Safinamide

An MAO-B inhibitor, FDA-approved as add-on treatment to levodopa/carbidopa for "off" episodes in Parkinson's disease.

psilodex.org/m/safinamide · 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: 20–26 h; Approximate, in adults. Source under Interaction below.

Named in state rules?

Not namedColorado Condition rules (3)

Not namedOregon

PendingNew Mexico

Cite asPsilodex, “Safinamide”, v2026.10.05. psilodex.org/m/safinamide

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

What it is used for

FDA status

FDA-approved

FDA-approved for

Parkinson's disease "off" episodes (add-on to levodopa/carbidopa)

Sources [1]

Other safety

The label contraindicates use with other MAOIs, opioids such as meperidine, methadone and tramadol, SNRIs, tricyclic antidepressants, cyclobenzaprine, stimulants, St John's wort and dextromethorphan.

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

Sources [1]

01 Interaction with psilocybin

Not studied with psilocybin; it mainly blocks one enzyme (MAO-B). Its label warns of high blood pressure and serotonin syndrome with serotonin-boosting drugs.

Detail No psilocybin data exist for safinamide. Human data come from other MAOIs (MAO inhibitors): with LSD, chronic MAOI use was associated with a decreased subjective response (Bonson & Murphy 1996). Psilocybin mushrooms taken during phenelzine produced no noticeable subjective effects (Barnett 2024, as summarized in Tap 2025). Safinamide is a selective MAO-B inhibitor at labeled doses (over 1000-fold selectivity over MAO-A). In lab studies, MAO-A converted psilocin (psilocybin's active form) to only minimal amounts of 4-HIAA (Thomann 2024; MAO-B not shown). So an effect on psilocin levels is theoretical. Class data on blood pressure: tranylcypromine increased psilocybin's blood-pressure and pupil effects in a small controlled study (Vojtěchovský 1968). One case report describes a hypertensive emergency (dangerously high blood pressure) with myocardial infarction (heart attack) (Barnett 2024). Label section 5.1 reports hypertension (high blood pressure), and section 5.2 reports serotonin syndrome with MAOIs and serotonergic drugs. No case with psilocybin has been reported. Separately, the label also describes falling asleep during daily activities, hallucinations or psychotic behavior, and a hyperpyrexia-confusion syndrome (high fever with confusion) with rapid dose reduction or withdrawal. Sources [1][2][3][4][5][6]

Human data with psilocybin: No data on this medication itself; related drugs studied (see text)
Half-life: 20–26 h (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

6 listed · counted on reports

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]
Withdrawal or rebound if stopped abruptly: Stopping suddenly can cause withdrawal or a rebound of symptoms. Sources [1]
MAO inhibition: Inhibits monoamine oxidase, the enzyme that breaks down serotonin and other monoamines. MAO also helps clear psilocin, so it can change how strong and how long the psilocybin effect is, and it raises serotonin levels. Sources [1]
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]
Raises blood pressure or heart rate: Raises blood pressure or heart rate. Psilocybin raises both for several hours, so the effects can add. 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 [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.

Parkinson's disease (severe chronic illness)
- 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

XADAGO (safinamide) tablets (Supernus) · FDA label (DailyMed) — MAO inhibition: 12.1 "XADAGO inhibits monoamine oxidase B (MAO-B), with more than 1000-fold selectivity over MAO-A." | Raises blood pressure or heart rate: 5.1 Hypertension "XADAGO may cause hypertension or exacerbate existing hypertension." | Serotonergic: 5.2 Serotonin Syndrome "In clinical trials, serotonin syndrome was reported in a patient treated with XADAGO and a selective serotonin reuptake inhibitor (SSRI)." | Sedating or CNS depressant: 5.3 "Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents." | Psychiatric reactions: 5.5 "Patients with a major psychotic disorder should ordinarily not be treated with XADAGO because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone." | Withdrawal or rebound if stopped abruptly: 5.7 "A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction" | 12.3 "Terminal half-life is 20-26 h."
Thomann J, Kolaczynska KE, Stoeckmann OV, et al. In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin. Front Pharmacol 2024;15:1391689. — Abstract: "recombinant CYP2D6 and CYP3A4 enzymes metabolized nearly 100% and 40% of psilocin, respectively." "MAO-A transformed psilocin into minimal amounts of 4-HIAA and 4-HTP." "In conclusion, MAO-A, CYP2D6, and CYP3A4 are involved in psilocin's metabolism." Introduction: "Around 33% of a psilocybin dose is renally excreted as 4-HIAA."
Bonson KR, Murphy DL. Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium. Behav Brain Res 1996;73:229–233.
Barnett BS, Koons CJ, Van den Eynde V, et al. Hypertensive emergency secondary to combining psilocybin mushrooms, extended release dextroamphetamine-amphetamine, and tranylcypromine. J Psychoactive Drugs 2024;57(3):297–303.
Vojtěchovský M, Hort V, Šafratová V. Influence of MAO inhibitors on psilocybine induced psychosis. Activitas Nervosa Superior 1968;10(3):278–279 (via Tap 2025).
Tap SC, Thomas K, Páleníček T, et al. Concomitant use of antidepressants and classic psychedelics: a scoping review. J Psychopharmacol 2025. — Summary table, Barnett et al. (2024): phenelzine + nortriptyline dose "No (serious) AEs"; subjective effects at both doses "Complete absence of acute subjective effects." Bonson & Murphy row: "MAOIs were associated with decreases in subjective LSD response."

Record history

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

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