Ibuprofen / diphenhydramine

An over-the-counter combination of ibuprofen (an NSAID) and diphenhydramine (a sedating antihistamine), FDA-approved for occasional sleeplessness with minor aches and pains.

psilodex.org/m/ibuprofen-diphenhydramine · data v2026.10.04

Clinical contraindication: None listed; No clinical contraindication identified.
Psilocybin evidence: No psilocybin data
Half-life: 1.8–2 h; Approximate, in adults. Source under Interaction below.

Named in state rules?

Not namedColorado

Not namedOregon

PendingNew Mexico

Cite asPsilodex, “Ibuprofen / diphenhydramine”, v2026.10.04. psilodex.org/m/ibuprofen-diphenhydramine

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

What it is used for

FDA status

FDA-approved

Availability

OTC

FDA-approved for

Occasional sleeplessness associated with minor aches and pains

Sources [1][2]

01 Interaction with psilocybin

It causes drowsiness and may, in theory, cause confusion under psilocybin; regular ibuprofen use can raise blood pressure, as psilocybin transiently does.

Detail Diphenhydramine is sedating and anticholinergic, with confusion or delirium possible in an altered state. Ibuprofen has no known interaction with occasional use; regular use can raise blood pressure, as psilocybin transiently does.

Human data with psilocybin: None known: no published human data with psilocybin
Half-life: Ibuprofen 1.8–2 h (FDA label, checked 2026-10-03) Diphenhydramine ~9 h (see diphenhydramine record).

Evidence types on this record

No psilocybin dataNo psilocybin data; record based on general references (product label, reference works, reviews)

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 [3]
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][2]
Raises blood pressure or heart rate: Raises blood pressure or heart rate. Psilocybin raises both for several hours, so the effects can add. Sources [4]

03 State rules

Plain-language summary · official text governs

CO4 CCR 755-1

Not named

No provision names this medication or its class.

Colorado · checked 2026-09-30

OROAR 333-333

Not named

No provision names this medication or its class.

Oregon · checked 2026-09-30

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 2026-10-02

04 Conditions to ask about

None linked

No condition named in state rules is linked to this medication.

05 Sources

ADVIL PM (ibuprofen, diphenhydramine HCl) Drug Facts (Haleon) · FDA label (DailyMed) — revised 2026-07-29 | cns_depressant: "drowsiness will occur"
Motrin PM (ibuprofen, diphenhydramine citrate) Drug Facts (Kenvue) · FDA label (DailyMed) — revised 2025-07-11 | cns_depressant: "drowsiness will occur"
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."
Ibuprofen tablets, Rx · FDA label (DailyMed) — revised 2024-01-16 | raises_bp_hr: "NSAIDs including ibuprofen tablets can lead to onset of new hypertension or worsening of preexisting hypertension" | half_life: "The serum half-life is 1.8 to 2.0 hours."
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

Record history

v2026.10.02First published.
2026-10-03Last reviewed against its sources.

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