Acetaminophen–diphenhydramine

An over-the-counter combination of acetaminophen (a pain reliever) and diphenhydramine (a sedating antihistamine) for occasional aches and pains with sleeplessness.

psilodex.org/m/acetaminophen-diphenhydramine · data v2026.10.05

Clinical contraindication: None listed; No label contraindication covering psilocybin was found. This is not a finding that the combination has been shown to be without risk.
Psilocybin evidence: No psilocybin data
Half-life: ~2–3 h; Approximate, in adults. Source under Interaction below.

Named in state rules?

Not namedColorado Condition rules (3)

Not namedOregon

PendingNew Mexico

Cite asPsilodex, “Acetaminophen–diphenhydramine”, v2026.10.05. psilodex.org/m/acetaminophen-diphenhydramine

Clinical data and state rules are separate facts. Both are shown; neither is a decision.

What it is used for

FDA status

Over the counter under an FDA monograph

Marketed under the OTC monograph (M013), not an individual FDA approval.

Availability

OTC

FDA-approved for

Occasional headaches and minor aches and pains with accompanying sleeplessness

Sources [1]

01 Interaction with psilocybin

It causes drowsiness and may cause confusion under psilocybin; acetaminophen has no known psilocybin interaction.

Detail Diphenhydramine is sedating and anticholinergic (blocks acetylcholine), and confusion or delirium is possible in an altered state. Acetaminophen has no known interaction. Separately, its label warns of severe liver damage above 4,000 mg of acetaminophen in 24 hours, with other acetaminophen-containing drugs, or with 3 or more alcoholic drinks a day.

Human data with psilocybin: No psilocybin data; based on how it works and its label
Half-life: acetaminophen ~2–3 h; diphenhydramine half-life not stated in FDA labels (FDA label, checked 2026-10-04)

Evidence types on this record

No psilocybin dataNo psilocybin data: no human data with psilocybin or another classic psychedelic; the text draws on the medication's own pharmacology and its label or reference facts

02 Pharmacology relevant to psilocybin

3 listed · counted on reports

Anticholinergic: Blocks acetylcholine. Can cause a fast heart rate, dry mouth, reduced sweating and heat intolerance, and confusion, more so at high doses or in combination. Sources [2]
Sedating or CNS depressant: Slows the central nervous system: drowsiness, slower reactions and impaired coordination, and slowed breathing at high doses. Effects add with other sedating substances. Sources [1]
Liver injury: The label or source warns of liver injury, from raised liver enzymes to liver failure. Liver disease also affects how the body clears psilocin. Sources [1]

03 State rules

Plain-language summary · official text governs

CO4 CCR 755-1

Not namedCondition rules (3)

No provision names this medication or its class.

Colorado · checked 2026-10-04

OROAR 333-333

Not named

No provision names this medication or its class.

Oregon · checked 2026-10-04

NM7.35.3 NMAC (proposed)

Pending

New Mexico's clinical rules (proposed 7.35.3 NMAC) are not final. No provision naming this medication has been found.

New Mexico · checked 2026-10-04

04 Conditions to ask about

Screening items in state rules

This medication is usually taken for a condition. State rules screen for some conditions directly, so the medication is a prompt to ask about them. Confirm with the participant; never assume a condition from the medication.

Liver disease if heavy use
- CO 2.5(A)(2) · Clinical Facilitator licensees
- CO 6.16(F)(2)(a) · Facilitators without a clinical facilitator license
- CO 6.16(F)(1) · All licensees

05 Sources

TYLENOL PM Extra Strength (acetaminophen, diphenhydramine HCl) Drug Facts (Kenvue) · FDA label (DailyMed) — revised 2026-07-22 | Marketing category: OTC Monograph Drug (M013) | "temporary relief of occasional headaches and minor aches and pains with accompanying sleeplessness" | Sedating or CNS depressant: "drowsiness will occur" | Liver injury: "Severe liver damage may occur if you take more than 4,000 mg of acetaminophen in 24 hours"
Diphenhydramine HCl injection (Fresenius Kabi) — Clinical Pharmacology · FDA label (DailyMed) — revised 2025-04-03 | Anticholinergic: "Diphenhydramine hydrochloride is an antihistamine with anticholinergic (drying) and sedative side effects."
Halman A, Kong G, Sarris J, Perkins D. Drug–drug interactions involving classic psychedelics: a systematic review. J Psychopharmacol 2024;38(1):3–18. — no reported interaction
Sarparast A, Thomas K, Malcolm B, Stauffer CS. Drug-drug interactions between psychiatric medications and MDMA or psilocybin: a systematic review. Psychopharmacology 2022;239(6):1945–1976. — no reported interaction
COMBOGESIC IV (acetaminophen and ibuprofen) injection label, section 12.3 · FDA label (DailyMed) — States acetaminophen half-life about 2 to 3 hours in adults. | [be408a5a] "The half-life of acetaminophen is about 2 to 3 hours in adults."
StatPearls (NCBI Bookshelf), drug monograph Indications section (per-drug link) — Terminal half-life roughly 9 h in adults; 5.4 h reported in children.

Record history

v2026.10.02First published.
2026-10-04Last reviewed against its sources.

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