Diphenhydramine

What it is

Diphenhydramine is a first-generation antihistamine, chemically 2-(diphenylmethoxy)-N,N-dimethylethylamine, sold as the hydrochloride (tablets, capsules, liquid, injection, topical) and as the citrate salt in some combination products. It is a white crystalline powder, freely soluble in water and alcohol, molecular weight 291.82. Launched in the 1940s, it is available over the counter in most countries as an allergy medicine, a nighttime sleep aid and an ingredient in cold and flu combinations, and by prescription as an injection.

What the research says

It blocks histamine H1 receptors, which relieves itching, weals and nasal allergy symptoms, and it blocks muscarinic receptors and crosses into the brain, which is where both its usefulness as a sedative and almost all of its problems come from. The evidence splits sharply by use. For short-term occasional sleeplessness there is old, small randomised evidence of benefit at 50 mg, and in the US that use is approved over the counter. For chronic insomnia a GRADE-based sleep-medicine guideline suggests not using it. Tolerance to the sedation is complete within three or four days of twice-daily use. For the common cold, pooled trials show no clinically significant benefit. The harms are substantial and well documented: it impaired driving more than a legally intoxicating dose of alcohol in a simulator trial, it raises delirium risk in hospitalised older people by about 70%, it is one of the drug classes in the cohort literature linking cumulative anticholinergic exposure to later dementia, and US poison-centre data show rising intentional overdose with 745 deaths over twelve years.

Evidence grade: Disputed.

How it works

Drug class: First-generation (sedating) H1 antihistamine with strong anticholinergic (antimuscarinic) activity; an ethanolamine derivative

Diphenhydramine competes with histamine for H1 receptors on the cells histamine acts on, which is how it damps down itching, weals, sneezing and runny nose. Unlike newer antihistamines it crosses freely into the brain, where blocking H1 receptors causes drowsiness, and it also blocks muscarinic acetylcholine receptors - the “atropine-like” action behind dry mouth, blurred vision, urinary hesitancy, constipation and confusion. It is widely distributed through the body including the central nervous system, partly excreted unchanged in urine and partly metabolised by the liver. (Source 1)

What it is used for

• This is the oldest and least trial-tested of its approved uses. The Cochrane review of H1-antihistamines for chronic spontaneous urticaria pooled 73 studies and 9,759 participants but reports no diphenhydramine comparison among the 23 comparisons with usable data; the only first-generation agent in those comparisons was hydroxyzine, which was no better than loratadine. The reviewers concluded no single H1-antihistamine stands out, and downgraded the evidence for imprecision. First-generation antihistamines are accepted as effective for allergic rhinitis symptoms, but modern practice prefers non-sedating agents because of the impairment. Evidence: limited. (Source 2)
• In the US this is an approved over-the-counter use, not an off-label one - diphenhydramine is a monograph nighttime sleep-aid ingredient. The supporting trials are old and small: a 111-patient crossover study found better sleep latency and restfulness, and a 184-patient trial found improved subjective sleep parameters, both at 50 mg. A 2025 expert consensus, funded by P&G, concluded it is effective for short-term insomnia in healthy adults and should be avoided in older people. Tolerance to the sedation is the catch: it was complete within three days in an objective crossover trial. Evidence: limited. (Source 3)
• Using it as an ongoing sleeping tablet is off-label and not supported. The American Academy of Sleep Medicine's 2017 GRADE-based guideline suggests clinicians not use diphenhydramine for sleep onset or sleep maintenance insomnia in adults. The consensus panel that is most favourable to the drug agrees its effectiveness “has only been demonstrated for short-term insomnia”. Evidence: not-supported. (Source 4)
• An approved indication of long standing; no controlled trial of diphenhydramine for motion sickness was reached in this search, so the evidence behind the approval is not characterised here. Evidence: limited. (Source 5)
• An approved use that sits awkwardly beside the safety literature: the people the label points to - older patients - are the group in whom diphenhydramine is most strongly associated with delirium and with cumulative anticholinergic risk. Evidence: limited. (Source 5)
• Diphenhydramine is in many combination cold products, but Cochrane's review of 18 trials and 4,342 participants found antihistamine monotherapy has only a limited effect on overall symptom severity on days one and two, no clinically significant effect on nasal obstruction, runny nose or sneezing, and no evidence of effectiveness in children. Evidence: not-supported. (Source 6)

Interactions

• Alcohol (label): Additive sedation, stated on the label. Separately, and more striking, a randomised simulator trial found diphenhydramine 50 mg impaired driving more than alcohol at about 0.1% blood alcohol concentration did - so the two together compound an effect each produces on its own, and the trial also showed people cannot judge their own impairment from how drowsy they feel. (Source 7)
• Other sedatives, hypnotics, tranquillisers and opioids (label): Additive central nervous system depression, per the label. The 2025 expert consensus goes further and says diphenhydramine should be avoided in people already taking sedative or hypnotic medication. (Source 7)
• Monoamine oxidase inhibitors (label): MAO inhibitors prolong and intensify the anticholinergic drying effects of antihistamines, per the label. (Source 7)
• Metoprolol and other beta blockers metabolised by CYP2D6 (pharmacokinetic study): Diphenhydramine is a competitive CYP2D6 inhibitor. In a controlled study in 16 genotyped men it halved metoprolol clearance and made the heart-rate and blood-pressure effects stronger and significantly longer lasting in extensive metabolisers. (Source 8)
• Venlafaxine and other CYP2D6-metabolised antidepressants and antipsychotics (pharmacokinetic study): Diphenhydramine 50 mg twice daily cut venlafaxine oral clearance from 104 to 43 L/hr in extensive metabolisers, raising exposure more than twofold. The authors warn that clinically significant interactions could occur with other CYP2D6 substrates. (Source 9)
• Hydrocodone and other opioids that need CYP2D6 for activation (case reports): Because hydrocodone depends on CYP2D6 to become hydromorphone, inhibiting the enzyme both blunts analgesia and extends the parent drug's half-life. A post-mortem case report attributed a fatal hydrocodone overdose to diphenhydramine taken for cold symptoms, with hydromorphone undetectable. (Source 10)
• Melatonin (case reports): Both are sold as over-the-counter sleep aids and are taken together by people self-treating insomnia. One autopsy case report found lethal concentrations of both and certified death as combined diphenhydramine and melatonin toxicity; the authors note that diphenhydramine toxicity is well documented while melatonin's lethality is not established. One case cannot establish a dose-dependent interaction, and the shared mechanism to expect is additive sedation. (Source 11)
• Other anticholinergic drugs and supplements (tricyclic antidepressants, bladder antimuscarinics, some antiparkinson drugs) (clinical trial): The risk here is cumulative rather than pairwise. Cohort and case-control studies measure total anticholinergic burden in standardised daily doses, and both the Seattle cohort and the English case-control study found dementia risk rising with cumulative exposure; the case-control authors conclude that reducing anticholinergic exposure in middle-aged and older people matters. (Source 12)
• Food and grapefruit (label): No food interaction with diphenhydramine was found in the literature we searched. The label records no food restriction. The only dietary point in the label's chemistry is that the drug is freely soluble in water and alcohol. (Source 1)

Stopping it

• For short courses there is nothing to taper, and the label treats it as a drug to stop if alertness is impaired. The clinically important fact about continuing it for sleep is the opposite of withdrawal: tolerance to the sedation is complete within three days of twice-daily dosing, so the benefit disappears while the anticholinergic exposure continues. (Source 13)
• A withdrawal syndrome does exist after sustained heavy use. A palliative care case report describes hyperactive delirium, autonomic dysfunction and increased muscle tone on stopping, managed with loxapine and a scheduled taper rather than abrupt cessation. (Source 14)
• The expert panel most favourable to the drug records that its addictive potential should not be overlooked even though dependence risk is lower than with other hypnotics - which is the argument for not letting short-term use drift into nightly use. (Source 15)
• For older people the deprescribing case is the cumulative-exposure literature rather than a withdrawal risk: the largest case-control study concludes that reducing anticholinergic exposure in middle-aged and older people is important. (Source 12)

What goes wrong

Tolerance to the sedative effect of diphenhydramine was complete within three to four days of twice-daily dosing. (Source 13)

• Randomized trial, Moderate certainty.
• Size: 15 healthy men aged 18 to 50.
• Who: healthy men.
• How long: 4 days, randomised double-blind crossover.
• Result: objective and subjective sleepiness significantly higher than placebo on day 1 but indistinguishable from placebo by day 4; performance impairment completely reversed by day 4.
• Funding: not stated in the record we read.

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.

Diphenhydramine 50 mg impaired driving performance more than alcohol at roughly 0.1% blood alcohol concentration. (Source 16)

• Randomized trial, High certainty.
• Size: 40 licensed drivers aged 25 to 44 with seasonal allergic rhinitis.
• Who: licensed drivers with seasonal allergic rhinitis.
• How long: four-period crossover, one dose per week, 1 hour of simulated driving each time.
• Result: lane keeping impaired after diphenhydramine and after alcohol compared with fexofenadine; coherence significantly better after alcohol or fexofenadine than after diphenhydramine; mean response time to a blocking vehicle slowest after alcohol (2.21 s) versus fexofenadine (1.95 s)
• Funding: not stated in the record we read; the trial compared a branded second-generation antihistamine with diphenhydramine, so sponsorship should be checked.

After participants took diphenhydramine, driving performance was poorest, indicating that diphenhydramine had a greater impact on driving than alcohol did.

People could not tell from their own drowsiness whether they were impaired. (Source 16)

• Randomized trial, High certainty.
• Size: 40 licensed drivers.
• Who: licensed drivers with seasonal allergic rhinitis.
• How long: four-period crossover.
• 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 record we read.

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 70% higher risk of delirium symptoms, with a dose-response. (Source 17)

• Cohort study, Moderate certainty.
• Size: 426 hospitalised medical patients, 114 (27%) exposed to diphenhydramine.
• Who: hospitalised medical patients aged 70 or older in a university hospital.
• How long: length of hospital stay (median 7 versus 6 days)
• Result: any delirium symptoms RR 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)
• Funding: not stated in the record we read.

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)

A quarter of diphenhydramine doses given to older inpatients were judged inappropriate. (Source 17)

• Cohort study, Moderate certainty.
• Size: 426 patients, 114 exposed.
• Who: hospitalised patients aged 70 or older.
• How long: hospital stay.
• Result: 24% of diphenhydramine doses administered inappropriately.
• Funding: not stated in the record we read.

Overall, 24% of diphenhydramine doses were administered inappropriately.

Higher cumulative use of strong anticholinergic drugs, of which first-generation antihistamines were one of the three commonest classes, was associated with more incident dementia. (Source 18)

• Cohort study, Moderate certainty.
• Size: 3,434 participants aged 65 or older with no dementia at entry; 797 (23.2%) developed dementia.
• Who: community-dwelling adults aged 65 and over in the Adult Changes in Thought study, Seattle.
• How long: mean follow-up 7.3 years, with 10-year cumulative exposure windows.
• Result: adjusted hazard ratios for dementia versus non-use 0.92 (95% CI 0.74-1.16) at 1-90 total standardised daily doses, 1.19 (0.94-1.51) at 91-365, 1.23 (0.94-1.62) at 366-1095 and 1.54 (1.21-1.96) above 1095, test for trend P<.001 (hazard ratios read from the JAMA Internal Medicine abstract page at https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2091745; the Europe PMC record truncates them). This is an observational association, not evidence that the drug causes dementia.
• Funding: not stated in the record we read.

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

US poison-centre data show intentional diphenhydramine exposures, severe effects and misuse in older adults all rising over twelve years, with 745 reported deaths. (Source 19)

• Survey study, Low certainty.
• Size: 158,774 intentional diphenhydramine exposures reported to US Poison Control Centers.
• Who: people aged 10 and over reported to the National Poison Data System, 2005-2016.
• How long: 12 years.
• Result: rate of intentional exposures up 63%; major adverse clinical effects up 91%; 745 total reported deaths, up 3.6%; about a 230% increase in misuse rates in both the 55-64 and 65-plus age groups.
• Funding: not stated in the record we read.

Major adverse clinical effects increased by 91%. There were 745 total reported deaths with a 3.6% increase across all age groups.

Diphenhydramine overdose produces antimuscarinic delirium with measurable serum concentrations far above the therapeutic range, and antimuscarinic signs can persist for days. (Source 20)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: a 48-year-old woman after ingesting 3.75 g (41.2 mg/kg)
• How long: 5 hospital days.
• Result: presenting serum diphenhydramine 1500 ng/mL against a therapeutic range of 25-112 ng/mL; two doses of physostigmine needed to avert intubation; dry mouth, difficulty urinating and mydriasis until hospital day 5.
• Funding: not stated in the record we read.

She had antimuscarinic delirium with a presenting serum diphenhydramine concentration of 1500 ng/mL (therapeutic range, 25-112 ng/mL) and required two doses of physostigmine to avert intubation prior to intensive care unit (ICU) admission.

A severe withdrawal syndrome has been described after long-term heavy diphenhydramine use, and abuse potential is documented. (Source 14)

• Case report, Very low certainty.
• Size: 1 patient.
• Who: a 61-year-old man with metastatic oesophageal carcinoma in palliative care.
• How long: not stated.
• Result: hyperactive delirium, autonomic dysfunction and increased muscle tone requiring loxapine and a scheduled taper.
• Funding: not stated.

who was initially admitted with a pain crisis but subsequently developed a severe DPH withdrawal syndrome consisting of hyperactive delirium, autonomic dysfunction, and increased muscle tone

The expert review most favourable to diphenhydramine still records an addictive potential that should not be overlooked. (Source 15)

• Expert review, not systematic, Low certainty.
• Size: narrative review plus a structured expert consensus (panel size not given in the record we read)
• Who: adults using diphenhydramine for short-term insomnia.
• How long: short term.
• Result: no rate given; the panel's position is that dependence risk is lower than for other hypnotics but not negligible, and that next-day residual sedation and cognitive impairment are frequently reported.
• Funding: industry-funded: the project was funded by P&G, a manufacturer of over-the-counter diphenhydramine sleep aids.

Additionally, while the risk of dependence is lower than that of other hypnotics, its addictive potential should not be overlooked.

Diphenhydramine at therapeutic doses halved the clearance of metoprolol and prolonged its effects on heart rate and blood pressure. (Source 8)

• Blood level study, Moderate certainty.
• Size: 16 healthy men genotyped as CYP2D6 extensive or poor metabolisers.
• Who: healthy men.
• How long: single 100 mg metoprolol dose at steady-state diphenhydramine or placebo.
• Result: metoprolol oral and non-renal clearance reduced twofold and partial metabolic clearance to alpha-hydroxymetoprolol 2.5-fold in extensive metabolisers; effects on heart rate, systolic blood pressure and aortic blood flow peak velocity more pronounced and significantly longer lasting.
• Funding: not stated in the record we read.

In vivo, diphenhydramine decreased metoprolol oral and nonrenal clearances twofold and metoprolol-->alpha-hydroxymetoprolol partial metabolic clearance 2.5-fold in extensive metabolizers

Diphenhydramine more than doubled venlafaxine exposure in CYP2D6 extensive metabolisers. (Source 9)

• Blood level study, Moderate certainty.
• Size: 15 male volunteers (9 extensive, 6 poor metabolisers)
• Who: healthy men phenotyped for CYP2D6.
• How long: venlafaxine 18.75 mg every 12 hours for 48 hours, with and without diphenhydramine 50 mg every 12 hours.
• Result: venlafaxine oral clearance fell from 104 (SD 60) to 43 (SD 23) L/hr in extensive metabolisers (p<0.05), with no change in renal clearance and no significant change in poor metabolisers.
• Funding: not stated in the record we read.

In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance

The label records sedation, confusion, disturbed coordination and convulsions among nervous-system adverse reactions, and hallucinations, convulsions or death in paediatric overdose. (Source 21)

• Official position, Certainty not rated.
• Size: not quantified; adverse reactions listed without rates.
• Who: adults and children given diphenhydramine.
• How long: any duration.
• Result: no rates given; the label underscores sedation, sleepiness, dizziness and disturbed coordination as the most frequent nervous-system reactions.
• Funding: label holder RemedyRepack Inc.; regulatory position, label updated September 2026.

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

What the evidence supports

Small old randomised trials found diphenhydramine 50 mg improved sleep latency, restfulness and sleep efficiency in mild to moderate insomnia. (Source 3)

• Expert review, not systematic, Low certainty.
• Size: 111 patients in the crossover study; 184 patients in the second trial, as described by the reviewers.
• Who: adults with mild to moderate insomnia.
• How long: short term.
• Result: significant improvements in sleep latency and restfulness versus placebo; improved subjective sleep parameters and increased sleep efficiency at 50 mg twice daily (no effect sizes reported in the review)
• Funding: industry-funded: the project was funded by P&G, which markets diphenhydramine sleep aids; the authors state they kept editorial control.

They compared 50 mg of diphenhydramine with a placebo in 111 patients with mild to moderate insomnia. Significant improvements were observed in sleep latency and restfulness with diphenhydramine.

What the evidence does not support

The sleep-medicine guideline that assessed the trials with GRADE suggests clinicians not use diphenhydramine for insomnia. (Source 4)

• Official position, Very low certainty.
• Size: systematic review of randomised trials underlying the guideline (number not given in the record we read)
• Who: adults with chronic insomnia.
• How long: chronic use.
• Result: a WEAK recommendation against use, which the guideline says reflects a lower degree of certainty rather than proven ineffectiveness.
• Funding: American Academy of Sleep Medicine task force of four sleep-medicine experts; the guideline notes that downgrading for funding source and publication bias is predictable in this field.

We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK).

For the common cold, antihistamines gave no clinically significant relief of nasal obstruction, runny nose or sneezing, and no benefit in children. (Source 6)

• Systematic review, Moderate certainty.
• Size: 18 randomised trials, 4,342 participants of whom 212 were children.
• Who: adults and children with naturally occurring or experimentally induced common cold.
• How long: days one to ten.
• Result: day one or two overall symptom benefit 45% versus 38% on placebo (OR 0.74, 95% CI 0.60 to 0.92); no difference at three to four or six to ten days; rhinorrhoea on day three MD -0.23 (95% CI -0.39 to -0.06) and sneezing MD -0.35 (95% CI -0.49 to -0.20), described by the reviewers as clinically non-significant.
• Funding: not stated in the review record we read.

Antihistamines have a limited short-term (days one and two of treatment) beneficial effect on severity of overall symptoms but not in the mid to long term. There is no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing.

Cochrane's urticaria review found no single H1-antihistamine superior and rated most of its evidence low certainty; no diphenhydramine comparison was reported. (Source 2)

• Systematic review, Low certainty.
• Size: 73 studies, 9,759 participants; 34 studies gave data for 23 comparisons.
• Who: adults and children with chronic spontaneous urticaria.
• How long: up to two weeks (short term) or up to three months (intermediate term)
• Result: the first-generation agent that appears in the reported comparisons is hydroxyzine 25 mg, which did not differ from loratadine 10 mg for complete suppression (RR 1.00, 95% CI 0.32 to 3.10); evidence downgraded for imprecision.
• Funding: not stated in the review record we read.

No single H1-antihistamine stands out as most effective.

A retrospective physician survey found no causal link between first-generation antihistamines and most falls in older patients. (Source 22)

• Survey study, Very low certainty.
• Size: 313,046 patients reviewed by 169 physicians; 9,922 had fallen; detailed data on 379 patients with 505 falls.
• Who: patients of German general practitioners and neurologists, analysed by age band.
• How long: previous six months.
• Result: total fall rate 3.2%, rising with age (1.1% under 65, 3.9% at 65-84, 9.9% at 85 and over); first-generation antihistamine intake documented in 9.5% (940) of fallers; no causal link judged in 72.5% (366) of the 505 detailed falls.
• Funding: not stated in the record we read; described as a retrospective post-authorisation safety study, a design usually commissioned by a marketing authorisation holder, which a reader should weigh.

The analysis of these cases indicates that in almost three quarters of falls (72.5%, 366 falls) there is no causal link between the intake of first-generation antihistamines and the fall.

A single dose of diphenhydramine did not measurably inhibit CYP2D6 in a debrisoquine probe study, which qualifies the interaction findings. (Source 23)

• Blood level study, Low certainty.
• Size: 12 young healthy men, all debrisoquine extensive metabolisers.
• Who: healthy men.
• How long: single oral doses of diphenhydramine 100 and 150 mg, one week apart.
• Result: no statistically significant increase in debrisoquine metabolic ratios with increasing dose (P>0.05, Page's test for trend) and no significant difference in median metabolic ratios before and after treatment.
• Funding: not stated in the record we read.

This investigation indicates that single-dose administration of diphenhydramine or terfenadine has no effect on the CYP2D6-mediated hydroxylation of debrisoquine in healthy volunteers.

Where the evidence is mixed

A much larger nested case-control study confirmed a dose-response for anticholinergics overall but did not find a significant dementia association for the antihistamine class specifically. (Source 24)

• Case-control study, Moderate certainty.
• Size: 58,769 patients with dementia and 225,574 matched controls aged 55 or older in English general practice.
• Who: adults aged 55 and over.
• How long: exposure windows of 1-11, 3-13 and 5-20 years before diagnosis.
• Result: adjusted OR 1.06 (95% CI 1.03-1.09) at 1-90 total standardised daily doses rising to 1.49 (1.44-1.54) above 1095; significant increases were reported for anticholinergic antidepressants, antiparkinson drugs, antipsychotics, bladder antimuscarinics and antiepileptics, with antihistamines not among the classes reported as significant; population-attributable fraction 10.3%.
• Funding: not stated in the record we read.

The adjusted OR for dementia increased from 1.06 (95% CI, 1.03-1.09) in the lowest overall anticholinergic exposure category (total exposure of 1-90 TSDDs) to 1.49 (95% CI, 1.44-1.54) in the highest category (>1095 TSDDs), compared with no anticholinergic drug prescriptions in the 1 to 11 years before the index date.

Sedation was reported more often with sedating antihistamines in the cold trials, but the difference did not reach statistical significance. (Source 6)

• Systematic review, Low certainty.
• Size: 18 trials, 4,342 participants.
• Who: adults and children with the common cold.
• How long: up to 10 days.
• Result: sedation more commonly reported with sedating antihistamines, differences not statistically significant.
• Funding: not stated in the review record we read.

Adverse events such as sedation were more commonly reported with sedating antihistamines although the differences were not statistically significant.

Where the research disagrees

Whether diphenhydramine should be used for insomnia at all

• American Academy of Sleep Medicine clinical practice guideline (2017), GRADE-based guideline built on a systematic review of randomised trials; a WEAK recommendation against use: We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK). (Source 4)
• Expert consensus panel, Journal of Clinical Medicine (2025), narrative review of preclinical and clinical evidence plus a structured expert consensus, funded by P&G, a manufacturer of over-the-counter diphenhydramine sleep aids: Diphenhydramine at a dose of 50 mg before sleep has been shown to be effective for short-term insomnia and can be used safely in healthy young and adult individuals. However, diphenhydramine should be avoided in the elderly, as well as in individuals with concurrent cardiac or pulmonary conditions, or those taking sedative/hypnotic medications. (Source 25)

Whether first-generation antihistamines carry a dementia signal of their own

• Gray and colleagues, Adult Changes in Thought cohort (2015), prospective population-based cohort of 3,434 adults aged 65 and over with pharmacy-dispensing exposure data; an observational association, not a causal finding: The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. (Source 18)
• Coupland and colleagues, QResearch nested case-control study (2019), nested case-control study of 58,769 dementia cases and 225,574 controls; found class-specific signals for several anticholinergic classes but did not report antihistamines among the significant ones: There were significant increases in dementia risk for the anticholinergic antidepressants (adjusted OR [AOR], 1.29; 95% CI, 1.24-1.34), antiparkinson drugs (AOR, 1.52; 95% CI, 1.16-2.00), antipsychotics (AOR, 1.70; 95% CI, 1.53-1.90), bladder antimuscarinic drugs (AOR, 1.65; 95% CI, 1.56-1.75), and antiepileptic drugs (AOR, 1.39; 95% CI, 1.22-1.57) all for more than 1095 TSDDs. (Source 24)

Whether sedating antihistamines meaningfully increase falls in older people

• Agostini and colleagues, prospective inpatient cohort (2001), prospective cohort of 426 hospitalised patients aged 70 and over with daily blinded assessment: Diphenhydramine administration in older hospitalized patients is associated with an increased risk of cognitive decline and other adverse effects with a dose-response relationship. (Source 17)
• Retrospective post-authorisation safety study, Die Pharmazie (2020), retrospective physician-questionnaire study with 3.8% physician response and causality judged by the treating physician - a design highly vulnerable to recall and attribution bias: This suggests that first-generation antihistamines do not play a relevant role in the fall incidents. (Source 22)

How much

• Reference intake: No reference intake exists - diphenhydramine is a medicine, not a nutrient. For the injection the dose is set by the prescriber; for over-the-counter products the label sets it. The dose that the trial literature and the 2025 expert consensus both centre on for sleeplessness is 50 mg before bed, which is also the standard adult over-the-counter sleep-aid dose. (Source 25)
• Upper limit: There is no tolerable upper intake level. The label's ceiling statement is qualitative rather than numerical: antihistamine overdose reactions range from central nervous system depression to stimulation, and in children overdose may cause hallucinations, convulsions or death. A clinical reference point from the toxicology literature is that a therapeutic serum concentration is 25-112 ng/mL, while an ingestion of 3.75 g produced 1500 ng/mL and delirium requiring intensive care. (Source 21)
• Studied: Insomnia: 50 mg before sleep (the dose in the trials the 2025 consensus reviewed, and in the 184-patient trial 50 mg twice daily). (Source 3)
• Studied: Tolerance study: diphenhydramine 50 mg or placebo twice a day for 4 days in 15 healthy men. (Source 13)
• Studied: Driving simulator trial: a single 50 mg dose, compared with fexofenadine 60 mg, alcohol to about 0.1% blood alcohol concentration, and placebo. (Source 16)
• Studied: CYP2D6 probe study: single oral doses of 100 mg and 150 mg in 12 healthy men. (Source 23)

A common belief, and what the research shows

The belief: Diphenhydramine is a harmless way to get to sleep because you can buy it without a prescription.

What the research shows: Over-the-counter status reflects a 1970s-era monograph, not an absence of harm. In a randomised simulator trial “After participants took diphenhydramine, driving performance was poorest, indicating that diphenhydramine had a greater impact on driving than alcohol did.” and “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 over 70 it was associated with a 70% higher risk of delirium symptoms. The sedative benefit itself does not last: in an objective crossover trial “On this dosing regimen, tolerance was complete by the end of 3 days of administration.” And the sleep-medicine guideline that graded the trials suggests clinicians not use it for insomnia. Even the manufacturer-funded expert consensus restricts its endorsement to short-term use in healthy adults and says it should be avoided in older people.

Questions and answers

What is it?

Diphenhydramine is a first-generation antihistamine, chemically 2-(diphenylmethoxy)-N,N-dimethylethylamine, usually sold as the hydrochloride salt. It is a white crystalline powder, freely soluble in water and alcohol, with a molecular weight of 291.82. It dates from the 1940s and is sold over the counter as an allergy medicine and nighttime sleep aid, in cold and flu combinations, and on prescription as an injection. (Source 1)

What does it do in the body?

It competes with histamine for H1 receptors on the cells histamine acts on, which relieves itching, weals, sneezing and runny nose. It also crosses into the brain, causing drowsiness, and blocks muscarinic receptors - an atropine-like action that dries secretions and causes blurred vision, urinary hesitancy and confusion. It is widely distributed through the body including the central nervous system, with part excreted unchanged in urine and part metabolised by the liver. (Source 1)

Is it good or bad for you?

Both, and which one depends on the dose, the duration and the person. For a short course in a healthy younger adult with hives or an occasional sleepless night, the trial evidence supports a modest benefit at 50 mg. For the common cold, pooled trials show no clinically significant benefit. For chronic insomnia a GRADE-based guideline suggests against it, and the sedation itself stops working within three days. In older adults it is clearly on the harm side: in hospitalised people over 70 it was associated with a 70% higher risk of delirium symptoms, and the manufacturer-funded expert panel itself says it should be avoided in the elderly and in people with heart or lung disease or on other sedatives. (Source 25)

How do you get more of it?

The question does not apply as it would for a nutrient - and for this drug the practical issue is the opposite. Diphenhydramine is readily available: it is sold over the counter in most countries, the 2025 consensus describes its availability and FDA approval as a significant milestone for access, and that easy availability is exactly what the poison-centre data link to rising misuse and overdose. (Source 25)

If it is harmful, what reduces it?

For a single dose, time: it is partly excreted unchanged in urine and partly cleared by the liver, so effects wear off over hours, though antimuscarinic signs after a large overdose have persisted for days. For overdose with delirium, the treatments reported are physostigmine and, where that is unavailable, transdermal rivastigmine. For long-term exposure, the intervention the literature points to is reducing use: the largest case-control study concludes that reducing anticholinergic exposure in middle-aged and older people is important, and the inpatient cohort found a quarter of doses given to older patients were inappropriate in the first place. (Source 12)

Why might someone be low in it or missing it?

This does not apply: diphenhydramine is a manufactured drug, not a substance the body makes or needs, so nobody is deficient in it. What does vary between people is how long it lasts and how strongly it acts, because its own clearance and its interaction with other drugs depend on liver enzyme activity, in particular CYP2D6 - the enzyme it inhibits, and whose activity differs genetically between extensive and poor metabolisers. (Source 1)

Which whole foods contain it or feed it?

No whole food contains diphenhydramine; it is synthetic. No food feeds or raises it, and no food interaction was found in the sources we searched. The only consumption that matters is alcohol, which the label says has additive effects with it - and that is a drug effect, not nutrition. (Source 7)

What happens if you do not have it?

Nothing happens from not taking it; there is no deficiency state and no withdrawal after short use. If it is withheld where it was being used for a cold, pooled randomised evidence says nothing is lost: antihistamines give no clinically significant effect on nasal obstruction, rhinorrhoea or sneezing, and no evidence of effectiveness in children. If it is withheld where it was being used for allergy, second-generation antihistamines are the non-sedating alternative that performed as well as placebo on driving in the simulator trial. (Source 6)

How can you test for it?

There is no routine test and no reason for one in ordinary use. Diphenhydramine can be measured in serum in a toxicology laboratory: the quoted therapeutic range is 25 to 112 ng/mL, and in one overdose the presenting concentration was 1500 ng/mL. That assay is a hospital toxicology tool for suspected poisoning, not a test anyone would use to guide normal dosing, and we found no validated bedside or home test. (Source 20)

References

1. DailyMed / US National Library of Medicine (RemedyRepack Inc.). DIPHENHYDRAMINE (diphenhydramine hydrochloride) injection, solution - US prescribing information. 2026. Read the source
2. Cochrane Database of Systematic Reviews. H1-antihistamines for chronic spontaneous urticaria. 2014. PMID 25397904, DOI 10.1002/14651858.CD006137.pub2. Read the source
3. 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
4. Journal of Clinical Sleep Medicine. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. 2017. PMID 27998379, DOI 10.5664/jcsm.6470. Read the source
5. DailyMed / US National Library of Medicine (RemedyRepack Inc.). DIPHENHYDRAMINE (diphenhydramine hydrochloride) injection, solution - US prescribing information. 2026. Read the source
6. Cochrane Database of Systematic Reviews. Antihistamines for the common cold. 2015. PMID 26615034, DOI 10.1002/14651858.CD009345.pub2. Read the source
7. DailyMed / US National Library of Medicine (RemedyRepack Inc.). DIPHENHYDRAMINE (diphenhydramine hydrochloride) injection, solution - US prescribing information. 2026. Read the source
8. 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
9. Journal of Clinical Psychopharmacology. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. 2001. PMID 11270914, DOI 10.1097/00004714-200104000-00009. Read the source
10. Drug Metabolism and Personalized Therapy. CYP2D6 inhibition by diphenhydramine leading to fatal hydrocodone overdose. 2024. PMID 38741525, DOI 10.1515/dmpt-2023-0081. Read the source
11. The American Journal of Forensic Medicine and Pathology. Case Report of Lethal Concentrations of the Over-the-Counter Sleep Aids Diphenhydramine and Melatonin. 2023. PMID 37195072, DOI 10.1097/PAF.0000000000000833. Read the source
12. JAMA Internal Medicine. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. 2019. PMID 31233095, DOI 10.1001/jamainternmed.2019.0677. Read the source
13. Journal of Clinical Psychopharmacology. Tolerance to daytime sedative effects of H1 antihistamines. 2002. PMID 12352276, DOI 10.1097/00004714-200210000-00012. Read the source
14. Journal of Palliative Medicine. Diphenhydramine Use Disorder and Complicated Withdrawal in a Palliative Care Patient. 2020. PMID 31808723, DOI 10.1089/jpm.2019.0308. Read the source
15. 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
16. Annals of Internal Medicine. Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator. 2000. PMID 10691585, DOI 10.7326/0003-4819-132-5-200003070-00004. Read the source
17. Archives of Internal Medicine. Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. 2001. PMID 11570937, DOI 10.1001/archinte.161.17.2091. Read the source
18. JAMA Internal Medicine. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. 2015. PMID 25621434, DOI 10.1001/jamainternmed.2014.7663. Read the source
19. Clinical Toxicology. Increased rates of diphenhydramine overdose, abuse, and misuse in the United States, 2005-2016. 2021. PMID 33688782, DOI 10.1080/15563650.2021.1892716. Read the source
20. Journal of Medical Toxicology. Diphenhydramine-Induced Antimuscarinic Delirium Treated with Physostigmine and Transdermal Rivastigmine. 2023. PMID 36575250, DOI 10.1007/s13181-022-00925-z. Read the source
21. DailyMed / US National Library of Medicine (RemedyRepack Inc.). DIPHENHYDRAMINE (diphenhydramine hydrochloride) injection, solution - US prescribing information. 2026. Read the source
22. Die Pharmazie. Retrospective post-authorisation safety study investigating the relationship of first-generation antihistamines with sedative effect and the risk of falls in older patients. 2020. PMID 33303062, DOI 10.1691/ph.2020.0784. Read the source
23. European Journal of Drug Metabolism and Pharmacokinetics. Effects of terfenadine and diphenhydramine on the CYP2D6 activity in healthy volunteers. 2002. PMID 12365197, DOI 10.1007/BF03190453. Read the source
24. JAMA Internal Medicine. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. 2019. PMID 31233095, DOI 10.1001/jamainternmed.2019.0677. Read the source
25. 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