Why is diphenhydramine (Benadryl) a common method for suicide, what symptoms and lethal effects does its overdose cause, and which tricyclic antidepressants are available and how do their overdoses present?

Diphenhydramine and Tricyclic Antidepressant Overdose: Mechanisms of Lethality and Clinical Presentation

Why Diphenhydramine (Benadryl) is Used in Suicide Attempts

Diphenhydramine is commonly used in suicide attempts because it is widely available as an over-the-counter medication, perceived as "safe" by the public, and can be lethal in overdose through cardiac sodium channel blockade. Between 2007 and 2020, adolescent diphenhydramine ingestions increased significantly, with suspected suicide attempts rising and associated with higher rates of serious outcomes including death 1.

Accessibility and Perception

• Available without prescription in multiple formulations
• Public perception as a "harmless" sleep aid or allergy medication masks its toxicity 2
• Easy to obtain in large quantities
• Social media has amplified awareness of its psychoactive effects at high doses 3

Demographics and Intent

• Suspected suicide accounts for 37.5% of intentional diphenhydramine ingestions 4
• Most cases (80% in one series) are certified as suicides, with depression being the most common psychiatric risk factor 3
• Females comprise approximately 59% of all ingestions 4

Lethal Mechanisms and Symptoms of Diphenhydramine Overdose

Diphenhydramine causes death through cardiac sodium channel blockade, leading to ventricular dysrhythmias and cardiovascular collapse, combined with anticholinergic toxicity causing seizures and CNS depression 5.

Cardiac Toxicity (Primary Lethal Mechanism)

Diphenhydramine is classified as a sodium channel blocker alongside tricyclic antidepressants 5. The cardiac effects include:

• QRS prolongation (>120 milliseconds indicates high toxicity)
• Ventricular dysrhythmias leading to cardiac arrest
• Hypotension and cardiogenic shock
• Terminal rightward axis deviation on ECG (best seen in lead aVR)

Neurological Toxicity

• Seizures (occur in 11.6% of all ingestions) 4
• Coma and altered mental status
• Agitation and delirium from anticholinergic effects

Anticholinergic Syndrome

• Hyperthermia
• Flushing and dry skin
• Mydriasis (dilated pupils)
• Urinary retention
• Intestinal ileus

Metabolic Derangements Associated with Severe Outcomes

The following findings strongly predict severe outcomes 4:

• Acidemia (pH < 7.2)
• QRS prolongation (>120 ms)
• Elevated anion gap (>20)

Lethal Blood Concentrations

• Therapeutic range: typically <100 ng/mL
• Toxic range: >1,000 ng/mL
• Lethal concentrations range from 3,300 to 285,000 ng/mL in documented fatalities 3
• One case series showed peripheral blood concentrations from 3,300 to 228,000 ng/mL in fatal cases 3

Critical pitfall: The wide variability in lethal concentrations means postmortem levels alone cannot definitively determine cause of death—circumstantial evidence and autopsy findings are essential 3.

Autopsy Findings

• Pulmonary edema (most common finding)
• Pill fragments in gastrointestinal tract
• Green-blue gastric mucosal discoloration may be present 6
• No specific pathognomonic findings, making diagnosis dependent on toxicology and scene investigation 3

Tricyclic Antidepressants: Available Agents

Common tricyclic and tetracyclic antidepressants include amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine 5.

These medications are the most commonly described and best-studied sodium channel blockers in overdose 5.

Tricyclic Antidepressant Overdose Presentation

TCA overdose presents with the "three C's"—Cardiac toxicity, Convulsions, and Coma—along with anticholinergic signs, and is the most common cause of death from prescription drug overdose 7.

Clinical Presentation Algorithm

Cardiac Manifestations (Primary cause of death):

• QRS prolongation to ≥100 milliseconds indicates highly toxic/lethal levels (>1,000 ng/mL) 7
• Ventricular dysrhythmias including ventricular tachycardia and fibrillation
• Hypotension progressing to cardiovascular collapse
• Terminal rightward axis deviation in lead aVR 5

Neurological Manifestations:

• Seizures (often precede cardiac arrest)
• Coma and decreased level of consciousness
• Agitation or delirium early in presentation

Anticholinergic Signs:

• Hyperthermia
• Flushing and dry mucous membranes
• Mydriasis (dilated pupils)
• Intestinal ileus and decreased bowel sounds
• Urinary retention

Treatment Priorities for Both Diphenhydramine and TCA Overdose

Sodium bicarbonate is the definitive treatment for life-threatening cardiotoxicity from both tricyclic antidepressants and diphenhydramine 5.

Management algorithm:

1. Establish airway with early intubation for severe cases
2. Cardiac monitoring with continuous ECG
3. Sodium bicarbonate bolus (hypertonic solution: 1000 mEq/L in adults, 500 mEq/L in children) for QRS >100 ms or ventricular dysrhythmias 5
4. Alkalinization to blood pH of 7.5 7
5. Gastric lavage and activated charcoal if presenting early
6. Benzodiazepines for seizures
7. VA-ECMO for refractory cardiogenic shock 5
8. Fluid replacement at maintenance levels (avoid overhydration)

Critical pitfall: Do NOT use typical antiarrhythmics like amiodarone or procainamide—these worsen sodium channel blockade. Lidocaine (class Ib) may be reasonable for refractory dysrhythmias 5.

Why These Overdoses Are Lethal

Both diphenhydramine and TCAs cause death through the same mechanism: cardiac sodium channel blockade leading to wide-complex dysrhythmias, ventricular fibrillation, and cardiovascular collapse. The combination of cardiac toxicity with seizures (which worsen acidosis and further impair cardiac conduction) creates a lethal cascade. The anticholinergic effects contribute to morbidity through hyperthermia and aspiration risk but are not the primary cause of death 5, 4, 7.