4-AcO-DiPT

Pre-existing valvular heart disease represents a relative contraindication given 4-OH-DiPT's documented 5-HT2B agonism. While acute risk from single exposures is likely minimal, repeated use in individuals with compromised cardiac valves is an unstudied risk.

Epilepsy or history of seizures is a relative contraindication. Seizure threshold modulation is a class-level concern for serotonergic psychedelics.

Personal or family history of psychotic disorders (schizophrenia, schizoaffective disorder) is an absolute contraindication. 5-HT2A agonist psychedelics can trigger acute psychotic episodes in predisposed individuals, with potential for prolonged psychiatric destabilization.

Bipolar disorder, especially type I, represents a relative contraindication due to risk of manic episode precipitation. Clinical psychedelic trials routinely exclude bipolar participants.

CYP2D6 poor metabolizers may experience altered drug metabolism. Clinical significance has not been confirmed in vivo, but caution is warranted particularly when combined with other CYP2D6 substrates.

Pregnancy and breastfeeding are absolute contraindications due to complete absence of reproductive safety data. A Phase 1 lactation study for RE104 (NCT06659263) has been completed but results are unpublished.

Concurrent use of monoamine oxidase inhibitors (MAOIs) — including pharmaceutical MAOIs (phenelzine, tranylcypromine, moclobemide) and ayahuasca-containing MAOIs (harmine, harmaline) — is absolutely contraindicated due to critical serotonin syndrome risk.

Concurrent lithium use is contraindicated with serotonergic psychedelics due to reports of seizures and severe adverse reactions. This is a class-level contraindication not specific to 4-AcO-DiPT.