Promethazine–dextromethorphan

A prescription cough syrup combining promethazine (a sedating antihistamine) and dextromethorphan (a cough suppressant), FDA-approved for cough and upper respiratory symptoms from allergy or colds.

psilodex.org/m/promethazine-dextromethorphan · 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: ~16–19 h; Approximate, in adults. Source under Interaction below.Effect duration: Dextromethorphan about 3–6 h; promethazine effects generally 4–6 h, sometimes up to 12 h

Named in state rules?

UnsettledColorado

Not namedOregon

PendingNew Mexico

Cite asPsilodex, “Promethazine–dextromethorphan”, v2026.10.05. psilodex.org/m/promethazine-dextromethorphan

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

What it is used for

FDA status

FDA-approved

Sources [1]

FDA-approved for

Cough and upper respiratory symptoms with allergy or the common cold

Sources [1]

Other safety

Boxed warning: promethazine is contraindicated under age 2 because of fatal respiratory depression. The label also warns of respiratory depression with compromised breathing and of neuroleptic malignant syndrome.

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

Sources [1]

01 Interaction with psilocybin

Its sedating, drying (anticholinergic) effects may add drowsiness or confusion with psilocybin; its dextromethorphan may add serotonin effects.

Detail Promethazine is a sedating, anticholinergic (drying, confusing) phenothiazine antihistamine. It may add drowsiness or confusion with psilocybin (no data). Dextromethorphan is serotonergic (serotonin-boosting) and, well above label doses, dissociative; in theory these effects add to psilocybin's. In a small human study, haloperidol (a D2 dopamine blocker) did not prevent psilocybin's effects. It increased anxiety, and psychosis-like (psychotomimetic) effects were reported as increased (Vollenweider 1998). Also, the label states promethazine may lower the seizure threshold. Sources [1][6][7]

Human data with psilocybin: No data on this medication itself; related drugs studied (see text)
Effect duration: Dextromethorphan about 3–6 h; promethazine effects generally 4–6 h, sometimes up to 12 h Sources [1]
Half-life: promethazine ~16–19 h; dextromethorphan ~2–3 h (extensive metabolizers) (article, checked 2026-10-03) Dextromethorphan half-life is ~15-20 h in CYP2D6 poor metabolizers. Promethazine clinical effects typically last 4-6 h, up to 12 h.

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

6 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 [1]
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]
Dissociative (NMDA antagonist): Blocks NMDA receptors and can cause dissociation: feeling detached from the body or surroundings. Effects can add to psilocybin’s. Sources [3]
Psychiatric reactions: The label or source warns of psychiatric effects such as psychosis, mania, hallucinations, suicidal thoughts or severe mood or behavior changes. Psilocybin can also bring up strong emotions, so these warnings are relevant to screening. Sources [1]
Lowers seizure threshold or carries seizure risk: Makes a seizure more likely, or has been linked to seizures. Sources [1]
Serotonergic: Increases serotonin activity, for example by blocking its reuptake or releasing it. Psilocybin acts on serotonin receptors, so effects can add together. With antidepressant use, the psilocybin response can be weaker. Sources [2]

03 State rules

Plain-language summary · official text governs

CO4 CCR 755-1

Unsettled · 2.2(A)(6)–(7)

Colorado's rule covers lithium and “antipsychotic medications” but doesn't define the term, so whether it covers this medication is not settled. This syrup contains promethazine, a phenothiazine (the chemical family of several antipsychotics) that blocks dopamine D2 receptors, but promethazine is approved for allergy, nausea and sedation, not for psychosis. If the provision covers it: Colorado rule 2.2(A)(6) states that Facilitator licensees may not provide natural medicine services to participants taking lithium or antipsychotic medications. Under 2.2(A)(7), services may proceed only after a referral from a licensed provider (MD, DO, APN, PA or clinical facilitator), medical clearance from the participant's provider, or a consultation and risk review with a provider licensed to diagnose and treat the condition identified as a risk factor; the Facilitator documents the consultation, and where it identifies heightened risk, the rule requires a safety plan and written informed consent.

2.2(A)(6)–(7) · Facilitator licensees

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

PROMETHAZINE DM (promethazine HCl and dextromethorphan HBr) oral solution (PAI; ANDA040649) · FDA label (DailyMed) — revised 2025-05-31 | "temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold" | Sedating or CNS depressant: "Promethazine and dextromethorphan may cause marked drowsiness" | Lowers seizure threshold or carries seizure risk: "Promethazine may lower seizure threshold." | Anticholinergic: "Concomitant use of other agents with anticholinergic properties should be undertaken with caution."; overdose "Atropine-like signs and symptoms" | Psychiatric reactions: "Hallucinations have also been reported." | "The duration of action after oral administration is approximately three to six hours."; promethazine "generally last four to six hours, although they may persist as long as 12 hours" | boxed "POTENTIAL FOR FATAL RESPIRATORY DEPRESSION"
NUEDEXTA (dextromethorphan/quinidine) — section 10 Overdosage · FDA label (DailyMed) — revised 2026-01-22 | Serotonergic: "Dextromethorphan may cause serotonin syndrome, and this risk is increased by overdose, particularly if taken with other serotonergic agents, SSRIs or tricyclic antidepressants."
AUVELITY (dextromethorphan–bupropion) — section 12.1 · FDA label (DailyMed) — revised 2026-08-17 | Dissociative (NMDA antagonist): "Dextromethorphan is an uncompetitive antagonist of the NMDA receptor"
Strenkoski-Nix LC, et al. Pharmacokinetics of promethazine hydrochloride after administration of rectal suppositories and oral syrup to healthy subjects. Am J Health Syst Pharm. 2000;57(16):1499-1505. doi:10.1093/ajhp/57.16.1499 — Mean half-life 16-19 h across oral syrup and rectal formulations (n=36).
StatPearls (NCBI Bookshelf), drug monograph Indications section (per-drug link) — Median elimination half-life ~2-3 h (extensive metabolizers); ~15-20 h (poor metabolizers).
Vollenweider FX, Vollenweider-Scherpenhuyzen MFI, Bäbler A, Vogel H, Hell D. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport 1998;9:3897–3902. — Abstract: "the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol."
Halman A, Kong G, Sarris J, Perkins D. Drug–drug interactions involving classic psychedelics: a systematic review. J Psychopharmacol 2024;38(1):3–18. — Table 2: "Haloperidol pretreatment reduced psilocybin effects on the Oceanic boundlessness, measures of derealisation and depersonalisation phenomena but increased anxiety without any effects on visual hallucinations or delayed response tasks."

Record history

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

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