had no serious clinical effects and needed no critical treatment; two patients had hallucinations.
• Funding: not stated in the abstract.

Limit of this finding: Poison-centre data under-capture severe cases that bypass the call and over-represent reassurance; the authors note only five children ingested more than 7.5 mg/kg, so the series says little about larger doses. The paper also contradicts itself on this figure: the results section says 99.7% (299/300) while its own conclusion says 99.6%. We quote the results section; a reader should not treat the two figures as describing different things.

Of the patients who ingested doses less than 7.5 mg/kg, 99.7% (299/300) did not require critical treatments or were without serious clinical effects.

Where the research disagrees

Whether diphenhydramine works as a hypnotic at all

• Culpepper and Wingertzahn, systematic review of randomised placebo-controlled trials of over-the-counter sleep agents, 2015, systematic review of randomised placebo-controlled trials with objective or next-day participant-reported endpoints: A review of randomized controlled studies over the past 12 years suggests commonly used OTC sleep-aid agents, especially diphenhydamine and valerian, lack robust clinical evidence supporting efficacy and safety. (Source 33)
• Morin and colleagues, multicentre randomised placebo-controlled trial in nine US sleep disorders centres, 2005, randomised, placebo-controlled, parallel-group trial with sleep diaries and polysomnography: Diphenhydramine produced significantly greater increases in sleep efficiency and a trend for increased total sleep time relative to placebo during the first 14 days of treatment. (Source 12)
• The same trial's polysomnography result, which is the objective arm of the same study, polysomnography within a randomised placebo-controlled trial: There was no significant group difference on any of the sleep continuity variables measured by polysomnography. (Source 12)

Whether the sedation that makes it useful as a sleep aid lasts long enough to be useful

• Richardson and colleagues, randomised double-blind crossover trial, 2002, randomised, double-blind, crossover trial with objective and subjective sleepiness measures in 15 healthy men: On this dosing regimen, tolerance was complete by the end of 3 days of administration. (Source 15)
• The US nighttime sleep-aid monograph, a regulatory position carried forward from the 1989 final monograph and current in the Code of Federal Regulations edition revised as of 1 April 2025, regulatory position, not a trial result: Adults and children 12 years of age and over: Oral dosage is 76 milligrams at bedtime if needed, or as directed by a doctor. (Source 35)

How much

• Reference intake: There is no reference intake, because this is a medicine and not a nutrient. How much a person takes is set by the product label or by a prescriber. As a position, the US over-the-counter antihistamine monograph, in the Code of Federal Regulations edition revised as of 1 April 2025, directs 38 to 76 mg every 4 to 6 hours for adults and children 12 and over, and 19 to 38 mg every 4 to 6 hours for children 6 to under 12, with a doctor to be consulted for children under 6. The nighttime sleep-aid monograph separately directs 76 mg at bedtime. For comparison, the same regulation directs 25 to 50 mg for the hydrochloride salt, which is the arithmetic of the salt difference: a citrate milligram is not a hydrochloride milligram. (Source 4)
• Upper limit: There is no toxicological upper limit of the kind set for nutrients. The regulatory ceiling, as a position of the US Food and Drug Administration recorded in the Code of Federal Regulations edition revised as of 1 April 2025, is 456 mg of diphenhydramine citrate in 24 hours for adults and children 12 and over, and 228 mg in 24 hours for children 6 to under 12. The corresponding ceiling for the hydrochloride salt in the same regulation is 300 mg in 24 hours. (Source 4)
• Studied: The driving simulator trial gave a single 50 mg dose of diphenhydramine to 40 licensed drivers with seasonal allergic rhinitis, against fexofenadine 60 mg, alcohol to about 0.1% blood alcohol concentration, and placebo. (Source 17)
• Studied: The tolerance trial gave diphenhydramine 50 mg or placebo twice a day for 4 days to 15 healthy men aged 18 to 50 in a randomised double-blind crossover design. (Source 15)
• Studied: The insomnia trial gave two tablets of diphenhydramine (25 mg) for 14 days followed by placebo for 14 days to 60 of 184 adults with mild insomnia. (Source 12)
• Studied: The bioequivalence modelling work used the marketed bilayer tablet containing ibuprofen 200 mg and diphenhydramine citrate 38 mg; this is the only study we found that is specific to the citrate salt and its dose. (Source 3)
• Studied: The alcohol interaction study gave diphenhydramine 50 mg and alcohol 32 ml alone and in combination to twelve healthy volunteers in a double-blind randomised crossover design. (Source 7)

A common belief, and what the research shows

The belief: Diphenhydramine citrate and diphenhydramine hydrochloride are interchangeable milligram for milligram, so 38 mg of the citrate in a night-time painkiller is a small dose.

What the research shows: They are not interchangeable by weight, because the citrate is the larger molecule and so carries less diphenhydramine per milligram. The regulator's own dosing reflects this. For over-the-counter antihistamine use the monograph directs, for the citrate, 'Adults and children 12 years of age and over: oral dosage is 38 to 76 milligrams every 4 to 6 hours, not to exceed 456 milligrams in 24 hours, or as directed by a doctor.' For the hydrochloride in the same regulation it directs 'Adults and children 12 years of age and over: oral dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300 milligrams in 24 hours, or as directed by a doctor.' The nighttime sleep-aid monograph pairs them the same way: 'Adults and children 12 years of age and over: Oral dosage is 76 milligrams at bedtime if needed, or as directed by a doctor.' for the citrate against 'Adults and children 12 years of age and over: Oral dosage is 50 milligrams at bedtime if needed, or as directed by a doctor.' for the hydrochloride. So 38 mg of the citrate is the regulator's equivalent of 25 mg of the hydrochloride, not of 38 mg of it. A second misconception sits on top of the first: that you can tell when you are too sedated to drive. The driving simulator trial found that 'Drowsiness ratings were not a good predictor of impairment, suggesting that drivers cannot use drowsiness to indicate when they should not drive.'

Questions and answers

What is it?

Diphenhydramine citrate is the citrate salt of diphenhydramine, a first-generation sedating antihistamine. It is the salt chosen for night-time analgesic and sleep-aid combinations rather than the hydrochloride found in most stand-alone products. Pharmacologically it is a histamine H1 receptor drug with pronounced central nervous system depressant effects. (Source 3)

What does it do in the body?

It occupies the histamine H1 receptor. Current pharmacology describes drugs of this class as inverse agonists rather than blockers: they hold the receptor in its inactive state and so damp the itch, sneezing, runny nose and leaky capillaries that histamine drives. Because it is fat-soluble it also enters the brain, which is why it sedates, and it blocks muscarinic receptors, which is where dry mouth, blurred vision and confusion come from. (Source 1)

Is it good or bad for you?

It depends entirely on the setting, and the balance is less favourable than its over-the-counter status suggests. For occasional sleeplessness a systematic review of randomised trials found it lacks robust evidence of benefit. For colds Cochrane found a day-one-and-two effect only. Against that, a driving simulator trial found it impaired driving more than alcohol, and in older adults the observational evidence links the class to delirium, falls and fractures. (Source 33)

How do you get more of it?

It is not a nutrient and there is no reason to seek more of it. It is sold without prescription, and the US OTC monograph sets the amount permitted for the citrate salt at 38 to 76 mg every four to six hours, with a daily ceiling of 456 mg. That is a regulatory position dating from the monograph, not a recommendation, and the amount anyone should take is a matter for a prescriber or pharmacist. (Source 4)

If it is harmful, what reduces it?

The drug clears itself; its antihistamine effect lasts up to about six hours. Where it has caused harm, management is supportive and specific to the harm: a published case series describes diphenhydramine overdose producing a wide-complex cardiac rhythm from sodium channel blockade that responded to hypertonic sodium bicarbonate. Reducing anticholinergic load generally means stopping or substituting the drug, which is a clinical decision. (Source 20)

Why might someone be low in it or missing it?

Does not apply. Diphenhydramine citrate is a manufactured medicine, not something the body makes or needs, so there is no deficiency state and no reason anyone would be low in it. The only sense in which someone can be without it is that they are not taking it. (Source 4)

We searched: We searched PubMed and Europe PMC for diphenhydramine deficiency, endogenous diphenhydramine and dietary diphenhydramine and found nothing, which is expected for a synthetic drug. The regulatory record treats it purely as a manufactured active ingredient with a labelled dose.

Which whole foods contain it or feed it?

Does not apply. No whole food contains diphenhydramine citrate. It reaches people only as a manufactured over-the-counter medicine, listed in the US regulations as an antihistamine active ingredient with a set dosage. (Source 4)

We searched: We searched PubMed and Europe PMC for dietary and food sources of diphenhydramine and found no reports of natural occurrence in food. The only sourcing in the record is pharmaceutical.

What happens if you do not have it?

Nothing happens that matters to health. It is not required for any body function. Not taking it for a cold means forgoing an effect Cochrane judged clinically insignificant for nasal obstruction, runny nose and sneezing, and for sleep it means forgoing a benefit a systematic review found poorly supported. (Source 32)

How can you test for it?

There is no routine clinical test, and none is needed. Blood concentrations can be measured in pharmacokinetic research and in post-mortem toxicology, but these are research and forensic tools rather than tests a member would have. The gaps extend to the labels themselves: the prescribing information for diphenhydramine hydrochloride injection states that detailed pharmacokinetic information for that product is not available. (Source 36)

We searched: We searched PubMed and Europe PMC for diphenhydramine therapeutic drug monitoring and plasma concentration assays and found pharmacokinetic and forensic studies but no validated clinical monitoring test.

References

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