In healthy volunteers, taking the antidepressant escitalopram for two weeks before a 25 mg dose of psilocybin did not reduce the positive mood effects of the psychedelic, but it significantly lessened bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects compared to placebo pretreatment. Escitalopram did not alter psilocin's pharmacokinetics; the half-life of free psilocin was 1.8 hours. It also did not change HTR2A or SCL6A4 gene expression, QTc intervals, or BDNF levels. Longer antidepressant pretreatment and studies in patients are needed to further define interactions between antidepressants and psilocybin.
In a double-blind, placebo-controlled crossover study with 23 healthy participants, daily paroxetine (an SSRI antidepressant) did not reduce the pleasant subjective effects of a single 100 μg dose of LSD, but it significantly lessened negative effects such as 'bad drug effect,' anxiety, and nausea. Paroxetine increased LSD's peak concentration and total exposure by 40% and 50%, respectively, by inhibiting the CYP2D6 enzyme, indicating this enzyme is involved in LSD metabolism. The interaction was strongest in normal CYP2D6 metabolizers and weakest in poor metabolizers. The findings suggest LSD can be safely added to SSRI treatment without dose adjustment when the SSRI inhibits CYP2D6, but no definitive recommendation can be made for other SSRIs.