Although not usually considered “drugs of abuse” by the public, over-the-counter (OTC) medications are implicated in a portion of overdose cases. Although the toxicity of some OTC medications (such as acetaminophen, aspirin, and diphenhydramine [DPH]) has been extensively reported in the medical literature, the lethality of other substances (including melatonin) has not been well established.1,2
Recent reports have found that 59% of older adults admit to taking nonprescription sleep aids, with many being unaware of the potential adverse effects and consequences of toxicity.3 This lack of knowledge is particularly dangerous considering the high potential for abuse of a portion of OTC medications, owing to both the lack of prescription necessary for purchase and the unregulated quantities one can buy in most circumstances. Furthermore, there has been a substantial increase in the use of OTC medications across all age groups. From 2005 to 2016, there was a 63% increase in intentional DPH exposure across all age groups with a much larger increase, 218%, in individuals who were 10 to 14 years old.3 In the case of melatonin, despite the importance of this hormone in the role of the circadian rhythm and the widespread effects it can have as an OTC supplement, little research has been done analyzing its toxicity and potential lethality. This is despite the fact that OTC drugs such as acetaminophen are used in up to 30% of suicide attempts.4 Regarding the specific demographics, women are more likely than men to use OTC drugs for self-harm. In pregnant women, OTC nonopioid analgesics are used in roughly half of all intentional poisoning suicide attempts. This is further complicated by the role of health care professionals in providing care because they are generally unaware of nonprescribed medications and do not keep a record of their use.4,5
The purpose of this report is to shed light on the potential misuse and toxicity of both DPH and melatonin, to encourage further investigation of the lethality of OTC medications, and to emphasize the importance of the role of death scene investigation and communication with laboratory consultants in “negative” autopsy cases. In addition, we hope this report will aid in increasing the general public's awareness of these potentially dangerous substances.
We report a case of death due to OTC sleep aid toxicity, in which there were elevated concentrations of both DPH and melatonin. A 21-year-old woman was found deceased within her secure residence approximately 27 hours after being last known alive. Scene investigation revealed the presence of 5 empty containers of DPH (soft gel, 50 mg, 160 pills missing) and a partially empty container of melatonin (fast dissolve, 10 mg, up to 48 pills missing). Also present was a handwritten note of apparent suicidal nature in addition to a receipt for the bottles of DPH and melatonin (time-stamped at approximately 1 hour before the last known communication from the decedent). Her reported past medical history included a previous suicidal attempt with acetaminophen and multiple psychiatric diagnoses. Recent stressors included breaking up with her significant other on the date she was last known alive.
Autopsy examination revealed no evidence of foul play or inflicted trauma. There was evidence of nonspecific pulmonary congestion (with associated bilateral pleural effusion [right, 150 mL; left, 200 mL]) and cerebral edema. In addition, the gastric mucosa was notable for a green-blue discoloration, and the gastric contents were consisted of a green-tan viscous material with admixed blue particulate material (consistent with the blue coloration of the soft-gel DPH found on the scene). Minimal underlying natural disease was noted, including microscopic hypertensive changes of the heart. Toxicologic specimens were obtained at approximately 48.5 hours after last known alive and 21.0 hours after time found. Based on the scene investigation, specific analyses for DPH and melatonin were performed on samples of both blood and gastric contents (in addition to routine toxicologic screening of blood and vitreous samples). Results of these analyses revealed iliac and cardiac blood DPH concentrations of 34 mg/L and 49 mg/L, respectively. Gastric contents revealed a DPH concentration of 2700 mg/L. Concentrations of melatonin in the iliac and cardiac blood were 3.9 mg/L and 4.4 mg/L, respectively. The gastric contents had a melatonin concentration of 130 mg/L. Additional prescription and OTC substances noted upon toxicologic analysis are reported in Table 1; they were each below their respective published lethal ranges and were determined to not contribute to death. Because of the elevated concentrations of both DPH and melatonin within the decedent's system, the death was certified as a suicide by acute combined DPH and melatonin toxicity.
TABLE 1 -
Results of Toxicology Analysis of the Postmortem Specimens
DPH: 34.00 mg/L
DPH: 49.00 mg/L
DPH: 2700.00 mg/L
||No volatiles detected
Melatonin: 3.900 mg/L
Melatonin: 4.40 mg/L
Melatonin: 130.00 mg/L
|Amphetamine: 180 μg/L
|Alprazolam: <5.0 μg/L
|Venlafaxine: 850 μg/L
|No volatiles detected
DPH, diphenhydramine. Bolded text indicates primary toxic agents.
Opioid and prescription abuse has received much attention, whereas OTC abuse has not been as well studied. An analysis performed by Nemanich et al3 to describe trends in suicide, abuse, and misuse of DPH found that there was a bimodal distribution in suicidal attempts using DPH with an increase in the pediatric (10–14 years old) and older adult (55+ years) age ranges. The age of the decedent in the current case is outside of the previously reported bimodal distribution; however, this case serves as a reminder that, despite the disproportionate increase of suicidal attempts within the pediatric and older adult populations, abuse of DPH may still occur across all age groups. The study of Nemanich et al3 also reported that nearly half of the exposures to DPH involved the presence of another drug. This finding correlates to the current case as melatonin was a coingestant. As far as we are aware, this is the first published analysis of a case where an individual died from elevated concentrations of both DPH and melatonin.
PHARMACOKINETICS AND TOXICITY
Diphenhydramine functions by competing with histamine for H-1 receptor sites.6 Locations of these receptors can be found throughout the body; however, the ones located within the central nervous system are responsible for the sedative side effect. In addition, DPH acts on muscarinic receptors causing anticholinergic effects such as tachycardia, dry mouth, and blurry vision, which become more prominent at higher concentrations. In cases of increased concentration/toxicity (often doses >1.0 g), DPH can function as a blocker of the heart's rectifier potassium ion channels due to its anticholinergic activity. Because of the role of these channels in cardiac repolarization, DPH can induce a prolonged QT interval and flattened T-wave, resulting in a greater risk of torsade de pointes and other arrhythmias.7,8 In addition to changes in cardiac repolarization noted in the setting of high DPH concentrations, the sedative effects are eclipsed by the severe anticholinergic complications that may occur, including cardiac arrhythmia, seizure, delirium/psychosis, and coma.7 The current recommended daily maximum intake of DPH is 300 mg by mouth.6 Peak serum levels are reached after approximately 2 to 3 hours while the drug has a half-life that is very age dependent: pediatric populations, 4 to 7 hours; adult populations, 7 to 12; and elderly populations, 9 to 18 hours.9 Further amplifying this drug's toxic effects on the body is its high volume of distribution owing to its lipophilic nature. We recorded iliac and cardiac blood concentrations of DPH at 34 mg/L and 49 mg/L, respectively, which corresponds with current literature reporting the lethal range of DPH as 2.4 to 70 mg/L.10
The secretion of endogenous melatonin is highly regulated by the circadian rhythm in humans, as its function is related to transmitting sleep signals.11 During the daytime, normal levels of melatonin are typically less than 0.0001 mg/L, while the peak concentration that occurs around 3 to 4 am is on average up to 0.0009 mg/L.10 In cases of overdose, this basal fluctuation was deemed to be negligible, and there is currently no comparable literature that delineates the average changes seen in postmortem concentrations.10,12
In addition to endogenous secretion, melatonin can be purchased over the counter. The receptors on which melatonin normally acts, typically G-protein coupled receptors, are distributed across the whole body. Signaling through these receptors leads to effects ranging from alterations in immune response and blood pressure to smaller scale modifications such as regulation of the cell cycle and melatonin's antioxidant protective properties.11
The breakdown of melatonin is performed primarily by the liver, which clears more than 90% of the melatonin in circulation through the use of cytochrome CYP1A2.11 Because this cytochrome is also involved in the metabolism of other pharmacologic substances, the serum concentrations and bioavailability of melatonin can be very dependent on concomitant drug use.11 Specifically, CYP1A2 inducers such as polycyclic aromatic hydrocarbon ingestion, smoking, and drugs such as omeprazole can function to lower levels of melatonin. Conversely, inhibitors such as quinolone antibiotics cimetidine, verapamil, and oral contraceptives will increase the levels of melatonin.13
Melatonin is also highly soluble in both lipids and water, allowing it to easily cross lipid membranes such as the blood brain barrier and enter the cerebrospinal fluid.8 We recorded iliac and cardiac blood concentrations of melatonin at 3.9 mg/L and 4.4 mg/L, respectively. Although a level of 1.4 mg/L has been published as lethal within the pediatric population, there is currently no literature that reports a lethal range of melatonin in adults.10 Of 2 previously reported case reports, one noted adverse effects after an oral dose of 24 mg resulting in lethargy and disorientation, whereas the other described lethargy and severe delayed hypotension after an oral dose of 180 mg.14,15 The currently reported case of combined DPH and melatonin toxicity had a potential oral ingestion of up to 480 mg of melatonin. The case descriptions by Holliman and Chyka as well as Johnson and Dotson support that the presence of melatonin on toxicologic analysis should not be overlooked and that exogenous melatonin supplements should be considered as a potential lethal agent in cases of suspected overdose.14,15
Further complicating matters can be the presence of multiple drugs in the decedent's system, as is seen in the case we present. Although the level of DPH by itself is well within the reported lethal ranges, the concentration of melatonin is also well above its published therapeutic ranges and the reported lethal range within the pediatric population. Although there have been no previous reports of lethal concentrations of melatonin within the adult population in the medical literature, this case highlights the need for further inquiry into the potentially lethal effects of this substance.
Toxicologic screening was also positive for several other substances, which were deemed noncontributory to the cause of death. Amphetamine was present and measured at 180 μg/L, whereas alprazolam was measured at <5.0 μg/L. Both of these substances were known to be prescribed to the decedent, and they were each within or below their respective therapeutic ranges. Venlafaxine was also noted at 850 μg/L, which is within its reported therapeutic range. A review of available medical records failed to reveal a known prescription for venlafaxine; however, with the patient's past psychiatric history, it is possible that this substance was prescribed and that the correct documentation was not available at the time of investigation. Although both amphetamine and alprazolam could hypothetically potentiate the cardiotoxic effects of DPH, the concentration of DPH in addition to the blood concentration of melatonin were deemed to be the predominant contributors to the decedent’s cause of death.
One factor that can complicate the analysis of postmortem drug concentrations is the phenomenon known as postmortem redistribution (PMR). Postmortem redistribution occurs after death and involves a shift in the concentration of a drug found in the blood because of diffusion or further metabolism/catabolism. Postmortem redistribution is described in terms of the comparison of the concentrations of a drug within both the cardiac blood and the peripheral blood, or cardiac to peripheral blood (C/P) ratio.16,17 Contributing factors that can act as confounding variables in the interpretation of PMR include the age and condition of the deceased, obtaining the samples at varying intervals after the time of death, the quantity of drugs taken, and the presence of multiple drugs. Two possible causes lead to PMR: first, an initially unabsorbed drug can be absorbed after death, or second, a drug that was absorbed before death can move between the various binding sites in the body. The former scenario can also be impacted by the metabolism and/or catabolism of the drug by the microbiota found in the body.17 In the second scenario, the reported level of a drug is inaccurate because of the movement, or diffusion, of the substance between the site of sample collection and the surrounding organs/tissues. Large variability of drug concentrations is most likely to occur in analytes that are lipophilic and have a high volume of distribution, 2 things that DPH and melatonin have in common.16,18 Drug concentrations in the femoral blood can appear artificially elevated because of diffusion from the bladder, through the iliac, and into the femoral circulation.14 According to McIntyre and Escott,16 statistical chance, variances in anatomy, and arteriovenous formation can increase the ratio of C/P for drugs that do not typically have a high redistribution ratio. Meanwhile, attempts at resuscitation can cause the C/P to decrease below 1.0.
Because of PMR and to maintain an objective analysis of drug concentrations, it is important to pull samples from both peripheral and central locations, as those from central locations are more likely to have higher concentrations. Currently, femoral blood draws are the recommended source of peripheral blood because of the possibility of unabsorbed drugs within the stomach at the time of death undergoing redistribution to mediastinal vessels and surrounding organs.19 Although a femoral source of blood is the preferred peripheral site within the literature, this current case demonstrates collection of blood from the iliac veins (which are located immediately proximal to the femoral vessels). The possibility of diffusion of gastric-derived drug(s) may be relevant in our present case given the appearance of the gastric contents, which were consistent with the soft gel DPH residue, in addition to the delay of sample collection of potentially up to 48.5 hours after death. In our case, blood was obtained from the heart and gastric contents as central sources, whereas iliac blood was drawn as a peripheral source.
Current literature reports that the C/P of DPH is anywhere from 0.3 to 21.0, indicating that the cardiac blood value could be up to 21 times greater than the peripheral value.10,19 Our case supports the current literature, as there is a DPH PMR of 1.44. In addition, the PMR of melatonin for our presented case is 1.13; however, with no current literature regarding melatonin PMR for comparison, this value has no immediate significance other than indicating that there is less redistribution compared with DPH in this specific case.
CORRELATION OF FINDINGS
Because of the potential of both PMR and interactions between medications, interpretation of toxicologic data can be challenging. In some cases, the initial autopsy findings and ancillary testing may not adequately explain the cause of death. In these situations, it is especially important to review all the available case information, including scene information and outside medical records. In the presented case, the presence of DPH and melatonin bottles on the scene allowed for targeted analysis of these substances, an inquiry that may not have been pursued if not for the decedent's medical history and scene findings. Typical toxicology testing would not quantitate, or even identify, the melatonin, and DPH quantification is variable depending on both the toxicologic laboratory procedures and practices of the pathologist. These considerations underline the importance of the relationship between the autopsy pathologist with their toxicologist, especially in cases where the toxicology report may first appear to be “noncontributory” and natural disease or trauma is not enough to explain the death. In these situations, the toxicologist can be an invaluable asset in suggesting additional testing based on the internal laboratory data/analysis results. It is also important to consider the fact that a lethal concentration can be dependent upon the individual and many different elements at play such as acute comorbidities, past medical history, body mass index, sex, and past drug use with associated tolerance. In addition, past medical history, such as previous suicidal attempts with OTC medications or recent stressors, and the current presentation should be kept in mind during the autopsy process and final determination of the cause and manner of death.
In this specific case, DPH was found to be within previously reported lethal ranges. The addition of melatonin to the cause of death was multifactorial, including the results of scene investigation (half-empty bottle of melatonin and receipt indicating purchase of a bottle on the date last known alive) and laboratory analysis showing (1) melatonin present at an elevated concentration within the gastric contents (indicating ingestion at a close proximity to the time of death) and (2) a blood concentration of melatonin which is 39- to 44-fold higher than the upper limit of the reported therapeutic range for oral ingestion.10 Because of the paucity of information of melatonin's mechanism of action and toxic effects with varying concentrations, there is need for further investigation.
To our knowledge, this case report is the first to describe a suicidal death due to elevated concentrations of both DPH and melatonin. It also supports the findings of others that warn of increasing abuse of OTC medications. Prevention of OTC misuse could include possible public health strategies such as regulated access, altered packaging (such as blister packs to help deter the use of large quantities in a single session), and further resources devoted to the treatment of mental health conditions. Further investigation is needed for common OTC medications that have little presence in current literature, such as melatonin. Finally, it is important to understand the significance of scene investigation and communication with laboratory colleagues in cases of possible drug overdose.
1. Guslandi M. Gastric toxicity of antiplatelet therapy with low-dose aspirin. Drugs
2. Ghanem CI, Pérez MJ, Manautou JE, et al. Acetaminophen from liver to brain: new insights into drug pharmacological action and toxicity. Pharmacol Res
3. Nemanich A, Liebelt E, Sabbatini AK. Increased rates of diphenhydramine
overdose, abuse, and misuse in the United States, 2005–2016. Clin Toxicol (Phila)
4. Mikhail A, Tanoli O, Légaré G, et al. Over-the-counter drugs and other substances used in attempted suicide presented to emergency departments in Montreal, Canada. Crisis
5. Shoib S, Patel V, Khan S, et al. Over-the-counter drug use in suicidal/self-harm behavior: scoping review. Health Sci Rep
6. Sicari V, Zabbo CP. Diphenhydramine
. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; January 2022 [cited 2022 Jun 16]. Available at: http://www.ncbi.nlm.nih.gov/books/NBK526010/
7. Radovanovic D, Meier PJ, Guirguis M, et al. Dose-dependent toxicity of diphenhydramine
overdose. Hum Exp Toxicol
8. Taglialatela M, Timmerman H, Annunziato L. Cardiotoxic potential and CNS effects of first-generation antihistamines. Trends Pharmacol Sci
9. Simons KJ, Watson WT, Martin TJ, et al. Diphenhydramine
: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children. J Clin Pharmacol
10. Baselt RC. Disposition of Toxic Drugs and Chemicals in Man
. 12th ed. Seal Beach, CA: Biomedical Publications; 2020.
11. Claustrat B, Leston J. Melatonin
: physiological effects in humans. Neurochirurgie
12. Zeitzer JM, Duffy JF, Lockley SW, et al. Plasma melatonin
rhythms in young and older humans during sleep, sleep deprivation, and wake. Sleep
13. Guo J, Zhu X, Badawy S, et al. Metabolism and mechanism of human cytochrome P450 enzyme 1A2. Curr Drug Metab
14. Holliman BJ, Chyka PA. Problems in assessment of acute melatonin
overdose. South Med J
15. Johnson HE, Dotson JM, Ellis CS, et al. Severe hypotension in an adolescent after a melatonin
overdose. J Child Adolesc Phychopharmacol
16. McIntyre I, Escott C. Postmortem drug redistribution. J Forensic Res
17. Kennedy M. Post-mortem drug concentrations. Intern Med J
18. Barrenetxe J, Delagrange P, Martínez JA. Physiological and metabolic functions of melatonin
. J Physiol Biochem
19. Pélissier-Alicot AL, Gaulier JM, Champsaur P, et al. Mechanisms underlying postmortem redistribution of drugs: a review. J Anal Toxicol