This week’s briefing highlights diphenhydramine, a first-generation antihistamine widely available over the counter and is commonly used to treat allergy symptoms, motion sickness, and insomnia. Although generally safe when used as directed, diphenhydramine can produce significant adverse effects when consumed in excessive amounts.

With broad availability and low cost, diphenhydramine has been identified as a substance of misuse, particularly among adolescents and young adults seeking its psychoactive and hallucinogenic effects at high doses.

This trend has increasingly appeared in recent surveillance reports, been highlighted by members of our Scientific Advisory Group, and was a key point of discussion at the recent College on Problems of Drug Dependence annual meeting, underscoring the importance of keeping a close eye on this substance moving forward.

As always, we welcome your input.

Nationally, 21,995 nonfatal EMS encounters were reported for suspected nonfatal overdose with diphenhdryamine indicated in the record from January 1, 2023 to June 30, 2026. The dispatch reasons included Overdose/Poisoning/Ingestion or Psychiatric Problem/Abnormal Behavior/Suicide Attempt. The national trends and demographics of these EMS encounters are shown below including age, sex, and race.
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Why are we reporting on this? Diphenhydramine, an over-the-counter first-generation antihistamine commonly sold under brand names like Benadryl, is being discussed on Reddit regarding nonmedical high-dose use, polysubstance combinations, and long-term health concerns. Online discussions reveal recurring themes including deliberate ingestion of large doses to induce delirium, the combination of diphenhydramine with opioids or dissociatives to enhance effects, and difficulties with chronic daily use and dependence.

What is diphenhydramine? Diphenhydramine is an over-the-counter H1-antihistamine and anticholinergic medication used to treat allergies, motion sickness, and temporary insomnia. While intended for short-term therapeutic use at low doses, high doses cross the blood-brain barrier and block muscarinic acetylcholine receptors, producing delirium, sedation, and severe physiological strain.

Public Health Impacts: Reddit discussants report substantial health concerns associated with nonmedical diphenhydramine use and chronic daily administration. Commenters frequently describe uncomfortable physiological and psychological effects, including severe physical heaviness, restless leg sensations, cognitive fog, persistent visual disturbances such as visual snow, and dysphoric hallucinations. Multiple discussions emphasize the risk of accidental overdose, severe motor impairment, and full-blown states of delirium leading to psychosis or physical injury. Additionally, commenters express concern regarding long-term daily use for sleep, citing fears of accelerated cognitive decline and severe rebound insomnia or withdrawal when attempting to quit.

How is it Being Discussed?  Reddit commenters discuss diphenhydramine across a range of contexts, spanning routine sleep management to high-dose recreational deliriant "trips." A recurring theme is the deliberate combination of diphenhydramine with other substances, including dissociatives like dextromethorphan (DXM) and research chemicals, or opioid agonists like kratom and 7-hydroxymitragynine (7-OH), to potentiate visual effects or counteract unwanted side effects like nausea. While some discussants experiment with dosage, many posts warn against high-dose use, characterizing the experience as inherently dysphoric, uncomfortable, and alarming. Commenters actively share strategies to reduce negative effects associated with diphenhydramine, personal accounts of addiction, and strategies for quitting daily use, while discussing the widespread availability and low cost of over-the-counter preparations.

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Image source: Figure 1. Frequency of substance-alone and co-occurring substances among top primary agent-positive syringes included in McNealy et al.

A recently published preprint study in medRxiv by McNealy et al. analyzed residue from used syringes (N=3,168), collected through five community-based syringe service programs in Jefferson County, Kentucky. Syringe contents were assessed using gas chromatography-mass spectrometry (GC-MS), and detected compounds were classified as adulterants, synthesis precursors or byproducts, and recreational drugs. Diphenhydramine (DPH) was identified as the top adulterant (n=1021; 40.48%), and was most commonly co-detected with fentanyl (n=670; 26.57%) and fentanyl + heroin (n=327; 12.97%). Historically, DPH is a known opioid adulterant, however, it was also among the most common adulterants detected with methamphetamine. Notably, 28.9% of syringes containing methamphetamine + DPH contained no opioids, suggesting that this combination cannot be explained solely by concurrent opioid use. Findings highlight the complex nature of the unregulated drug supply and evolving patterns in polysubstance use.

Read the full study here.

Image source: Graphs highlighting findings from UK HRH data as published in its newsletters.

More recent data from syringe residue checking continues to support similar trends. Authors of the publication above are among key personnel affiliated with the University of Kentucky Harm Reduction Hub (UK HRH) including principal co-investigators Rachel Vickers-Smith and Amanda Fallin-Bennett. UK HRH's March 2026 newsletter focused on methamphetamine, highlighted the frequency of common adulterants detected in methamphetamine-containing syringes and reported that methamphetamine + DPH accounted for 15.9% of detections. Data from April and May continue to show DPH among the top 10 most frequent substances detected.

Image source: America’s Poison Centers logo.

In June, America’s Poison Centers issued a health advisory in response to an increase in exposure cases involving diphenhydramine reported to US poison centers. This increase appears to be largely driven by teens misuse of diphenhydramine for recreational purposes, rather than accidental medication errors. Between 2024 to 2025, cases involving diphenhydramine increased faster than exposure cases to any substance among teens. In 2026, intentional recreational misuse accounted for 13.7% of teen diphenhydramine-only cases compared to 7.3% in 2020.

Read the full health advisory here.

Image source: UNC Street Drug Analysis Lab regional live report.

An interactive report from the UNC Street Drug Analysis Lab provides a regional overview of mail-in drug checking samples from January 2022 – April 2026, analyzed using data gas chromatography–mass spectrometry (GC-MS). Of the 90 substances routinely detected by the lab, 20 appear across the four regions of the US at similar rates. The remaining 70 are assigned to a regional cluster, meaning that single region accounts for at least 35% of its national signal. The Midwest region included 12 substances that were clustered, with diphenhydramine being the most commonly detected. It was identified in 89% of Midwest samples, compared with detection rates of less than 6% in the other US regions.

Learn more about the UNC Street Drug Analysis Lab at opioiddata.org

Read the full report here.

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The NDEWS Weekly Briefing curates emerging data and findings from across the Early Warning Network, which includes three core components: our Scientific Advisory Group (SAG), comprised of national experts and federal partners; our Sentinel Site Directors (SSDs), who lead local surveillance in key geographic regions; and our Community-Based Health Experts, who provide on-the-ground insights from populations most impacted by drug trends. Together, these contributors generate timely, multidisciplinary and impactful information, ranging from peer-reviewed research findings to local surveillance data. These contributions inform public health and research communities.

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If you miss or want to learn more about NDEWS Original Content, you can find our archived content on the NDEWS website:

     • NDEWS Hotspot Alerts using substance-related EMS data
     • NDEWS Rapid Street Reporting (RSR) survey data reports
     • NDEWS Web Monitoring Team Reddit Alerts
     • NDEWS Sentinel Site Reports
     • Previous issues of the NDEWS Weekly Briefings

The Weekly Briefing is a newsletter published each week by the National Drug Early Warning System (NDEWS) Coordinating Center, which is funded by the National Institute on Drug Abuse (U01DA051126) to the University of Florida (MPI: Cottler (contact), Co-Is: Goldberger, Nixon, Striley), NYU Langone Health (MPI: Palamar), and Florida Atlantic University (Co-I: Barenholtz). Any item may be reproduced provided the source is acknowledged.