Diphenhydramine hydrochloride

What it is

Diphenhydramine hydrochloride is the hydrochloride salt of diphenhydramine, a first-generation ethanolamine H1-antihistamine introduced in 1946. The prescription injection label gives its chemical name as 2-(Diphenylmethoxy)-N,N-dimethylethylamine hydrochloride, formula C17H21NO HCl, molecular weight 291.82, and describes it as a white crystalline powder freely soluble in water and alcohol. It is the salt form in nearly every consumer product: 25 mg or 50 mg oral capsules and tablets, liquids for children, nighttime sleep aids, and a 50 mg/mL solution for intravenous or deep intramuscular use. Because it crosses into the brain and also blocks muscarinic receptors, it is sedating and drying as well as antihistaminic.

What the research says

The honest summary is that diphenhydramine does several things reliably and few of them are the things it is most used for. It blocks H1 receptors, so it suppresses the histamine weal, and it blocks them in the brain too, so it sedates. For hay fever and urticaria that is a real pharmacological effect, but a 2025 World Allergy Organization Journal review argues second-generation antihistamines match its efficacy with fewer adverse effects. For sleep, a 1,295-patient postpartum trial from 1978 found it beat placebo, a 2005 multicentre trial found only a modest effect with few comparisons reaching significance, and a controlled crossover found tolerance to its sedative effect was complete after three days of twice-daily dosing. For anaphylaxis, where it is on the label as an adjunct, a Cochrane review found no eligible trials at all. For acute cough and for the common cold, Cochrane reviews found antihistamines no better than placebo in children and clinically insignificant in adults. For acute migraine as an add-on to metoclopramide, a randomised trial was stopped for futility. Against that, the harm literature is large and consistent: it impaired driving more than alcohol did in a simulator trial, it tripled inattention in hospitalised older patients, cumulative anticholinergic exposure tracks with incident dementia in a long cohort, it was the most frequent index ingredient in paediatric cough-and-cold fatalities, and it is both abused and used in suicide with sodium-channel-blocking cardiotoxicity in overdose.

Evidence grade: Disputed.

How it works

Drug class: First-generation ethanolamine H1-receptor antagonist (antihistamine) with anticholinergic activity

Diphenhydramine competes with histamine for H1 receptors on the cells histamine acts on, which blunts itch, weal, sneezing and runny nose. It is also an anticholinergic, which produces the dryness, and it crosses into the central nervous system, which produces the sedation. The label states that it is widely distributed throughout the body including the central nervous system, that part of the drug is excreted unchanged in the urine and the rest metabolised by the liver. (Source 1)

What it is used for

• The peripheral antihistamine effect is real: in a controlled comparison of six H1-antagonists, every drug tested including diphenhydramine significantly suppressed the histamine-induced weal. Whether it is the right antihistamine is the contested part, because a 2025 review in the World Allergy Organization Journal argues second-generation agents match its efficacy with fewer adverse effects and should replace it. Evidence: established. (Source 2)
• The injection label lists anaphylaxis adjunct and allergic reactions to blood or plasma among its indications, but a Cochrane systematic review searching five databases plus pharmaceutical companies and international experts found no randomised or quasi-randomised trial of H1-antihistamines in anaphylaxis at all. The label position and the trial evidence are therefore not the same thing. Evidence: disputed. (Source 3)
• A 1,295-patient postpartum double-blind study found 12.5, 25 and 50 mg all beat placebo on sleep latency, duration, night awakening, global evaluation and morning alertness, with little gain from higher doses. A 184-patient multicentre placebo-controlled trial found only modest subjective improvement, significantly greater sleep efficiency over the first 14 days but no significant difference on any polysomnographic sleep continuity variable. And a crossover trial found tolerance to the sedative effect was complete by the end of three days of twice-daily dosing. Evidence: limited. (Source 4)
• The over-the-counter label claims relief of runny nose and sneezing due to the common cold. A Cochrane review of 18 trials in 4,342 participants found a short-term benefit on overall symptom severity on day one or two (45% with antihistamines versus 38% with placebo, odds ratio 0.74, 95% CI 0.60 to 0.92) but no difference beyond that, and judged the effect on individual symptoms clinically non-significant, with no evidence of effectiveness in children. Evidence: limited. (Source 5)
• A Cochrane review of 29 placebo-controlled trials in 4,835 people found three adult trials in which antihistamines were no more effective than placebo for cough symptoms and found antihistamines no more effective than placebo in children. Its authors concluded there is no good evidence for or against over-the-counter medicines in acute cough, and specifically flagged antihistamines in children as drugs with the potential to cause serious harm. Evidence: not-supported. (Source 6)
• The injection label lists active treatment of motion sickness as an indication. The comparative trial evidence is weak: a Cochrane review of scopolamine for motion sickness found that comparisons with other agents were few, suggested scopolamine was equivalent to antihistamines, and concluded that no conclusions can be made on the comparative effectiveness of scopolamine and other agents such as antihistamines. Evidence: limited. (Source 3)
• This is a long-standing label indication for the injectable form when oral therapy is impossible or contraindicated. We found no controlled trial of diphenhydramine in parkinsonism in our searches, so this is a regulatory position carried forward rather than a current evidence base, and it sits uneasily beside the cohort evidence on anticholinergic exposure and cognition in older people. Evidence: unknown. (Source 3)
• A randomised double-blind trial in 208 patients was halted for futility at the planned interim analysis: 40% of patients given intravenous diphenhydramine 50 mg plus metoclopramide had sustained headache relief at 48 hours versus 37% given placebo plus metoclopramide, a 3% difference with a 95% confidence interval of -10% to 16%. Evidence: not-supported. (Source 7)
• In a double-blind randomised study of 96 children having magnetic resonance imaging, adding oral diphenhydramine 1.25 mg/kg to midazolam 0.5 mg/kg cut inadequate sedation from 20 of 49 children (41%) to 9 of 50 (18%), p<0.01, without lengthening recovery. One small single-centre trial is not a literature. Evidence: limited. (Source 8)
• The prescription label explicitly contraindicates this because of necrosis risk, and separately records that local necrosis has been associated with subcutaneous or intradermal use of intravenous diphenhydramine. Evidence: not-supported. (Source 9)

Interactions

• Alcohol (label): Drowsiness adds up. The prescription label records an additive effect with alcohol, and the over-the-counter label tells users to avoid alcoholic drinks. This matters more than it sounds because in the simulator trial diphenhydramine alone impaired driving more than alcohol alone did. (Source 10)
• Monoamine oxidase inhibitors (MAOIs) (label): MAO inhibitors prolong and intensify the drying anticholinergic effects, which is the label's stated basis for caution rather than a pharmacokinetic study. (Source 10)
• Metoprolol and other CYP2D6 substrates with a narrow therapeutic index (pharmacokinetic study): Diphenhydramine inhibits CYP2D6, so drugs cleared by that enzyme build up. In 16 healthy men it halved metoprolol clearance in extensive metabolisers and prolonged metoprolol's effects on heart rate, systolic blood pressure and aortic blood flow peak velocity, with no effect in poor metabolisers. (Source 11)
• Sedatives, tranquillisers and other CNS depressants (label): The over-the-counter label asks for a pharmacist or doctor check before use with sedatives or tranquillisers, and warns that these increase drowsiness. (Source 12)
• Other diphenhydramine-containing products, including creams and gels applied to the skin (label): Diphenhydramine appears in more than 300 formulations, and doubling up is the commonest way to exceed the dose by accident. The label says plainly not to combine products, naming topical ones specifically. (Source 12)
• Valerian (theoretical): Taken for the same purpose and at the same time of night as diphenhydramine. In the one trial that ran them as separate arms, valerian-hops and diphenhydramine each produced only modest subjective improvement over placebo, and no interaction between them was tested because no combined arm existed. The herbal-sedative literature flags herb-drug interactions as a possibility for some sedative species rather than a documented event. (Source 13)
• Kava (theoretical): A sedating herb whose safety record is the concerning one in this group. We found no study of kava combined with diphenhydramine, so any additive sedation is inferred from the shared pharmacology rather than measured. (Source 13)
• St John's wort (theoretical): Named in the herbal-sedative literature as the species for which herb-drug interactions are a real possibility, through its effects on drug metabolism. We found no study of it with diphenhydramine specifically, so this is a theoretical concern carried over from its behaviour with other drugs. (Source 13)
• Dimenhydrinate (sold for motion sickness) (pharmacokinetic study): Dimenhydrinate is a theoclate salt of diphenhydramine, so taking both means taking diphenhydramine twice. A kinetic study in 8 volunteers measured plasma diphenhydramine after dimenhydrinate given orally, sublingually and intravenously, confirming it delivers diphenhydramine systemically. (Source 14)

Stopping it

• There is no withdrawal syndrome described for diphenhydramine, but there is something arguably more important for anyone using it to sleep: tolerance to the sedative effect develops within days. In a randomised double-blind crossover in 15 healthy men taking 50 mg twice a day, sleepiness and performance impairment were significant on day 1 and had returned to placebo levels by day 4. (Source 15)
• The same study's authors noted the speed of this with some emphasis, which bears on how long any sleep benefit can last. (Source 15)
• Stopping after 14 nights of 50 mg did not produce rebound insomnia in the one trial that looked: in 184 adults with mild insomnia there were no significant residual effects, no serious adverse events and no rebound insomnia following discontinuation. (Source 16)
• The trialists restated that in their conclusions, which is the strongest reassurance available on stopping, from a single 28-day trial in mild insomnia. (Source 17)
• On deliberate deprescribing of anticholinergics in older people, the Cochrane evidence is thin rather than reassuring: three trials in 299 participants gave very low certainty results, and the reviewers could neither support nor refute the idea that stopping these drugs improves cognition. (Source 18)

What goes wrong

In a simulator trial, driving performance was poorest after diphenhydramine, worse than after alcohol taken to roughly 0.1% blood alcohol concentration, and the participants' own drowsiness ratings did not predict their impairment. (Source 19)

• Randomized trial, Moderate certainty.
• Size: 40 licensed drivers aged 25 to 44.
• Who: Licensed drivers with seasonal allergic rhinitis.
• How long: Single dose, four-treatment four-period crossover, 1 hour of driving per session at weekly intervals.
• Result: Lane keeping (steering instability and crossing the centre line) impaired after alcohol and diphenhydramine 50 mg compared with fexofenadine; mean response time to a blocking vehicle slowest after alcohol (2.21 seconds) versus fexofenadine (1.95 seconds); self-reported drowsiness did not predict lack of coherence.
• Funding: not stated in the abstract; the trial received NCRR NIH support per the PubMed grant record.

After participants took diphenhydramine, driving performance was poorest, indicating that diphenhydramine had a greater impact on driving than alcohol did. 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 a 1.7-fold risk of any delirium symptom and a 3-fold risk of inattention, with a dose-response relationship, and a quarter of the doses given were judged inappropriate. (Source 20)

• Cohort study, Low certainty.
• Size: 426 hospitalised medical patients aged 70 years or older, of whom 114 (27%) received diphenhydramine.
• Who: Hospitalised medical patients aged 70 or older at a university hospital.
• How long: Daily assessments during hospitalisation.
• Result: Any delirium symptoms relative risk 1.7 (95% CI 1.3-2.3); inattention RR 3.0 (95% CI 1.5-5.9); disorganised speech RR 5.5 (95% CI 1.0-29.8); altered consciousness RR 3.1 (95% CI 1.6-6.1); urinary catheter placement RR 2.5 (95% CI 1.0-6.0); median length of stay 7 versus 6 days (P=.009); 24% of doses administered inappropriately.
• Funding: not stated.

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) and for individual delirium symptoms, including inattention (RR, 3.0; 95% CI, 1.5-5.9), disorganized speech (RR, 5.5; 95% CI, 1.0-29.8), and altered consciousness (RR, 3.1; 95% CI, 1.6-6.1).

The authors of that cohort concluded diphenhydramine use in older hospitalised patients is associated with increased risk of cognitive decline and other adverse effects with a dose-response relationship. It is a cohort study, so this is an association and not proof of cause. (Source 21)

• Cohort study, Low certainty.
• Size: 426 patients, 114 exposed.
• Who: Hospitalised medical patients aged 70 or older.
• How long: During hospitalisation.
• Result: See the Results reference for the relative risks; the abstract states a dose-response relationship was demonstrated for most adverse outcomes.
• Funding: not stated.

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

In a population-based cohort followed for a mean of 7.3 years, higher cumulative anticholinergic exposure tracked with incident dementia, and first-generation antihistamines were among the three most commonly used anticholinergic classes. This is an association across a drug class, not a demonstration that diphenhydramine causes dementia. (Source 22)

• Cohort study, Low certainty.
• Size: 3,434 participants aged 65 or older with no dementia at entry; 797 (23.2%) developed dementia.
• Who: Members of an integrated health care delivery system in Seattle, Washington, aged 65 or older.
• How long: Mean follow-up 7.3 years; exposure measured as total standardised daily doses dispensed over 10 years, excluding the most recent 12 months.
• Result: Adjusted hazard ratios for dementia versus non-use: 0.92 (95% CI 0.74-1.16) for 1 to 90 total standardised daily doses; 1.19 (95% CI 0.94-1.51) for 91 to 365; 1.23 (95% CI 0.94-1.62) for 366 to 1095; 1.54 (95% CI 1.21-1.96) for more than 1095; test for trend P < .001; 637 of 797 dementia cases (79.9%) were Alzheimer disease.
• Funding: US National Institutes of Health including National Institute on Aging support per the PubMed grant record.

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.

The authors of the dementia cohort stated their finding as an association and called for awareness rather than claiming causation; the study's own framing is that anticholinergic cognitive impairment had generally been considered reversible. (Source 23)

• Cohort study, Low certainty.
• Size: 3,434 participants.
• Who: Community-dwelling older adults.
• How long: Data through 30 September 2012.
• Result: See the Results reference for the hazard ratios; the abstract records that results were robust in secondary, sensitivity and post hoc analyses.
• Funding: US National Institutes of Health support per the PubMed grant record.

Limit of this finding: This is an observational study of older adults, so it can show that heavier anticholinergic use went together with more dementia, but it cannot show that the drugs caused it; the authors' own word is 'associated'. The sentence quoted here also carries no numbers. In the study's results, only the heaviest exposure group had a risk estimate whose confidence interval excluded no effect; the three lighter groups did not. First-generation antihistamines were one of three common drug types in the exposure measure, so this is not a study of diphenhydramine alone.

Higher cumulative anticholinergic use is associated with an increased risk for dementia.

The dementia cohort was a prospective population-based study, which is its strength, and an observational design, which is its limit; the exposure was measured from pharmacy dispensing records rather than from what people actually swallowed. (Source 24)

• Cohort study, Low certainty.
• Size: 3,434 participants 65 years or older with no dementia at study entry.
• Who: Adult Changes in Thought study participants in Group Health, Seattle.
• How long: Recruitment 1994-1996 and 2000-2003, follow-up every 2 years, data through September 2012.
• Result: No effect estimate in this section; it records the design, the setting and the follow-up interval.
• Funding: US National Institutes of Health support per the PubMed grant record.

Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington.

Diphenhydramine was the index ingredient in 28 of 40 (70%) paediatric deaths judged related or potentially related to over-the-counter cough and cold medications, and most of those deaths followed deliberate non-therapeutic administration by a caregiver, including 7 cases where the medicine was used to sedate the child. (Source 25)

• Case series, Low certainty.
• Size: 180 eligible fatalities reviewed; 40 judged related or potentially related.
• Who: Children under 12 years old, United States, 2008 to 2016.
• How long: Surveillance over 9 years.
• Result: 40 of 180 fatalities judged related or potentially related; 24 of 40 (60.0%) in children under 2 years; 22 of 40 (55.0%) involved nontherapeutic intent; diphenhydramine the most frequent index ingredient in 28 of 40 (70.0%); 6 of 40 (15.0%) administered to murder the child; 7 of 40 (17.5%) deaths followed intentional use to sedate the child.
• Funding: Authors were Denver Health employees; several report grants from the Consumer Healthcare Products Association outside the submitted work per the conflict of interest statement.

Limit of this finding: Every percentage here has 40 as its denominator, the deaths judged related or potentially related, not the 180 fatalities reviewed. Most of these deaths followed a caregiver deliberately giving the medicine for a non-therapeutic reason, including to sedate or to kill the child, so the series describes misuse and not the risk of a labelled dose. Several authors report funding from the industry trade association.

The most frequently involved index ingredient was diphenhydramine (n = 28; 70.0%).

Across a multisystem paediatric surveillance programme, the overall adverse-event rate for cough and cold ingredients was low in absolute terms, but tachycardia, somnolence, hallucinations, ataxia, mydriasis and agitation each occurred in more than 20% of cases, and no fatality involved a therapeutic dose. (Source 26)

• Case series, Low certainty.
• Size: 4,202 cases reviewed; 3,251 (77.4%) at least potentially related.
• Who: Children under 12 years of age.
• How long: Five data sources, expert panel adjudication.
• Result: Accidental unsupervised ingestions 67.1% and medication errors 13.0%; adverse events in more than 20% of cases were tachycardia, somnolence, hallucinations, ataxia, mydriasis and agitation; 20 cases (0.6%) resulted in death, 70.0% of them in children under 2; overall reported adverse-event rate 0.573 cases per 1 million units sold (95% CI 0.553-0.593), or 1 case per 1.75 million units.
• Funding: Several authors have received grant funding or fees from the Consumer Healthcare Products Association per the conflict of interest statement.

Limit of this finding: The '>20%' threshold is the source's own published figure, confirmed in the publisher's full text, and it is a surprising one: six separate adverse events each in more than a fifth of cases. These are cases reported to poison centres and surveillance systems, overwhelmingly accidental ingestions by unsupervised children rather than labelled doses, so the percentages describe what happens in reported incidents and are not a side-effect rate for ordinary use. Several authors report funding from the industry trade association.

AEs occurring in >20% of all cases included tachycardia, somnolence, hallucinations, ataxia, mydriasis, and agitation. Twenty cases (0.6%) resulted in death; most were in children <2 years of age (70.0%) and none involved a therapeutic dose.

The US Food and Drug Administration's position, current as of 8 February 2018, is that children under 2 should not be given any cough and cold product containing an antihistamine, and it names convulsions, rapid heart rates and death among reported side effects. (Source 27)

• Official position, Certainty not rated.
• Size: Not applicable; the page cites an estimated 1,519 children under 2 treated in US emergency departments during 2004-2005.
• Who: Children under 2 years of age.
• How long: Not applicable.
• Result: No rate per exposure given; the page reports an estimated 1,519 children less than 2 years of age treated in US emergency departments for adverse events during 2004-2005.
• Funding: US government agency.

Children under 2 years of age should not be given any kind of cough and cold product that contains a decongestant or antihistamine because serious and possibly life-threatening side effects could occur. Reported side effects of these products included convulsions, rapid heart rates and death.

A forensic series of 68 non-fatal and 55 fatal diphenhydramine poisonings concluded the drug is not less poisonous than other prescribed hypnotics; the authors describe a blood concentration above 5 mcg/mL as potentially lethal, but their own survivors reached 8.9 mcg/mL. (Source 28)

• Case series, Low certainty.
• Size: 68 non-fatal and 55 fatal poisonings.
• Who: Cases investigated at one institute of legal medicine, 1992 to 2004.
• How long: 12 years of casework.
• Result: Diphenhydramine concentrations 0.5 to 8.9 mcg/mL in non-fatal cases and 0.3 to 119 mcg/mL in fatal cases; a concentration above 5 mcg/mL regarded as potentially lethal; rhabdomyolysis in three cases; symptoms ranged from somnolence and sedation to tachycardia, anticholinergic syndrome, agitation, hallucinations, confusion, tremor, convulsions, delirium and coma.
• Funding: not stated.

Limit of this finding: The paper's own two numbers do not line up. It calls a blood concentration above 5 mcg/mL potentially lethal, yet the people who survived in the same series had concentrations ranging up to 8.9 mcg/mL, and some who died had as little as 0.3 mcg/mL. So 5 mcg/mL is a level of concern, not a dividing line: a single blood level cannot tell anyone whether a poisoning will be fatal. This is also casework from one legal-medicine institute, with many cases involving other drugs alongside diphenhydramine, so it says nothing about how often any of this happens.

From the results it follows that diphenhydramine is not less poisonous than other prescribed hypnotics.

Deaths from diphenhydramine alone are recorded across all ages including infants, and the lethal blood concentrations in infants were far lower than in adults. (Source 29)

• Case series, Very low certainty.
• Size: Deaths from two data sources: English-language literature 1946-2003 and US poison centre annual reports 1983-2002.
• Who: Infants, children and adults.
• How long: 57 years of literature and 20 years of surveillance data.
• Result: Mean diphenhydramine level 19.53 mg/L (range 0.087-48.5) in adults at mean age 35.6 years; 7.4 mg/L (1.3-13.7) in children at mean age 8.6 years; 1.53 mg/L (1.1-2.2) in infants at mean age 31 weeks; 6 infant homicides reported; commonest symptoms cardiac dysrhythmias, seizure activity and sympathetic pupil responses.
• Funding: not stated.

Combined results from both data sets show the following mean (and range) for age and DPH levels: Adult, 35.6 years (18-84) and 19.53 mg/L (0.087-48.5); pediatric, 8.6 years (1.25-17) and 7.4 mg/L (1.3-13.7); infant, 31 weeks (6 weeks-11 months) and 1.53 mg/L (1.1-2.2), respectively.

A 14-year-old girl died after taking diphenhydramine as part of a social-media challenge, with a postmortem femoral blood concentration of 49,658 ng/mL. (Source 30)

• Case report, Very low certainty.
• Size: 1 case.
• Who: A 14-year-old girl.
• How long: Single acute ingestion.
• Result: Postmortem femoral blood diphenhydramine 49,658 ng/mL; autopsy showed marked bilateral pulmonary congestion and oedema and bright pink granular material in the oesophagus, stomach, duodenum and proximal jejunum.
• Funding: not stated.

A postmortem femoral blood sample result identified a lethal blood concentration of diphenhydramine (49,658 ng/ml).

Massive diphenhydramine overdose produces sodium-channel-blocking cardiotoxicity; in one case a new left bundle branch block appeared and resolved after sodium bicarbonate. (Source 31)

• Case report, Very low certainty.
• Size: 1 case.
• Who: A 35-year-old woman who ingested 100 tablets of diphenhydramine 25 mg (46 mg/kg) with alcohol.
• How long: Single acute ingestion.
• Result: Whole blood diphenhydramine 7,324.9 ng/mL at six hours (stated therapeutic range 25-112 ng/mL); two generalized tonic-clonic seizures; PR interval 54 ms, QRS duration 152 ms with new left bundle branch block; hypokalaemia 2.3 mmol/L; lactate 10.4 mmol/L; serum ethanol 187 mg/dL; resolution after 150 mEq sodium bicarbonate.
• Funding: The authors declare no competing financial interests or personal relationships.

Limit of this finding: One case, and one of its numbers cannot be right as printed: a PR interval of 54 ms is close to physiologically impossible (the normal range is about 120 to 200 ms) and is almost certainly a misprint for 154 ms, alongside the QRS of 152 ms. The figure was checked against the publisher's own full text and it really is what the paper prints. The authors' closing suggestion that sodium bicarbonate is the treatment is their inference from this single patient, not a tested recommendation.

A whole blood diphenhydramine concentration, taken six hours post-presentation, was elevated at 7324.9 ng/mL (therapeutic levels: 25-112 ng/mL).

Diphenhydramine is one of the two most-studied over-the-counter drugs in the misuse literature, with adolescents and young adults named as vulnerable groups. (Source 32)

• Systematic review, Low certainty.
• Size: 92 articles taken into consideration; 12 of them focused on diphenhydramine.
• Who: Case reports, surveys and retrospective case series of over-the-counter drug misuse.
• How long: Literature review registered as PROSPERO CRD42020209261.
• Result: Of 92 included articles, 54 focused on dextromethorphan and 12 on diphenhydramine; no prevalence estimate could be given because of a lack of appropriate monitoring systems.
• Funding: One author was a member of the UK Advisory Council on the Misuse of Drugs and is a member of an EMA Advisory Board; other authors declare consultancy, speaker and research grant relationships with multiple pharmaceutical companies.

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

The prescription label lists the drug's adverse reactions by body system, and the genitourinary and nervous-system lists are where the anticholinergic burden shows: urinary retention, blurred vision, confusion, tinnitus and convulsions are all listed, none of them among the six reactions the label marks as its most frequent. (Source 33)

• Official position, Certainty not rated.
• Size: Not applicable (label listing)
• Who: Patients receiving diphenhydramine hydrochloride injection.
• How long: Not applicable.
• Result: The label gives no rates. It marks its most frequent reactions in italics, and only six carry that mark: Sedation, sleepiness, dizziness and disturbed coordination under Nervous System, Epigastric distress under Gastrointestinal System, and Thickening of bronchial secretions under Respiratory System. Convulsions, agranulocytosis, hemolytic anemia, anaphylactic shock and urinary retention are listed but not marked, so the label does not present them as frequent.
• Funding: not stated (manufacturer label)

Limit of this finding: This label marks its most frequent reactions in italics rather than giving numbers, and italics do not survive into plain text. Only six reactions are marked: sedation, sleepiness, dizziness, disturbed coordination, epigastric distress and thickening of bronchial secretions. The serious items in the same lists, such as convulsions, agranulocytosis and anaphylactic shock, are not marked as frequent. Read the long lists as everything that has been reported, in no order of likelihood, and not as a list of common effects.

Urinary frequency, difficult urination, urinary retention, early menses.

The label warns that antihistamines should be used with considerable caution in narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy or bladder-neck obstruction, and that older patients are more likely to get dizziness, sedation and hypotension. (Source 34)

• Official position, Certainty not rated.
• Size: Not applicable (label warning)
• Who: Patients with the listed conditions, children, and people approximately 60 years or older.
• How long: Not applicable.
• Result: No rates given; in pediatric patients the label states antihistamines in overdosage may cause hallucinations, convulsions or death, and that in young children they may produce excitation.
• Funding: not stated (manufacturer label)

Limit of this finding: The label's own sentence about local necrosis reads 'associated with the use of subcutaneous or intradermal use of intravenous diphenhydramine', which repeats 'use of' and describes giving an intravenous product by a different route. That is how the approved label prints it and it is kept unaltered here; the point it is making is that injecting this product under or into the skin has caused tissue death.

Antihistamines should be used with considerable caution in patients with narrow-angle glaucoma, stenosing peptic ulcer, pyloroduodenal obstruction, symptomatic prostatic hypertrophy or bladder-neck obstruction.

Histamine H1 receptor antagonists are among the drug classes reported to induce or precipitate acute angle-closure glaucoma in people whose anterior chamber angles are already narrow, and bilateral involvement and even blindness have occurred with drug-induced glaucoma. (Source 35)

• Expert review, not systematic, Very low certainty.
• Size: Not applicable (review); the review states the incidence of drug-induced glaucoma is uncertain.
• Who: People predisposed with narrow angles of the anterior chamber.
• How long: Not applicable.
• Result: No incidence figures; the review states the incidence of drug-induced glaucoma is uncertain despite a high worldwide prevalence of glaucoma.
• Funding: not stated.

Several classes of drugs, including adrenergic agonists, cholinergics, anticholinergics, sulpha-based drugs, selective serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, anticoagulants and histamine H(1) and H(2) receptor antagonists, have been reported to induce or precipitate acute angle-closure glaucoma, especially in individuals predisposed with narrow angles of the anterior chamber.

At 75 mg, diphenhydramine impaired psychomotor performance in healthy elderly volunteers to about the same degree as temazepam 15 mg, and raising the dose from 50 to 75 mg bought no extra sedation. (Source 36)

• Randomized trial, Low certainty.
• Size: 14 healthy elderly volunteers (mean age 71.6 years, range 65-89)
• Who: Healthy older adults.
• How long: Single doses, double-blind randomised crossover, assessments to 8 hours post-dose.
• Result: Both doses of diphenhydramine (50 and 75 mg) elicited significantly greater sedation than placebo (p<0.05); no difference in sedation between 50 and 75 mg; psychomotor impairment on manual tracking after 75 mg versus placebo (p<0.05), less than with temazepam 30 mg (p<0.001) but similar to temazepam 15 mg (non-significant); no psychomotor impairment detected with 50 mg.
• Funding: not stated.

Psychomotor impairment was evident after administration of 75 mg diphenhydramine in comparison with placebo on the manual tracking test (p < 0.05); this was less than the impairment with 30 mg temazepam (p < 0.001) but similar to that with 15 mg temazepam (NS).

A 2025 review argued that diphenhydramine's therapeutic ratio is poor enough that it should no longer be widely prescribed or remain readily available over the counter, noting Germany and Sweden have restricted access to first-generation antihistamines. (Source 37)

• Expert review, not systematic, Low certainty.
• Size: Not applicable (narrative review of practice patterns and adverse-event prevalence)
• Who: Children and older adults identified as the higher-risk groups.
• How long: Not applicable.
• Result: No pooled effect estimate; the review reports diphenhydramine remains available in over 300 formulations, most over the counter.
• Funding: The authors state they have no relationships that may pose a conflict of interest.

Based on a comprehensive evaluation of practice patterns and the prevalence and incidence of adverse clinical events, we believe that diphenhydramine has reached the end of its life cycle, and in its class of therapies it is a relatively greater public health hazard.

A cross-sectional survey in primary and community care reported associations between antihistamine sedative properties and daytime sleepiness, cognitive failures and work and social adjustment, but every one of those regression coefficients is printed with a negative sign, so the direction of the association cannot be read off the paper, and its authors say causality cannot be inferred in any case. (Source 38)

• Survey study, Very low certainty.
• Size: 385 participants; 130 (33.8%) used first-generation agents and 130 (33.8%) used highly sedating agents.
• Who: Adults managed in primary care and community health settings.
• How long: Single cross-sectional questionnaire.
• Result: Multivariable regression coefficients for sedative properties: Epworth Sleepiness Scale B = -1.60, P < .001; Cognitive Failures Questionnaire B = -5.84, P < .001; Work and Social Adjustment Scale B = -3.21, P < .001. The signs on these coefficients are negative, which is hard to reconcile with the stated direction of effect; see the caveat beside this finding.
• Funding: The authors declared no potential conflicts of interest.

Limit of this finding: The paper's own numbers do not match the direction its text implies. Every coefficient it reports for sedative properties is negative (Epworth Sleepiness Scale B = -1.60, Cognitive Failures Questionnaire B = -5.84, Work and Social Adjustment Scale B = -3.21). Taken at face value a negative coefficient means less sleepiness, fewer cognitive failures and less impairment with more sedating antihistamines, which is the opposite of what the paper's discussion argues. The sign depends on how the paper coded its sedation variable and it does not say. Do not conclude from this study either that sedating antihistamines worsen daytime function or that they improve it. It is a one-off questionnaire study and it cannot show cause either way.

Cognitive failures (CFQ) were associated with female sex (B = 4.67, P = .009), higher stress (B = 8.75, P < .001), night-shift work (B = 6.20, P < .001), and sedative properties (B = -5.84, P < .001).

Diphenhydramine is a potent competitive inhibitor of CYP2D6 in vitro and halved metoprolol clearance in people who are extensive CYP2D6 metabolisers, prolonging metoprolol's effects on heart rate and blood pressure. (Source 11)

• Blood level study, Moderate certainty.
• Size: 16 subjects with genetically determined high or low CYP2D6 activity.
• Who: Healthy men, extensive and poor CYP2D6 metabolisers.
• How long: Single 100 mg metoprolol dose given during steady-state diphenhydramine or placebo.
• Result: In vitro inhibitory constant 2 micromol/L, with a sixfold increase in the Michaelis-Menten constant of metoprolol; in vivo diphenhydramine halved metoprolol oral and non-renal clearance and cut metoprolol to alpha-hydroxymetoprolol partial metabolic clearance 2.5-fold in extensive metabolisers (all P < .05) but not in poor metabolisers (P > .2)
• Funding: not stated.

In vivo, diphenhydramine decreased metoprolol oral and nonrenal clearances twofold and metoprolol-->alpha-hydroxymetoprolol partial metabolic clearance 2.5-fold in extensive metabolizers (all P < .05) but not in poor metabolizers (P > .2).

What the evidence supports

In a double-blind controlled study in 1,295 postpartum patients, diphenhydramine at 12.5, 25 and 50 mg was an effective hypnotic compared with placebo, with little extra benefit from the higher doses. (Source 4)

• Randomized trial, Low certainty.
• Size: 1,295 post-partum patients.
• Who: Post-partum patients who complained of, or anticipated, a sleep problem.
• How long: Single oral dose, double blind.
• Result: Effective versus placebo on sleep latency, sleep duration, awakening in the night, global evaluation and morning alertness at all three doses; no numerical effect sizes reported in the abstract; raising the dose within 12.5-50 mg produced a minimal increase in effectiveness.
• Funding: not stated.

Methapyrilene and diphenhydramine, at all doses, were found to be effective hypnotics in comparison to placebo, based on sleep latency, sleep duration, awakening in the night, global evaluation, and morning alertness.

Every H1-antagonist tested, including diphenhydramine 50 mg, significantly suppressed the histamine-induced weal, so the peripheral antihistamine effect is not in doubt; what separated diphenhydramine was that it alone significantly lengthened the P300 cognitive latency. (Source 2)

• Randomized trial, Low certainty.
• Size: 15 healthy subjects.
• Who: Healthy adults.
• How long: Single dose, assessments before and 2 to 2.5 hours after dosing.
• Result: Only diphenhydramine increased the P300 latency significantly compared with baseline and placebo; subjective somnolence significantly greater than baseline and placebo after cetirizine, ketotifen and diphenhydramine; all drugs suppressed the histamine weal significantly.
• Funding: not stated.

Limit of this finding: This is 15 healthy volunteers, one dose each, measured at a single point 2 to 2.5 hours afterwards, so it shows what one dose did on one afternoon rather than what regular use does. The ranking sentence in this passage also places terfenadine below placebo, which is a reminder that the ordering is not itself a test of significance: the paper found a significant lengthening of the P300 latency for diphenhydramine only.

All the H1-receptor antagonists suppressed the histamine induced weal significantly compared with baseline.

Adding oral diphenhydramine to oral midazolam more than halved sedation failure in children having magnetic resonance imaging, without prolonging recovery. (Source 8)

• Randomized trial, Low certainty.
• Size: 96 children.
• Who: Children undergoing magnetic resonance imaging.
• How long: Single oral dose; prospective randomised double-blind.
• Result: Inadequate sedation in 20 of 49 children (41%) on midazolam alone versus 9 of 50 (18%) on midazolam plus diphenhydramine 1.25 mg/kg (P<0.01); earlier onset of sedation (P<0.01) and higher sedation scores (P<0.01); time to complete recovery not significantly different.
• Funding: not stated.

Limit of this finding: This trial measured whether children could be sedated for a scan, not whether the drug was safe. Its finding that time to complete recovery did not differ is a null result on one outcome, and it is not a safety conclusion; the safety discussion lives in a part of the paper not quoted here.

In children who received midazolam alone, 20 (41%) were inadequately sedated, compared with 9 (18%) children who received midazolam and diphenhydramine combination (P < 0.01).

An expert consensus review concluded the available evidence indicates diphenhydramine is effective for acute insomnia in adults. This is a consensus statement, the weakest design in this write-up, and it is recorded as a position. (Source 39)

• Official position, Low certainty.
• Size: Not stated (narrative review plus expert consensus process)
• Who: Adults with short-term insomnia.
• How long: Not applicable.
• Result: No pooled effect size; the authors state the evidence is strong for recommending diphenhydramine for acute insomnia in adults.
• Funding: The authors state they maintained full independence; the paper is a consensus publication and no funder is named in the abstract.

Limit of this finding: This is an expert consensus statement, which is opinion informed by evidence rather than a measurement, and it is the weakest design in this write-up. The same review states, without a reference, that insomnia affects at least a third of the world's population, which should not be read as a measured prevalence. A 2025 review in another journal reaches the opposite conclusion about whether diphenhydramine should still be sold freely; both are recorded here.

The available evidence indicates that diphenhydramine is an effective treatment for acute insomnia in adults, offering a safe and affordable option for most patients suffering from this condition.

What the evidence does not support

A Cochrane systematic review searching five databases plus pharmaceutical companies and international experts found no randomised or quasi-randomised trial of H1-antihistamines for the treatment of anaphylaxis. (Source 40)

• Systematic review, Certainty not rated.
• Size: Zero eligible studies.
• Who: People being treated for anaphylaxis.
• How long: Searches to June and July 2006.
• Result: No studies satisfied the inclusion criteria, so no effect estimate exists.
• Funding: not stated.

We found no studies that satisfied the inclusion criteria.

The reviewers' own conclusion was that they could make no recommendation for clinical practice, which is a different statement from saying the drug does not work. (Source 41)

• Systematic review, Certainty not rated.
• Size: Zero eligible studies.
• Who: People being treated for anaphylaxis.
• How long: Searches to 2006.
• Result: No effect estimate; the review calls for randomised controlled trials while noting these would be challenging to design and execute.
• Funding: not stated.

Based on this review, we are unable to make any recommendations for clinical practice.

Intravenous diphenhydramine added to metoclopramide did not improve acute migraine outcomes, and the trial was stopped early for futility. (Source 7)

• Randomized trial, Moderate certainty.
• Size: 208 eligible patients consented and were randomised, of 420 approached.
• Who: Adults younger than 65 presenting to a US emergency department with acute moderate or severe migraine meeting ICHD-2 criteria.
• How long: Primary outcome at 48 hours.
• Result: Sustained relief at 48 hours in 40 of 100 (40%) on diphenhydramine versus 38 of 103 (37%) on placebo, 95% CI for the 3% difference -10% to 16%; 1 hour improvement 5.1 versus 4.8 on a 0 to 10 scale, 95% CI for the 0.3 difference -0.6 to 1.1; rates of adverse effects including akathisia comparable.
• Funding: not stated.

Of patients randomized to diphenhydramine, 40% (40/100) reported sustained relief at 48 hours, as did 37% (38/103) of patients randomized to placebo (95% confidence interval [CI] for difference of 3%: -10% to 16%).

The trialists' conclusion was unambiguous. (Source 42)

• Randomized trial, Moderate certainty.
• Size: 208 randomised patients.
• Who: Adults with acute migraine in a US emergency department.
• How long: 48 hours.
• Result: No benefit on the primary outcome; see the Results reference for the numbers.
• Funding: not stated.

Intravenous diphenhydramine, when administered as adjuvant therapy with metoclopramide, does not improve migraine outcomes.

A Cochrane review found antihistamines no more effective than placebo for cough, in adults and in children. (Source 6)

• Systematic review, Low certainty.
• Size: 29 placebo-controlled randomised trials, 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: Searches to March 2014; trial durations varied.
• Result: Three adult trials found antihistamines no more effective than placebo for cough symptoms; in children, antihistamines (three studies) were no more effective than placebo; pooling was judged inappropriate because of heterogeneity, so no summary effect estimate was produced; higher numbers of adverse effects occurred in participants taking preparations containing antihistamines and dextromethorphan.
• Funding: not stated.

Three trials found that antihistamines were no more effective than placebo in relieving cough symptoms.

The same reviewers concluded there is no good evidence for or against over-the-counter cough medicines and singled out antihistamines in children as drugs known to have the potential to cause serious harm. (Source 43)

• Systematic review, Low certainty.
• Size: 29 trials, 4,835 people.
• Who: Children and adults with acute cough.
• How long: Searches to March 2014.
• Result: No summary effect estimate; the review reports that many studies were poorly reported, making risk of bias assessment difficult.
• Funding: not stated.

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.

For the common cold, the short-term benefit of antihistamines on overall symptom severity is small and disappears after the first two days, and the effect on individual symptoms was judged clinically non-significant. (Source 44)

• Systematic review, Moderate certainty.
• Size: 18 randomised controlled trials, 4,342 participants of whom 212 were children.
• Who: People with naturally occurring or experimentally induced common cold, antihistamine monotherapy versus placebo.
• How long: Searches to August 2015; outcomes at days 1-2, 3-4 and 6-10.
• Result: Day one or two: 45% had a beneficial effect with antihistamines versus 38% with placebo (odds ratio 0.74, 95% CI 0.60 to 0.92); no difference at three to four days or six to ten days; rhinorrhoea on day three mean difference -0.23 (95% CI -0.39 to -0.06) on a four or five point scale; sneezing on day three mean difference -0.35 (95% CI -0.49 to -0.20) on a four point scale.
• Funding: not stated.

Limit of this finding: The three numbers in this sentence look contradictory and are not. More people benefited on antihistamines (45 per cent) than on placebo (38 per cent), yet the odds ratio is printed as 0.74, below 1. That is because Cochrane modelled the odds of NOT benefiting. The source's wording is reproduced exactly; read the 45 against 38 as the direction of effect, and note that the review found the advantage gone by day three.

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).

The same Cochrane review found no evidence that antihistamines work for colds in children. (Source 45)

• Systematic review, Moderate certainty.
• Size: 18 trials, 4,342 participants; only two trials included children.
• Who: Children with the common cold.
• How long: Searches to August 2015.
• Result: Only two trials included children and the results were conflicting; no pooled paediatric effect estimate.
• Funding: not stated.

There is no evidence of effectiveness of antihistamines in children.

In the largest modern placebo-controlled insomnia trial of diphenhydramine we found, the hypnotic effect was modest, few comparisons with placebo reached significance, and there was no significant difference on any polysomnographic measure of sleep continuity. (Source 16)

• Randomized trial, Moderate certainty.
• Size: 184 adults (110 women, 74 men; mean age 44.3 years), of whom 60 received diphenhydramine.
• Who: Adults with mild insomnia at 9 US sleep disorders centres.
• How long: Diphenhydramine 2 tablets of 25 mg for 14 days then placebo for 14 days.
• Result: Diphenhydramine produced significantly greater increases in sleep efficiency and a trend for increased total sleep time relative to placebo during the first 14 days; no significant group difference on any sleep continuity variable measured by polysomnography; no alteration of sleep stages 3-4 or REM; no rebound insomnia after discontinuation.
• Funding: Study drug extracts supplied by a manufacturer; funding not stated in the abstract and the second author's affiliation is to an extract manufacturer.

Modest improvements of subjective sleep parameters were obtained with both the valerian-hops combination and diphenhydramine, but few group comparisons with placebo reached statistical significance.

Tolerance to diphenhydramine's sedative effect was complete after three days of twice-daily dosing: by day 4 both objective and subjective sleepiness on the drug were indistinguishable from placebo. (Source 15)

• Randomized trial, Moderate certainty.
• 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 significantly higher than placebo on day 1; by day 4 indistinguishable from placebo; significant performance impairment on day 1 completely reversed by day 4.
• Funding: not stated.

By day 4, however, levels of sleepiness on diphenhydramine were indistinguishable from placebo. Similarly, diphenhydramine produced significant impairment of performance that was completely reversed by day 4.

For motion sickness, the comparative evidence against the standard drug is too thin to rank antihistamines: a Cochrane review could draw no conclusion on scopolamine versus antihistamines. (Source 46)

• Systematic review, Low certainty.
• Size: 14 studies, 1,025 subjects.
• Who: Adults and children without known vestibular, visual or central nervous system pathology.
• How long: Searches to 14 April 2011.
• Result: Scopolamine more effective than placebo; comparisons with antihistamines suggested equivalence but were few; no randomised trial examined treatment of established motion sickness symptoms.
• Funding: not stated.

No conclusions can be made on the comparative effectiveness of scopolamine and other agents such as antihistamines and calcium channel antagonists.

The other side of the anticholinergic-and-cognition question is also unresolved: a Cochrane review of trials that deliberately reduced anticholinergic burden found insufficient evidence that doing so improves cognition, at very low certainty. (Source 18)

• Systematic review, Very low certainty.
• Size: 3 randomised controlled trials, 299 participants.
• Who: Older adults, cognitively mixed populations including some with dementia.
• How long: Outcomes assessed after one to three months.
• Result: One trial reported improved Digit Symbol Substitution Test performance (treatment difference 0.70, 95% CI 0.11 to 1.30) without a difference in the proportion with reduced burden; another found no significant difference on CERAD immediate recall (0.54, 95% CI -0.91 to 2.05), delayed recall (-0.23, 95% CI -0.85 to 0.38), recognition (0.77, 95% CI -0.39 to 1.94) or Mini-Mental State Examination (0.39, 95% CI -0.96 to 1.75); GRADE very low certainty.
• Funding: not stated.

Limit of this finding: A Cochrane review finding insufficient evidence is not the same as finding no effect. These reviewers say explicitly that the evidence cannot support or refute the idea, on three trials in 299 people followed for one to three months, at very low certainty. Nothing here says that cutting anticholinergic medicines does or does not help thinking.

There is insufficient evidence to reach any conclusions on the effects of anticholinergic burden reduction interventions on cognitive outcomes in older adults with or without prior cognitive impairment.

Where the evidence is mixed

The forensic literature contains an explicit disagreement with the misuse literature on whether diphenhydramine is actually taken recreationally. (Source 28)

• Case series, Very low certainty.
• Size: 68 clinical and 55 death cases.
• Who: Poisoning cases at one institute of legal medicine, 1992 to 2004.
• How long: 12 years.
• Result: The authors state that despite hallucinogenic effects, abuse for recreational purposes was not observed in their series; the 2021 systematic review by contrast found 12 published articles on diphenhydramine misuse.
• Funding: not stated.

Limit of this finding: Both sides of this disagreement are weak. The forensic series is 12 years of casework at a single institute, and 'not observed until now' means these particular investigators did not see recreational use in their own cases; it is not a measurement of how common it is. Read it as one group reporting what they did not see, not as evidence that recreational use is rare.

However, despite the hallucinogenic effects, an abuse for recreational purposes was not observed until now.

Where the research disagrees

Whether diphenhydramine should still be available over the counter at all

• Clark, Meltzer and Naclerio, World Allergy Organization Journal, 2025, Narrative review of practice patterns and the prevalence and incidence of adverse clinical events: We recommend it should no longer be widely prescribed or continue to be readily available over the counter. (Source 37)
• Ariza-Salamanca and colleagues, Journal of Clinical Medicine, 2025 (expert consensus), Review of preclinical and clinical evidence plus an expert consensus process, on its use as an over-the-counter medication for short-term insomnia: Experts concur that there is strong evidence supporting the recommendation of diphenhydramine for the treatment of acute insomnia in adults. (Source 39)

Whether diphenhydramine is misused recreationally

• Schifano and colleagues, Frontiers in Psychiatry, 2021, Systematic review of published clinical data on over-the-counter drug misuse, PROSPERO CRD42020209261: Most articles focused here on DXM (n = 54) and diphenhydramine (n = 12). (Source 32)
• Pragst, Herre and Bakdash, Forensic Science International, 2006, Forensic survey of 68 clinical and 55 death cases at one institute of legal medicine, 1992 to 2004: However, despite the hallucinogenic effects, an abuse for recreational purposes was not observed until now. (Source 28)

How much

• Reference intake: For the prescription injectable form the dose is set by the prescriber: the label states 'DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND THE RESPONSE OF THE PATIENT.' and gives adults 10 to 50 mg intravenously at a rate generally not exceeding 25 mg/min, or deep intramuscularly, with 100 mg if required. For over-the-counter oral use the label sets it: Benadryl Allergy Liqui-Gels, 25 mg per capsule, 'adults and children 12 years and over: 1 to 2 capsules' every 4 to 6 hours. Both are recorded as label positions, not recommendations. (Source 47)
• Upper limit: The injectable label's ceiling is a maximum daily dosage of 400 mg in adults, and 5 mg/kg/24 hours or 150 mg/m²/24 hours in paediatric patients other than premature infants and neonates, with a maximum daily dosage of 300 mg. The over-the-counter oral label's ceiling is 'do not take more than 6 doses in 24 hours', with children under 6 told not to use the product at all. No dietary upper limit exists; this is a drug, not a nutrient. (Source 47)
• Studied: The 1978 postpartum hypnotic trial gave an oral dose of diphenhydramine hydrochloride of 12.5, 25 or 50 mg to 1,295 patients. (Source 4)
• Studied: The 2005 multicentre insomnia trial gave 2 tablets of diphenhydramine 25 mg nightly for 14 days followed by placebo for 14 days, to 60 of 184 adults with mild insomnia. (Source 48)
• Studied: The tolerance study gave 15 healthy men diphenhydramine 50 mg or placebo twice a day for 4 days. (Source 15)
• Studied: The driving-simulator trial gave a single 50 mg dose, compared against fexofenadine 60 mg, alcohol to roughly 0.1% blood alcohol concentration, and placebo in 40 licensed drivers. (Source 49)
• Studied: The migraine trial gave diphenhydramine 50 mg intravenously alongside metoclopramide 10 mg intravenously, versus placebo plus metoclopramide, in 208 adults. (Source 7)
• Studied: The paediatric sedation trial gave oral diphenhydramine 1.25 mg/kg with midazolam 0.5 mg/kg in 96 children. (Source 8)
• Studied: The healthy-elderly pharmacodynamic study gave single doses of 50 mg and 75 mg to 14 volunteers with a mean age of 71.6 years. (Source 36)

A common belief, and what the research shows

The belief: It is the old, well-tested antihistamine, and because it is sold without a prescription and is 'non habit forming' it is the safe choice, especially for getting a child or an older relative to sleep.

What the research shows: Age on the market is not the same as evidence, and the two uses named here are the two the literature treats most harshly. For sleep, tolerance is the problem: in a controlled crossover at 50 mg twice daily, 'tolerance was complete by the end of 3 days of administration'. For children, diphenhydramine was the index ingredient in 28 of 40 (70.0%) paediatric cough-and-cold deaths judged related or potentially related to the medicine, 7 of those deaths followed intentional use to sedate the child, and the over-the-counter label states in plain words not to use it 'to make a child sleepy'. The FDA's position, current as of 8 February 2018, is that 'Children under 2 years of age should not be given any kind of cough and cold product that contains a decongestant or antihistamine because serious and possibly life-threatening side effects could occur.' For older adults, exposure in hospital carried a relative risk of 1.7 (95% CI 1.3-2.3) for any delirium symptom. And on impairment generally, the simulator trial found 'diphenhydramine had a greater impact on driving than alcohol did', with drowsiness ratings failing to predict it.

Questions and answers

What is it?

Diphenhydramine hydrochloride is the hydrochloride salt of diphenhydramine, a first-generation antihistamine on the market since 1946 and the active ingredient in Benadryl and in most over-the-counter nighttime sleep aids. Chemically it is 2-(Diphenylmethoxy)-N,N-dimethylethylamine hydrochloride, a white crystalline powder freely soluble in water and alcohol. It comes as 25 mg and 50 mg oral capsules and tablets, children's liquids, and a 50 mg/mL injection for intravenous or deep intramuscular use. (Source 50)

What does it do in the body?

It competes with histamine for the receptors histamine acts on, which is how it damps sneezing, runny nose, itch and weal. It also blocks muscarinic receptors, which dries secretions, and it crosses into the brain, which is why it makes people sleepy and, in overdose or in vulnerable people, confused. The label describes it as an antihistamine with anticholinergic (drying) and sedative side effects, widely distributed through the body including the central nervous system. (Source 1)

Is it good or bad for you?

Both, and which one depends heavily on who is taking it. For an adult with hay fever or hives it does something measurable; for an adult taking it to sleep, it works for a night or two and then tolerance closes the gap with placebo. The harms cluster in the young and the old: diphenhydramine was the index ingredient in 70% of paediatric cough-and-cold deaths judged related to the medicine, hospitalised patients aged 70 and over had a 1.7-fold risk of delirium symptoms, and cumulative anticholinergic exposure tracks with incident dementia in a long cohort. A 2025 review in the World Allergy Organization Journal argues the balance has tipped. (Source 37)

How do you get more of it?

There is no reason to want more of it: it is a manufactured drug, not a nutrient, and the published evidence runs toward using less. If someone is taking it, the over-the-counter label sets the amount at 1 to 2 capsules of 25 mg every 4 to 6 hours for adults and children 12 and over, with no more than 6 doses in 24 hours, and the product is not for children under 6. That is the label's position, recorded here and not offered as advice. (Source 5)

If it is harmful, what reduces it?

Stopping is what clears it; there is no taper and no withdrawal syndrome in the literature we searched, and in the one trial that checked, stopping after 14 nights caused no rebound insomnia. In overdose the problem is cardiac as well as neurological, from sodium channel blockade, and sodium bicarbonate is used: in one 46 mg/kg ingestion a new left bundle branch block resolved after 150 mEq. On systematically reducing anticholinergic drugs in older people, Cochrane found only three small trials at very low certainty. (Source 31)

Why might someone be low in it or missing it?

Nobody is deficient in diphenhydramine; the body does not make it or need it. The question that does apply is who should not be given it, and the prescription label is specific: it should not be used in neonates or premature infants, it is contraindicated in nursing mothers because of the higher risk of antihistamines for infants, and it should not be used as a local anaesthetic because of local necrosis risk. (Source 9)

Which whole foods contain it or feed it?

No food contains diphenhydramine; it is entirely synthetic and has no dietary source. The only thing worth knowing on the food and drink side is what not to combine it with: the label records an additive effect with alcohol and with other central nervous system depressants, and the over-the-counter label tells users to avoid alcoholic drinks while taking it. (Source 10)

What happens if you do not have it?

Nothing happens; there is no deficiency state. Not taking it means forgoing an antihistamine effect that second-generation agents are argued to match with fewer adverse effects, and forgoing a sedative effect that a controlled study showed is gone within three days of regular use. For acute cough the Cochrane evidence says there is nothing to forgo, and for anaphylaxis the Cochrane review found no trials at all on which to judge. (Source 37)

How can you test for it?

There is no routine test anyone needs for diphenhydramine, and no monitoring test on the label. Blood diphenhydramine concentration is measured in poisoning and forensic work, by methods such as high performance liquid chromatography with photodiode array detection, and interpretive thresholds exist: a forensic series found concentrations of 0.5 to 8.9 mcg/mL in survivors and 0.3 to 119 mcg/mL in fatalities, and regarded above 5 mcg/mL as potentially lethal. Those ranges overlap, so a single concentration does not by itself settle whether a case is lethal, and in deaths the heart-blood concentration can be much higher than the venous one because of agonal aspiration. (Source 28)

References

1. DailyMed (US National Library of Medicine), label of Hikma Pharmaceuticals USA Inc. product distributed by Cardinal Health. Diphenhydramine Hydrochloride Injection, USP Rx only - Clinical Pharmacology section of the FDA-approved label (SPL effective 2026-05-05). 2026. Read the source
2. Clinical and Experimental Allergy. Comparison of the central nervous system effects produced by six H1-receptor antagonists (Results section of the abstract). 1996. PMID 8889266, DOI 10.1111/j.1365-2222.1996.tb00649.x. Read the source
3. DailyMed (US National Library of Medicine), label whose SPL labeler is Cardinal Health 107, LLC; the label names Hikma Pharmaceuticals USA Inc. under 'Manufactured by:'. Diphenhydramine Hydrochloride Injection, USP Rx only - the complete Indications and Usage section of the FDA-approved label with all three of its subsections (Antihistaminic; Motion Sickness; Antiparkinsonism), each under its own heading exactly as the label prints it, in document order (SPL effective 2026-05-05). 2026. Read the source
4. Journal of Clinical Pharmacology. Hypnotic activity of diphenhydramine, methapyrilene, and placebo. 1978. PMID 357456, DOI 10.1002/j.1552-4604.1978.tb02459.x. Read the source
5. DailyMed (US National Library of Medicine), label of Kenvue Brands LLC product. Benadryl Allergy Liqui-Gels - Active ingredient (in each capsule), Purpose, Uses and Directions sections of the OTC Drug Facts label, each section under its own heading exactly as the label prints it, the Uses sub-bullets kept as separate lines, and the Directions dose table rebuilt one age band per row with a colon and a space supplied as the cell separator because the label prints the two cells side by side with no punctuation between them; Active ingredient, Purpose and Uses are consecutive sections but the label's whole Warnings block stands between Uses and Directions and is held in dailymed-benadryl-warnings (SPL effective 2026-05-07). 2026. Read the source
6. Cochrane Database of Systematic Reviews. Over-the-counter (OTC) medications for acute cough in children and adults in community settings (the Main results section of the abstract, in full). 2014. PMID 25420096, DOI 10.1002/14651858.CD001831.pub5. Read the source
7. Annals of Emergency Medicine. Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department-Based Randomized Clinical Trial (the complete Results section of the abstract). 2016. PMID 26320523, DOI 10.1016/j.annemergmed.2015.07.495. Read the source
8. Paediatric Anaesthesia. Oral sedation with midazolam and diphenhydramine compared with midazolam alone in children undergoing magnetic resonance imaging (Results section of the abstract, which is three sentences). 2006. PMID 16719877, DOI 10.1111/j.1460-9592.2005.01820.x. Read the source
9. DailyMed (US National Library of Medicine), label whose SPL labeler is Cardinal Health 107, LLC; the label names Hikma Pharmaceuticals USA Inc. under 'Manufactured by:'. Diphenhydramine Hydrochloride Injection, USP Rx only - the complete Contraindications section of the FDA-approved label with all four of its subsections (Use in Neonates or Premature Infants; Use in Nursing Mothers; Use as a Local Anesthetic; Antihistamines are also Contraindicated in the Following Conditions), each under its own heading exactly as the label prints it, in document order; the one word the label sets in italics and underlines, 'not', is enclosed in asterisks here because those marks cannot be carried in plain text, and the double space in 'Because of the' is the label's own (SPL effective 2026-05-05). 2026. Read the source
10. DailyMed (US National Library of Medicine), label whose SPL labeler is Cardinal Health 107, LLC; the label names Hikma Pharmaceuticals USA Inc. under 'Manufactured by:'. Diphenhydramine Hydrochloride Injection, USP Rx only - the Precautions section of the FDA-approved label with its first three subsections (General; Information for Patients; Drug Interactions), each under its own heading exactly as the label prints it, in document order and with no section between them omitted; the Carcinogenesis, Mutagenesis, Impairment of Fertility, Pregnancy and Pediatric Use subsections that follow are not included (SPL effective 2026-05-05). 2026. Read the source
11. Clinical Pharmacology and Therapeutics. Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. 2000. PMID 10824625, DOI 10.1067/mcp.2000.106464. Read the source
12. DailyMed (US National Library of Medicine), label of Kenvue Brands LLC product. Benadryl Allergy Liqui-Gels - the Warnings section of the OTC Drug Facts label with all six of its subsections, in document order; three of them carry their own heading in the SPL and are printed under it here ('Do not use'; 'Ask a doctor before use if you have'; 'When using this product'), and the other three carry no heading element at all, so they are printed as the continuous sentences the label prints, opening 'Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers', 'If pregnant or breast-feeding' and 'Keep out of reach of children' (SPL effective 2026-05-07). 2026. Read the source
13. Integrative Cancer Therapies. Safety and efficacy of herbal sedatives in cancer care (narrative review; the passage is the reviewers' interpretation of other investigators' trials, not measured results). 2004. PMID 15165499, DOI 10.1177/1534735404265003. Read the source
14. Biopharmaceutics & Drug Disposition. Diphenhydramine kinetics following intravenous, oral, and sublingual dimenhydrinate administration. 1990. PMID 2328304, DOI 10.1002/bdd.2510110302. Read the source
15. Journal of Clinical Psychopharmacology. Tolerance to daytime sedative effects of H1 antihistamines. 2002. PMID 12352276, DOI 10.1097/00004714-200210000-00012. Read the source
16. Sleep. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial (Results section of the abstract). 2005. PMID 16335333, DOI 10.1093/sleep/28.11.1465. Read the source
17. Sleep. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial (Conclusions section of the abstract). 2005. PMID 16335333, DOI 10.1093/sleep/28.11.1465. Read the source
18. Cochrane Database of Systematic Reviews. Anticholinergic deprescribing interventions for reducing risk of cognitive decline or dementia in older adults with and without prior cognitive impairment (Authors' conclusions section of the abstract). 2023. PMID 38063254, DOI 10.1002/14651858.CD015405.pub2. Read the source
19. Annals of Internal Medicine. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator (Conclusions section of the abstract). 2000. PMID 10691585, DOI 10.7326/0003-4819-132-5-200003070-00004. Read the source
20. Archives of Internal Medicine. Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients (Results section of the abstract). 2001. PMID 11570937, DOI 10.1001/archinte.161.17.2091. Read the source
21. Archives of Internal Medicine. Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients (Conclusions section of the abstract, which is two sentences). 2001. PMID 11570937, DOI 10.1001/archinte.161.17.2091. Read the source
22. JAMA Internal Medicine. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study (Results section of the abstract). 2015. PMID 25621434, DOI 10.1001/jamainternmed.2014.7663. Read the source
23. JAMA Internal Medicine. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study (Conclusions and Relevance section of the abstract, which is two sentences). 2015. PMID 25621434, DOI 10.1001/jamainternmed.2014.7663. Read the source
24. JAMA Internal Medicine. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study (Design, Setting, and Participants section of the abstract). 2015. PMID 25621434, DOI 10.1001/jamainternmed.2014.7663. Read the source
25. Pediatrics. Pediatric Fatalities Associated With Over-the-Counter Cough and Cold Medications (Results section of the abstract). 2021. PMID 34607934, DOI 10.1542/peds.2020-049536. Read the source
26. Pediatrics. Safety Profile of Cough and Cold Medication Use in Pediatrics (Results section of the abstract). 2017. PMID 28562262, DOI 10.1542/peds.2016-3070. Read the source
27. US Food and Drug Administration (content current as of 02/08/2018). Use Caution When Giving Cough and Cold Products to Kids. 2018. Read the source
28. Forensic Science International. Poisonings with diphenhydramine--a survey of 68 clinical and 55 death cases.. 2006. PMID 16857332, DOI 10.1016/j.forsciint.2006.01.019. Read the source
29. The American Journal of Forensic Medicine and Pathology. Fatality from diphenhydramine monointoxication: a case report and review of the infant, pediatric, and adult literature. 2006. PMID 16501346, DOI 10.1097/01.paf.0000188093.45675.ee. Read the source
30. Journal of Forensic Sciences. A TikTok "Benadryl Challenge" death - A case report and review of the literature. 2023. PMID 36173026, DOI 10.1111/1556-4029.15149. Read the source
31. Toxicology Reports. Left bundle branch block morphology on electrocardiogram after massive diphenhydramine overdose. 2025. PMID 40391056, DOI 10.1016/j.toxrep.2025.102029. Read the source
32. Frontiers in 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
33. DailyMed (US National Library of Medicine), label whose SPL labeler is Cardinal Health 107, LLC; the label names Hikma Pharmaceuticals USA Inc. under 'Manufactured by:'. Diphenhydramine Hydrochloride Injection, USP Rx only - the complete Adverse Reactions section of the FDA-approved label under its own heading, with the label's own body-system headings kept as lead-ins, in document order; the six terms the label sets in italics to mark its most frequent reactions (Sedation; sleepiness; dizziness; disturbed coordination; Epigastric distress; Thickening of bronchial secretions) are enclosed in asterisks here because italics cannot be carried in plain text (SPL effective 2026-05-05). 2026. Read the source
34. DailyMed (US National Library of Medicine), label whose SPL labeler is Cardinal Health 107, LLC; the label names Hikma Pharmaceuticals USA Inc. under 'Manufactured by:'. Diphenhydramine Hydrochloride Injection, USP Rx only - the complete Warnings section of the FDA-approved label with both of its subsections, 'Use in Pediatric Patients' and 'Use in the Elderly (approximately 60 years or older)', each under its own heading exactly as the label prints it, in document order; the one word the label sets in italics in this section, 'overdosage', is enclosed in asterisks here because italics cannot be carried in plain text (SPL effective 2026-05-05). 2026. Read the source
35. Drug Safety. Drug-induced glaucomas: mechanism and management. 2003. PMID 12908846, DOI 10.2165/00002018-200326110-00002. Read the source
36. Journal of Clinical Psychopharmacology. Acute pharmacological effects of temazepam, diphenhydramine, and valerian in healthy elderly subjects. 2003. PMID 12826988, DOI 10.1097/01.jcp.0000084033.22282.b6. Read the source
37. World Allergy Organization Journal. Diphenhydramine: It is time to say a final goodbye. 2025. PMID 39925982, DOI 10.1016/j.waojou.2025.101027. Read the source
38. Journal of Primary Care & Community Health. Impact of Antihistamines on Sleep, Cognition, and Daily Functioning: Evidence From Primary and Community Care (Results section of the abstract). 2026. PMID 42011952, DOI 10.1177/21501319261442260. Read the source
39. Journal of Clinical Medicine. Expert Consensus on the Use of Diphenhydramine for Short-Term Insomnia: Efficacy, Safety, and Clinical Applications. 2025. PMID 40429293, DOI 10.3390/jcm14103297. Read the source
40. Allergy. H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review (the Methods and Results sections of the abstract, in document order, each under its own section label; the Results section is one sentence). 2007. PMID 17620060, DOI 10.1111/j.1398-9995.2007.01435.x. Read the source
41. Allergy. H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review (Conclusions section of the abstract, which is two sentences). 2007. PMID 17620060, DOI 10.1111/j.1398-9995.2007.01435.x. Read the source
42. Annals of Emergency Medicine. Diphenhydramine as Adjuvant Therapy for Acute Migraine: An Emergency Department-Based Randomized Clinical Trial (Conclusion section of the abstract, which is one sentence). 2016. PMID 26320523, DOI 10.1016/j.annemergmed.2015.07.495. Read the source
43. Cochrane Database of Systematic Reviews. Over-the-counter (OTC) medications for acute cough in children and adults in community settings (Authors' conclusions section of the abstract). 2014. PMID 25420096, DOI 10.1002/14651858.CD001831.pub5. Read the source
44. Cochrane Database of Systematic Reviews. Antihistamines for the common cold (the complete Main results section of the abstract). 2015. PMID 26615034, DOI 10.1002/14651858.CD009345.pub2. Read the source
45. Cochrane Database of Systematic Reviews. Antihistamines for the common cold (Authors' conclusions section of the abstract). 2015. PMID 26615034, DOI 10.1002/14651858.CD009345.pub2. Read the source
46. Cochrane Database of Systematic Reviews. Scopolamine (hyoscine) for preventing and treating motion sickness (Authors' conclusions section of the abstract). 2011. PMID 21678338, DOI 10.1002/14651858.CD002851.pub4. Read the source
47. DailyMed (US National Library of Medicine), label whose SPL labeler is Cardinal Health 107, LLC; the label names Hikma Pharmaceuticals USA Inc. under 'Manufactured by:'. Diphenhydramine Hydrochloride Injection, USP Rx only - the complete Dosage and Administration section of the FDA-approved label, including its final paragraph, with the label's own subsection headings kept as lead-ins and the rows in document order; the label's superscript in 'mg/m²' is rendered with a Unicode superscript two (SPL effective 2026-05-05). 2026. Read the source
48. Sleep. Valerian-hops combination and diphenhydramine for treating insomnia: a randomized placebo-controlled clinical trial (Interventions section of the abstract). 2005. PMID 16335333, DOI 10.1093/sleep/28.11.1465. Read the source
49. Annals of Internal Medicine. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator (Results section of the abstract). 2000. PMID 10691585, DOI 10.7326/0003-4819-132-5-200003070-00004. Read the source
50. DailyMed (US National Library of Medicine), label whose SPL labeler is Cardinal Health 107, LLC; the label names Hikma Pharmaceuticals USA Inc. under 'Manufactured by:'. Diphenhydramine Hydrochloride Injection, USP Rx only - the complete Description section of the FDA-approved label (SPL effective 2026-05-05); the structural-formula image that the label prints after 'The structural formula is as follows:' is a bitmap and cannot be carried in text, so the line marking its place is shown and the molecular formula that follows it is given with Unicode subscripts. 2026. Read the source