Diphenhydramine
Diphenhydramine is a first-generation antihistamine of the ethanolamine class1, first developed in 1943 by George Rieveschl2 and widely available over the counter under the brand name Benadryl1. Primarily used to treat allergies and insomnia1, it possesses anticholinergic properties2 functionally similar to tropane alkaloids found in nightshade plants. At high doses, it acts as a potent deliriant, producing intensely realistic hallucinations alongside significant physical discomfort and dysphoria.
Contents
Dosage & Duration
Dosage
The dose-response relationship for diphenhydramine is nonlinear. At amounts under 300 mg, effects generally include restlessness, muscle relaxation, and altered bodily sensations. Above 500 mg, a deliriant state may emerge, characterized by vivid visual and auditory hallucinations. Doses between these ranges often produce dysphoria and significant discomfort. Amounts approaching or exceeding 2 grams carry serious risk of fatal overdose, especially in combination with stimulants or MAOIs.
Duration
Subjective Effects
Effects vary widely by individual, dose, and context.
Physical
The physical effects of DPH are usually described as extremely uncomfortable. They can be broken down into several components which progressively intensify proportional to dosage. These are described below and generally include:
The levels of dysphoria experienced, however, vary between people with a very small percentage of users reporting that they do not seem to experience them at all.
Cognitive
The head space of DPH is described by many as generally negative and dysphoric throughout the trip, often consisting of extreme paranoia and feelings of impending doom. It is largely confusing and disorienting often leading to a complete inability to communicate or understand normal language. The most prominent of these effects include:
Visual
Distortions
As for visual distortions and alterations, effects experienced are detailed below:
Hallucinatory States
The effects of DPH are extremely efficient at inducing delirious hallucinations which can be broken into the two categories described below:
Suppressions
DPH does not enhance visual stimuli in the way that psychedelics do. Instead, they tend to degrade and decrease visual aptitude resulting in increasing hallucinations and degrading vision. These components are detailed below.
Auditory
The auditory effects of DPH are common in their occurrence and exhibit a range of effects which commonly includes:
Reagent Testing
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Pharmacology
Pharmacodynamics
Diphenhydramine acts primarily as an inverse agonist of the histamine H1 receptor, both peripherally (where it reduces allergic symptoms) and within the central nervous system (where it produces sedation and drowsiness).3 It is also a potent competitive antagonist at muscarinic acetylcholine receptors, and this anticholinergic activity is considered primarily responsible for its deliriant properties at high doses.3 Additional pharmacological actions include inhibition of serotonin reuptake, blockade of intracellular sodium channels and voltage-gated potassium channels, weak antagonism at the 5-HT2C receptor, and inhibition of histamine N-methyltransferase.456
Pharmacokinetics
Diphenhydramine has an oral bioavailability of approximately 40 to 60%, reflecting extensive first-pass metabolism in the liver, with peak plasma concentrations occurring about 2 to 3 hours after administration.7 It is metabolized primarily through two successive N-demethylations catalyzed by the cytochrome P450 enzymes CYP2D6 (which shows the highest affinity for the substrate), CYP1A2, CYP2C9, and CYP2C19.8 The resulting metabolites undergo further acetylation or oxidation, followed by conjugation with glycine and glutamine before excretion in urine. Only about 1% of a dose is excreted unchanged. The elimination half-life in healthy adults ranges from approximately 2.4 to 9.3 hours.79
Dangerous
Highest riskThese combinations are considered extremely harmful and should always be avoided. Reactions to these drugs taken in combination are highly unpredictable and have a potential to cause death.
Unsafe
AvoidThere is considerable risk of physical harm when taking these combinations, they should be avoided where possible.
Caution
Use cautionThese combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.
Tolerance
Deliriants
Harm Potential
Addiction & Dependence
Psychological
LowGenerally considered to have low abuse potential due to its dysphoric effects; most individuals who try recreational doses do not wish to repeat the experience. However, cases of abuse and addiction have been documented, particularly among adolescents without access to other drugs and individuals with mental health conditions such as schizophrenia who may self-administer large doses to treat extrapyramidal symptoms.1011
Physical
LowProduces dependence with chronic use, though the severity and specific withdrawal symptoms are not well-documented in the literature.10
Toxicity
Regular recreational use has been anecdotally linked to kidney and bladder damage with symptoms similar to ketamine cystitis; these reports are associated with chronic high-dose use patterns and remain unstudied.
Chronic high-dose use may cause persisting hallucinations and impairments in cognition and memory; cumulative anticholinergic use later in life has been tentatively linked to increased risk of cognitive decline and dementia.15
The drug is extensively metabolized by the liver; caution is advised in individuals with hepatic impairment as half-life is prolonged in patients with chronic liver disease.3
Psychosis Risk
Causes psychosis and delirium at significantly higher rates than other hallucinogens such as psychedelics and dissociatives. Toxic psychosis, delirium, and complete inability to distinguish hallucinations from reality are characteristic features at recreational doses. Users may lose control of their actions and respond to delusional environments, risking injury to themselves or others. Numerous experience reports describe psychotic delirium, amnesia, and serious consequences including hospitalization and death.
Seizure Risk
High doses and overdoses have been linked to seizures and convulsions, with risk increasing particularly at overdose-level doses.1617 Children are more susceptible to CNS excitation including convulsions at elevated doses.17 Benzodiazepines are recommended as first-line treatment to decrease seizure likelihood in overdose cases.16
History & Culture
Discovery and Development
Diphenhydramine was discovered in 1943 by chemist George Rieveschl and his student Fred Huber during research into muscle relaxants at the University of Cincinnati.18 Huber performed the initial synthesis, after which Rieveschl partnered with…
Trip Reports
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Legality
International
Diphenhydramine is not scheduled under the 1961, 1971, or 1988 United Nations drug-control conventions. UNODC's Legislative and Policy System lists diphenhydramine hydrochloride among substances not under international control.
By Country
References
Source Pages
Citations
- (2017). Diphenhydramine. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. https://www.ncbi.nlm.nih.gov/books/NBK548470/123
- (2025). Diphenhydramine: A Review of Its Clinical Applications and Potential Adverse Effect Profile. Journal of Pediatric Pharmacology and Therapeutics. https://pmc.ncbi.nlm.nih.gov/articles/PMC12288571/12
- (2021). StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK526010/1234
- (October 2000). Block of sodium currents in rat dorsal root ganglion neurons by diphenhydramine. Brain Research, 881(2), 190–8. https://doi.org/10.1016/s0006-8993(00)02860-21
- (February 1999). Block of potassium currents in guinea pig ventricular myocytes and lengthening of cardiac repolarization in man by the histamine H1 receptor antagonist diphenhydramine. The Journal of Pharmacology and Experimental Therapeutics, 288(2), 858–65. https://doi.org/10.1016/s0022-3565(24)38031-01
- (October 2005). Structural basis for inhibition of histamine N-methyltransferase by diverse drugs. Journal of Molecular Biology, 353(2), 334–344. https://doi.org/10.1016/j.jmb.2005.08.0401
- Paton DM, & Webster DR. (1985). Pharmacokinetics and bioavailability of diphenhydramine in man. Journal of Pharmacokinetics and Biopharmaceutics. https://pubmed.ncbi.nlm.nih.gov/2866055/1234
- Akutsu T, Kobayashi K, Sakurada K, Ikegaya H, Furihata T, & Chiba K. (2007). Identification of Human Cytochrome P450 Isozymes Involved in Diphenhydramine N-Demethylation. Drug Metabolism and Disposition, 35(1), 72-78. https://doi.org/10.1124/dmd.106.0121531
- Blyden GT, Greenblatt DJ, Scavone JM, & Shader RI. (1986). Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children. Journal of Clinical Pharmacology. https://pubmed.ncbi.nlm.nih.gov/2391399/123
- (January 2009). Diphenhydramine abuse and detoxification: a brief review and case report. Journal of Psychopharmacology, 23(1), 101–5. https://doi.org/10.1177/026988110708380912
- (2021). Treatment of Schizophrenia and Comorbid Diphenhydramine Dependence With Clozapine. The Journal of Clinical Psychiatry: Primary Care Companion. https://www.psychiatrist.com/pcc/treatment-schizophrenia-comorbid-diphenhydramine-dependence-clozapine/1
- (2024). Anticholinergic Toxicity. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK534798/123
- (2020). QT interval prolongation and rhabdomyolysis associated with diphenhydramine toxicity: a case report. Journal of Medical Case Reports. https://pmc.ncbi.nlm.nih.gov/articles/PMC7425623/12
- Nishino T. (2018). Cardiac arrest caused by diphenhydramine overdose. Acute Medicine & Surgery. https://doi.org/10.1002/ams2.3511
- (2015). Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. https://doi.org/10.1001/jamainternmed.2014.76631
- (2021). Diphenhydramine Toxicity. https://pubmed.ncbi.nlm.nih.gov/32491510/123
- (n.d.). Diphenhydramine- diphenhydramine hydrochloride injection, solution. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=921b9f64-1096-46db-866a-67f0f9ff6790#diphenhydramine-injection-label12
- (2007-09). George Rieveschl, Inventor of Benadryl, Dies. University of Cincinnati News. https://www.uc.edu/news/articles/legacy/healthnews/2007/09/george-rieveschl-inventor-of-benadryl-dies.html12
- (n.d.). George Rieveschl, Ph.D. — Engineering & Science Hall of Fame. Engineering & Science Hall of Fame. https://eshalloffame.org/inductee/george-rieveschl-ph-d/1
- (n.d.). Rulemaking History for OTC Nighttime Sleep-Aid Drug Products. U.S. Food & Drug Administration. https://fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/ucm071897.htm1
- (2014). Classics in Chemical Neuroscience: Fluoxetine (Prozac). ACS Chemical Neuroscience. https://pmc.ncbi.nlm.nih.gov/articles/PMC3894728/1
- (2020-09-24). FDA warns about serious problems with high doses of the allergy medicine diphenhydramine (Benadryl). U.S. Food & Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-problems-high-doses-allergy-medicine-diphenhydramine-benadryl12
- (n.d.). Healthdirect Australia medicine record, Diphenhydramine. healthdirect.gov.au. https://www.healthdirect.gov.au/medicines/medicinal-product/aht%2C22404/diphenhydramine1
- (n.d.). Healthdirect Australia medicine record, Diphenhydramine. healthdirect.gov.au. https://www.healthdirect.gov.au/medicines/brand/amt%2C732691000168100/benadryl-original1
- (n.d.). Benadryl Original. healthdirect. https://www.healthdirect.gov.au/medicines/brand/amt,732691000168100/benadryl-original1
- (n.d.). BASG-approved Calmaben package leaflet. medikamente.basg.gv.at. https://medikamente.basg.gv.at/documents/1-23847__DOTC_GEBR_INFO.pdf1
- (n.d.). BASG-approved Calmaben package leaflet. basg.gv.at. https://www.basg.gv.at/en/consumers/facts-worth-knowing-about-medicines/prescription-requirement1
- (n.d.). Calmaben coated tablets. Montavit. https://www.montavit.com/en/products/recovery-sleep/calmaben-coated-tablets/1
- (n.d.). ANVISA Instrução Normativa nº 285, de 7 de março de 2024 (LMIP), current consolidated text. anvisalegis.datalegis.net. https://anvisalegis.datalegis.net/action/ActionDatalegis.php?acao=abrirTextoAto&tipo=INM&numeroAto=00000285&seqAto=000&valorAno=2024&orgao=DC/ANVISA/MS&codTipo=&desItem=&desItemFim=&cod_menu=1696&cod_modulo=134&pesquisa=true1
- (n.d.). ANVISA Instrução Normativa nº 285, de 7 de março de 2024 (LMIP), current consolidated text. gov.br. https://www.gov.br/anvisa/pt-br/setorregulado/regularizacao/medicamentos/medicamentos-isentos-de-prescricao/lista-de-medicamentos-isentos-de-prescricao-lmip1
- (n.d.). CALMABEN tab x 20. Subra Online Pharmacy. https://subra.bg/en/otc-health-care/stress-and-lack-of-sleep/calmaben/4/10601
- (n.d.). Health Canada Drug Product Database, Allergy Care. health-products.canada.ca. https://health-products.canada.ca/dpd-bdpp/info?code=99813&lang=eng1
- (2022-05-26). Product information – Diphenhydramine hydrochloride 12.5 mg (DIN 02505649). Drug Product Database. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=995021
- (n.d.). Danish Medicines Agency notice on sedating antihistamines. laegemiddelstyrelsen.dk. https://laegemiddelstyrelsen.dk/da/nyheder/2022/sloevende-antihistaminer-aendrer-udleveringsbestemmelse-og-kan-fra-i-dag-kun-koebes-paa-apoteket/1
- (n.d.). ANSM public medicines database record for ACTIFED RHUME JOUR ET NUIT. base-donnees-publique.medicaments.gouv.fr. https://base-donnees-publique.medicaments.gouv.fr/medicament/60206332/extrait1
- (n.d.). Arzneimittelverschreibungsverordnung; BfArM medicine-information regime. gesetze-im-internet.de. https://www.gesetze-im-internet.de/amvv/BJNR363210005.html1
- (n.d.). Arzneimittelverschreibungsverordnung; BfArM medicine-information regime. bundesgesundheitsministerium.de. https://www.bundesgesundheitsministerium.de/themen/krankenversicherung/online-ratgeber-krankenversicherung/arznei-heil-und-hilfsmittel/zugang-zu-arzneimitteln1
- (n.d.). Diphenhydramin & Co. bei Schlafstörungen. PTAheute. https://www.ptaheute.de/serien/vorsicht-missbrauch/nicht-ohne-tuecke-diphenhydramin-und-co1
- (n.d.). BPOM product-registration record EREG10010512600060: VALDRES, registration number DTL0721633517A1. cekbpom.pom.go.id. https://cekbpom.pom.go.id/produk/EREG10010512600060/05/detail1
- (n.d.). PMDA package insert for ジフェンヒドラミン塩酸塩注10mg「日新」. info.pmda.go.jp. https://www.info.pmda.go.jp/go/pack/4411400A1033_1_04?view=body&lang=ja1
- (n.d.). PMDA package insert for ジフェンヒドラミン塩酸塩注10mg「日新」. info.pmda.go.jp. https://www.info.pmda.go.jp/psearch/PackinsSearch?dragname=%A5%B8%A5%D5%A5%A7%A5%F3%A5%D2%A5%C9%A5%E9%A5%DF%A5%F3%B1%F6%BB%C0%B1%F61
- (n.d.). Medicines Regulations 1984, Schedule 1. legislation.govt.nz. https://www.legislation.govt.nz/regulation/public/1984/0143/latest/DLM96863.html1
- (n.d.). Medicines Regulations 1984, Schedule 1. medsafe.govt.nz. https://www.medsafe.govt.nz/profs/class/classintro.asp1
- (2018-09). Changes Regarding the Use of Sedating Antihistamines. Medsafe – Prescriber Update. https://www.medsafe.govt.nz/profs/PUArticles/September%202018/ChangesSedatingAntihistamines.htm1
- (n.d.). Poisons Act 1938. sso.agc.gov.sg. https://sso.agc.gov.sg/Act/PA1938?ProvIds=Sc-1
- (n.d.). MFDS Drug Safety Korea product record for 그밤엔연질캡슐(디펜히드라민염산염). nedrug.mfds.go.kr. https://nedrug.mfds.go.kr/pbp/CCBBB01/getItemDetail?itemSeq=2025020751
- (n.d.). Swissmedic medicines information for Benocten® Tabletten/Tropfen zum Einnehmen, Lösung. swissmedicinfo.ch. https://www.swissmedicinfo.ch/detailpage/367360381
- (n.d.). Swissmedic medicines information for Benocten® Tabletten/Tropfen zum Einnehmen, Lösung. swissmedicinfo.ch. https://www.swissmedicinfo.ch/api/Medication/36736038/GetMedicationByPackungsnummer1
- (n.d.). Swissmedic medicines information for Benocten® Tabletten/Tropfen zum Einnehmen, Lösung. swissmedicinfo.ch. https://www.swissmedicinfo.ch/api/Medication/36736038/GetDokumentSectionItems1
- (n.d.). Who can and cannot take diphenhydramine. NHS. https://www.nhs.uk/medicines/diphenhydramine/who-can-and-cannot-take-diphenhydramine/1
- (n.d.). FDA OTC Monograph M010, Nighttime Sleep-Aid Drug Products. dps.fda.gov. https://dps.fda.gov/omuf/1
- (n.d.). FDA OTC Monograph M010, Nighttime Sleep-Aid Drug Products. fda.gov. https://www.fda.gov/drugs/otc-monograph-drugs/otc-monograph-reform1
- (n.d.). FDA OTC Drug Monograph – Nighttime Sleep Aid (M010/Part 338). fdahelp.us (FDA OTC Monograph reference). https://www.fdahelp.us/fda_otc/sleep-aid.html1
- (n.d.). Zambia – Risk Services. Risk Services. https://riskservices.berkeley.edu/zambia1
Further Reading
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