Diphenhydramine (DPH) is not a common drug of abuse; however, it is encountered in cases of overdose both in the clinical setting and in postmortem death investigations. Diphenhydramine is an over-the-counter first-generation H1 receptor antagonist.1,2 It is used to treat allergy and common cold symptoms including sneezing, itching, watery eyes, hives, rashes, and cough.3,4 In addition to these symptoms, DPH is also used in the treatment of motion sickness and in the induction of sleep.2 Diphenhydramine is available in tablet, capsule, chewable tablet, syrups/elixir, injectable, and topical forms.3 It is available alone or in combination with other agents and includes trade as well as generic names such as Benadryl (New Brunswick, NJ), Sominex (Brentford, England), Diphenhist (Dublin, Ireland), Dicopanol (Hyderabad, India), and more. The normal maximum adult dosage range is 25 to 50 mg 3 to 4 times daily and 50 mg at bedtime for sleep.5 Diphenhydramine concentrations of 25  to 112  ng/mL in the blood are considered therapeutic; 1000 to greater than 5000 ng/mL, toxic; and 5000 to 39,000 ng/mL, lethal.5,6 Diphenhydramine has a terminal elimination half-life of 9.2 ± 2.5 hours.5,6
Diphenhydramine has been implicated as the cause of death in both intentional and unintentional overdose cases.7,8 Although its normal use is considered safe, DPH is abused.9,10Substance abuse is defined as the use of a compound in a manner that results in long-term physical, mental, or social problems.11 However, recent publications on DPH abuse alone are lacking, with available literature focusing primarily on DPH abuse in combination with other compounds, controlled clinical studies, and abuse in adolescents with chronic illnesses.12,13
Cases obtained from the Tarrant County Medical Examiner’s Office (TCME) in Fort Worth, Tex, and the District of Columbia Office of the Chief Medical Examiner (DC OCME) were evaluated, involving DPH at toxic as well as lethal concentrations and in which this compound was the primary cause or a contributing factor in the death. Presented are the findings of this evaluation and detailed histories of those cases involving disturbing levels of DPH, including at least 1 evidenced case of DPH abuse leading to death.
The toxicology laboratories in both TCME and DC OCME analyze antemortem and postmortem specimens collected after autopsies, drug-facilitated sexual assault cases, and samples from suspected driving under the influence/driving while intoxicated cases. Toxicology reports, autopsy reports, and death investigator narratives from the TCME cases (January 2012–June 2013) involving DPH at toxic and lethal levels were obtained from the Crypt laboratory information management system. Identical information (January 2011–June 2013) was obtained from the DC OCME via the access database laboratory information management system. Blood (femoral, subclavian, inferior vena cava, and hospital admission) and urine are routinely analyzed in these cases: in addition, samples of gastric, decomposition fluid, liver, or other tissues may be analyzed on a case-by-case basis. Blood concentrations are presented in the following case histories, which allows for a direct comparison to the therapeutic, toxic, and lethal concentrations cited previously.
A 61-year-old white man was found deceased at his residence. On examination of the individual by death investigators, he was found to be cold to the touch and rigor mortis was present; lividity was fixed and consistent with the position of the body. There was no sign of visible trauma. The decedent had a history of alcohol use with at least 1 driving-while-intoxicated arrest. The individual was found next to a bed with a number of unidentified blue pills scattered on the floor next to him. However, no container for the pills was discovered. No prescription bottles or illegal drugs/paraphernalia were found at the scene. The decedent was last seen alive approximately 48 hours before being found in his residence. There were no signs of struggle or foul play at the scene.
The femoral blood sample had a lethal concentration of 6645 ng/mL of DPH.
A 60-year-old white man was found in the hedge line of a private residence, unresponsive, shortly after entering a retail store and consuming approximately 200 DPH capsules. The individual was on his right side, fully dressed, with some abrasions on his back. He was cool to the touch; lividity was present and consistent with the position of the body. Rigor mortis was present yet breakable and was also consistent with the position of the body. Pink/purple foam was emitting from the nares. The decedent had a medical history of back pain, hypertension (HTN), cerebrovascular accident, suicidal threats, and suicidal attempts via overdose of medications. He also had a history of rages and outburst of intense anger including on the day of his death. After consuming a large number of pills, the decedent traversed approximately half of a mile before succumbing to the effects and collapsing in the hedge line of a residence.
His femoral blood had a lethal concentration of 12,210 ng/mL of DPH.
A 37-year-old white man was discovered supine and unresponsive on his bedroom floor with reddish purge emitting from the mouth. The decedent had a long history of alcoholism and was released from a rehabilitation unit 2 days before being discovered. The body was found with rigor mortis present, slightly movable and consistent with the position viewed. No obvious trauma was observed.
Toxicological examination revealed a lethal DPH concentration of 21,263 ng/mL in the femoral blood sample collected from the decedent. Acetaminophen was also found at a lethal concentration of 595,600 ng/mL in the femoral blood.
A 36-year-old white woman was found unresponsive in the bathroom of a private residence. Rigor mortis was present, slightly movable, and consistent with the position viewed. Lividity was present, blanchable, and consistent with position in which the body was found. Purge was present emitting from the decedent’s nose. The decedent had a medical history of leukemia and thyroid cancer. Contusions were observed on the decedent’s abdomen and on several areas of possible needle marks. No obvious trauma was observed. The decedent had a prescription for fentanyl “suckers” for pain management. The decedent’s mother stated that the decedent had not voiced any complaints and that her daughter had made social plans for the evening of her death. Further investigation revealed that the decedent had contacted a friend and inquired about DPH abuse using injection with saline the week before the death. Numerous syringes, empty DPH capsules, and 4 empty pink containers labeled 0.9% sodium chloride for inhalation were also observed near the decedent.
Toxicological examination revealed a lethal DPH concentration of 14,541 ng/mL in the femoral blood sample collected from the decedent. In addition, fentanyl was found at a concentration of 11 ng/mL in the femoral blood. Norfentanyl, a major inactive metabolite of fentanyl, was quantitated at a concentration of 8 ng/mL in the same specimen. Fentanyl is a short-acting synthetic opioid analgesic often used for breakthrough pain management and as a preoperative anesthetic. Fentanyl is at least 80 times more potent than morphine.14,15
A 36-year-old black man was found vomiting and urinating on himself outside a grocery store. The decedent was transported to the emergency room (ER) of a local hospital by emergency medical services personnel and was catatonic with “tense muscle” on arrival. He continued to vomit, and a nasogastric tube was inserted. Oral contrast was administered, and the individual was taken for a computed tomographic scan. Approximately 5 minutes after leaving the ER, the decedent experienced a seizure followed by cardiac arrest and was taken back to the ER. Advanced cardiac life support protocol was attempted without success, and the individual was pronounced dead. The urine toxicology screen in the ER was positive for phencyclidine, and the medical records showed that the decedent was receiving treatment for schizophrenia and bipolar disorder.
His inferior vena cava blood had a toxic concentration of 2870 ng/mL of DPH and also a toxic concentration of 180 ng/mL of phencyclidine.
A 53-year-old white woman was found having a seizure inside her vehicle by police. The decedent was transported to the hospital, and emergency medical services personnel reported that they stopped the seizure during transport. On arrival to the ER, the decedent became unresponsive and was in asystolic state (a state of no cardiac electrical activity). She was intubated, and advanced cardiac life support protocols were initiated without success. The decedent had a medical history of hypothyroidism, HTN, and insomnia. There was no trauma to her head or body.
Toxicological examination found a potentially lethal concentration of 7060 ng/mL of DPH in the femoral blood specimen and a concentration of 78.1 mg/kg of DPH in the liver specimen. The femoral blood contained citalopram at a therapeutic concentration of 850 ng/mL but contained doxepin at a lethal concentration of 9360 ng/mL. Citalopram and doxepin are both used in the treatment of depression.
A 22-year-old black woman was observed having a seizure in a library. Emergency medical services personnel were called, and on arrival, the decedent was asystolic. Cardiopulmonary resuscitation was conducted without success, and the decedent was pronounced dead. According to the ER physician, the individual had Benadryl in her system. The decedent had taken a photograph of the bottles of Benadryl and sent the photograph through text message to an unknown person, stating her intention to commit suicide. The decedent’s medical history showed that she attempted suicide via Benadryl overdose 2 years prior. The death investigator inventoried 7 bottles of Benadryl, each with a stated quantity of 100 tablets per bottle of 25-mg dose of DPH per capsule. Only 1 tablet was remaining in the bottles.
Toxicological examination revealed a lethal concentration of 12,300 ng/mL of DPH in the femoral blood sample. Diphenhydramine was also found in the liver at a concentration of 31.2 mg/kg.
Diphenhydramine is a common, readily accessible, over-the-counter medication used to treat allergies and to induce sleep. Diphenhydramine is commonly combined with other over-the-counter drugs such as acetaminophen and ibuprofen for the alleviation of pain at night with the added benefit of sleep. It is evident from the data collected during this work that the readily accessible nature of the drug can lend itself to intentional overdose as well as, in rare cases, addiction and abuse of the drug.16
Diphenhydramine-related deaths received by the TCME and the DC OCME laboratories were uncommon, and it was rarely seen as a drug of abuse in casework. In part, the adverse effects elucidated by Preston et al17 in their clinical evaluation of DPH as a drug of abuse revealed that DPH resulted in “restlessness, tension, cramps in the legs, numbness and tingling, elevated blood pressure, vomiting, irritability/dysphoria, agitation, hostility, and aggressivity.” In addition, the large amount of drug required for intentional overdose may be a deterrent. This is evidenced by the staggering amount of DPH that the decedents ingested or administered in the case of intravenous injection. Our cases revealed a mean DPH blood level of 8626 ng/mL (range, 2440–21,263 ng/mL).
Diphenhydramine adversely affects alertness, reaction time, concentration, time estimation, tracking, learning ability, memory, vigilance, divided attention, psychomotor performance, and attention within the first 2 to 3 hours after dose.18,19 Diphenhydramine impairment has been shown even when the user does not report feelings of sedation.6,20–22 Monoamine oxidase inhibitors, benzodiazepines, sedatives-hypnotics, tranquilizers, and other central nervous system depressants also increase the adverse effects of DPH.1 More serious adverse effects of DPH misuse can include seizures and ventricular dysrhythmias, both of which may lead to death.
In addition to the cases detailed previously, Table 1 summarizes other cases that involved alarming levels of DPH both alone and in combination with other drugs in which DPH was a contributor to the death but not necessarily the sole cause. Diphenhydramine alone was only seen in 3 (27.2%, n = 11) of the cases reported in this study. Concomitant use of DPH with other compounds is common and was seen in most of these cases (7/11 cases, 63.6%). These included prescription drugs (36.3%), over-the-counter medications (18.1%), and illicit compounds (18.1%). Its use with alcohol can result in increased drowsiness, sedation, and decreased motor skills. Ethanol was detected in 3 (27.2%) of the cases. All of the evaluated cases had individuals with some type of medical history, with 7 (63.6%) individuals having documented psychological issues and 3 (27.2%) individuals having documented substance abuse–related issues. Congruent with DPH overdose in the clinical setting, 5 (45.4%) cases had a documented seizure before death.
In forensic toxicology laboratories, DPH abuse is often difficult to discern when medical documentation is incomplete or absent. Diphenhydramine abuse does occur, but it is uncommon.21,22 Diphenhydramine is more commonly seen as a secondary finding in drug-abuse cases where it is used as the “cutting” agent or to change the “gummy” consistency of the drug of choice. For example, DPH has been used with heroin in a formulation referred to as “cheese.”12,21 Diphenhydramine is used as the cutting agent or to change the gummy consistency of the heroin to a dry powder.12 However, in those cases where DPH is the drug of choice, a review of a “Drug-Forum” for DPH “user” comments revealed the terms and/or phrases “high,” “hallucinations,” “shield,” “voices,” “psychosis,” “tripping,” “social anxiety reduction,” “euphoria,” and “living in the dark” when describing their experiences.23 The users of DPH alone self-reported single doses of 500 to 1000 mg, with some reporting that they would redose after a “couple” of hours but stating that the exact amount of time that passed was difficult to judge on the basis of the effects of the drug. The users also reported that they occasionally mix DPH with other drugs such as tramadol, oxycodone, amphetamine, and heroin. Diphenhydramine abuse has been documented in adults with psychiatric diagnoses including drug abuse and schizophrenia, in adolescents with histories of drug abuse, and in adults chronically abusing antihistamines as sedatives.24
The case 4 of our study follows a pattern of drug-seeking behavior similar to those documented in the article of Dinndorf et al24 examining the risk for DPH abuse in children and adolescents with chronic illnesses. Diphenhydramine abuse was evidenced in this case. The decedent had researched its abuse potential and had numerous needle marks on her body using injections of the drug. In addition to DPH, the decedent was also using fentanyl “suckers.” The use of an opiate with DPH is documented in the literature.12,25
The number of DPH-related fatalities seen at the TCME and the DC OCME varied over the period examined with a steep increase of 1 year and a decline in another. Possibly more important is the access to information regarding the use of DPH as a drug of abuse. As a drug of abuse for those seeking a euphoric experience or those individuals with social anxiety, DPH is readily accessible and easily administered. If the abuse of this compound continues to increase, we would expect a continued rise in the number of fatalities. The cause of death in 3 (27.2%) cases was ruled as DPH toxicity/intoxication, that in 7 (63.6%) cases was ruled as mixed-drug intoxication, and that in 1 (9.1%) case was ruled as undetermined. The medical examiner’s finding for the manner of death in 4 (36.3%) of these cases was ruled as suicide, that in 3 (27.2%) cases was ruled as accident, 3 (27.2%) cases was ruled as undetermined, and that in 1 (9.1%) case was ruled as atherosclerotic coronary artery disease.
The National Poison Data System (NPDS) collects data from all poison centers in the United States. The data are then reported in an annual report.26 In the year 2011 report, there were 1995 fatalities among all cases reported. Among these deaths, DPH was noted to be a coingestant in 104 cases (5% of all deaths). However, it was felt to be the primary agent in only 42 (approximately 2%) cases. Among these, it was combined with acetaminophen in 24 (approximately 1.2%) cases. Thus, there were only 18 deaths (0.9% of all deaths) where DPH alone was the primary cause of death. Among these 18 deaths, 9 were women. The age range of the deaths was 18 to 68 years with a mean age of 36 years. The reason for exposure was suicide in 12 cases, misuse in 1 case, abuse in 2 cases, and unknown in 3 cases.26 Of the individuals in this examination, 72.7% were classified as “white” and 27.2% were classified as “black.” The age range of the individuals in this study was 22 to 67 years (mean, 42 years), with 6 (55%) of the cases involving men and 5 (45%) of the cases involving women. Sex and age range determined in this study agreed with the NPDS data as does the rarity of the documented DPH abuse cases.
Examination of DPH’s role in death investigations was deemed necessary because of the levels of DPH quantified in several cases during the examined period and to gain a better understanding of the DPH’s role as a drug of abuse within these 2 different geographical jurisdictions. Our investigation revealed that large amounts of DPH was either intentionally ingested for the purpose of suicide or ingested in combination with some other compound. There was also a rare occurrence of documented intravenous administration in at least 1 case. In comparison with the previously published data, the cases presented here generally involved much higher concentrations of DPH. Furthermore, the average age of the population presented here was older than those in some of the previous examinations on the DPH’s role in death investigation and abuse. However, the increase in age may be a national trend on the basis of the NPDS data. As people continue to seek alternative legal drugs to abuse and with the ease of obtaining information via online forums on DPH abuse, there is a potential to see the number of cases involving the excessive use of DPH increase.
1. Brunton L, Chabner B, Knollmann B . Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw Hill; 2010 .
2. Unno K, Ozaki T, Mohammad S, et al. First and second generation H(1) histamine receptor antagonists produce different sleep-inducing profiles in rats. Eur J Pharmacol. 2012; 683: 179–185.
3. Albert KS, Hallmark MR, Sakmar E, et al. Pharmacokinetics of diphenhydramine in man. J Pharmacokinet Biopharm. 1975; 3: 159–170.
4. Leurs R, Church M, Taglialatela M. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy. 2002; 32: 489–498.
5. Molina DK. Handbook of forensic toxicology for medical examiners (practical aspects of criminal & forensic investigations). N Engl J Med. 2009; 351: 2203–2217.
6. Baselt RC . Disposition of Toxic Drugs and Chemicals in Man. 9th ed. Seal Beach, CA: Biomedical Publications; 2011 .
7. Rinder CS, D’Amato SL, Rinder HM, et al. Survival in complicated diphenhydramine overdose. Crit Care Med. 1988; 16: 1161–1162.
8. Thakur AC, Aslam AS, Aslam AF, et al. QT interval prolongation in diphenhydramine toxicity. Int J Cardiol. 2005; 98: 341–343.
9. Feldman MD, Behar M. A case of massive diphenhydramine abuse and withdrawal from use of the drug. JAMA. 1986; 255: 3119–3120.
10. Thomas A, Nallur DG, Jones N, et al. Diphenhydramine abuse and detoxification: a brief review and case report. J Psychopharmacol. 2009; 23: 101–105.
11. Engs RC . Alcohol and Other Drugs: Self Responsibility. Bloomington, IN: Tichenor Publishing Company; 1987 .
12. Maxwell J, Coleman J, Feng SY, et al. Cheese: an old drug in a new wrapper. Drug Alcohol Depend. 2012; 126: 161–167.
13. Wogoman H, Steinberg M, Jenkins AJ. Acute intoxication with guaifenesin, diphenhydramine, and chlorpheniramine. Am J Forensic Med Pathol. 1999; 20: 199–202.
14. McIntyre IM, Anderson DT, Gary RD, et al. Postmortem fentanyl concentrations: a review. J Forensic Res. 2012; 3: 1–10.
15. McIntyre IM, Gary RD, Estrada J, et al. Antemortem and postmortem fentanyl concentrations: a case report. Int J Legal Med. 2013; 128: 65–67.
16. Koppel C, Ibe K, Tenczer J. Clinical symptomatology of diphenhydramine overdose: an evaluation of 136 cases in 1982 to 1985. J Toxicol Clin Toxicol. 1987; 25: 53–70.
17. Preston KL, Wolf B, Guarino JJ, et al. Subjective and behavioral effects of diphenhydramine, lorazepam and methocarbamol: evaluation of abuse liability. J Pharmacol Exp Ther. 1992; 262: 707–720.
18. Gupta S, Bhuvneshwar K, Gillani Z, et al. Effects of fexofenadine, cetirizine and diphenhydramine on psychomotor performance in adult healthy volunteer. JK Science. 2004; 6: 201–205.
19. Van Ruitenbeek P, Vermeeren A, Riedel WJ. Cognitive domains affected by histamine H(1)-antagonism in humans: a literature review. Brain Res Rev. 2010; 64: 263–282.
20. Jones J, Dougherty J, Cannon L. Diphenhydramine-induced toxic psychosis. Am J Emerg Med. 1986; 4: 369–371.
21. Karch SB. Diphenhydramine toxicity: comparisons of postmortem findings in diphenhydramine-, cocaine-, and heroin-related deaths. Am J Forensic Med Pathol. 1998; 19: 143–147.
22. Kuffner E, Patel M. Fatality from diphenhydramine monointoxication: a case report and review of the infant, pediatric, and adult literature. Am J Forensic Med Pathol. 2010; 31: 106
24. Dinndorf PA, McCabe MA, Frierdich S. Risk of abuse of diphenhydramine in children and adolescents with chronic illnesses. J Pediatr. 1998; 133: 293–295.
25. Feng S, Marr J, Goto C, et al. Clinical characteristics of pediatric abusers of black tar heroin/tylenol PM (cheese) in Dallas, Texas. North American Congress of Clinical Toxicology; New Orleans. Clin Toxicol. 2007; 45: 605–648.
26. Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2011 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol. 2012; 50: 911–1164.