Naproxen–diphenhydramine

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

psilodex.org/m/naproxen-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: 12–17 h; Approximate, in adults. Source under Interaction below.

Named in state rules?

Not namedColorado

Not namedOregon

PendingNew Mexico

Cite asPsilodex, “Naproxen–diphenhydramine”, v2026.10.05. psilodex.org/m/naproxen-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]

Other safety

The label warns that NSAIDs other than aspirin increase the risk of heart attack, heart failure and stroke, and that naproxen can cause severe stomach bleeding.

About the medication itself, separate from any interaction with psilocybin.

Sources [1]

01 Interaction with psilocybin

It causes drowsiness and may cause confusion with psilocybin; regular naproxen use can raise blood pressure, as psilocybin briefly does.

Detail Diphenhydramine is sedating and anticholinergic (blocks the nerve chemical acetylcholine). Confusion or delirium is possible in an altered state. Naproxen has no known interaction with occasional use. Regular naproxen use can raise blood pressure, as psilocybin briefly does.

Human data with psilocybin: No psilocybin data; based on how it works and its label
Half-life: Naproxen 12–17 h (FDA label, checked 2026-10-04) Diphenhydramine ~9 h (see diphenhydramine record).

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

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 2026-10-04

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

None linked

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

05 Sources

ALEVE PM (diphenhydramine HCl, naproxen sodium) Drug Facts (Bayer; NDA205352) · FDA label (DailyMed) — revised 2025-12-04 | "for relief of occasional sleeplessness when associated with minor aches and pains" | Sedating or CNS depressant: "drowsiness will occur" | "NSAIDs, except aspirin, increase the risk of heart attack, heart failure, and stroke."
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."
NAPROXEN tablet (ScieGen, Rx) · FDA label (DailyMed) — revised 2026-03-18 | Raises blood pressure or heart rate: "NSAIDs, including naproxen tablets can lead to new onset of hypertension or worsening of pre-existing hypertension" | "The elimination half-life of naproxen is unchanged across products ranging from 12 to 17 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.
2026-10-04Last reviewed against its sources.

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