Acute Effects and Pharmacokinetics of LSD after Paroxetine or Placebo Pre-Administration in a Randomized, Double-Blind, Cross-Over Phase I Trial.

RCTPubMedMay 19, 2025PMID: 40022427 DOI

Abstract

Psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), are being investigated for the treatment of depressive and anxiety disorders, for which concomitant treatment with selective serotonin reuptake inhibitors (SSRIs) is prevalent. The present study investigated the acute response to single doses of LSD (100 g) after daily administration of paroxetine (10 mg for 7 days, followed by 20 mg for 35 days) or placebo (42 days) using a randomized, double-blind, cross-over design in 23 healthy participants. Paroxetine did not alter pleasant subjective effects of LSD but significantly reduced "bad drug effect," "anxiety," and "nausea." No differences in autonomic effects or QTc interval after LSD administration were found between both conditions. The strong cytochrome P450 2D6 (CYP2D6) inhibitor paroxetine led to higher maximal concentrations and total exposures of LSD (geometric mean ratios of 1.4 and 1.5, respectively) indicating relevant involvement of CYP2D6 in its metabolism. The extent of this inhibition was nominally highest in genetic CYP2D6 normal metabolizers and lowest in poor metabolizers. The present findings suggest that add-on treatment with LSD to an SSRI is well-tolerated. The pharmacokinetic and pharmacodynamic interactions indicate that no dose adjustment of LSD seems necessary in the presence of an SSRI that inhibits CYP2D6. For SSRIs that do not relevantly inhibit CYP2D6, a dose increase of LSD might be appropriate, but due to lacking data and potential other pharmacokinetic interactions with these compounds, no definitive dose recommendation can be made.

Authors (13)

LeadClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Clinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Alen JelušićClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Avram TolevClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Isabelle StraumannClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Isidora AvedisianClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Livio ErneClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Jan ThomannClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Dino LuethiClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

Edna GrünblattDepartment of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.

Henriette Meyer Zu SchwabedissenDepartment of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.

Matthias E LiechtiClinical Pharmacology and Toxicology, Department of Biomedicine, Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

MeSH Terms

HumansParoxetineCross-Over StudiesDouble-Blind MethodMaleAdultFemaleLysergic Acid DiethylamideYoung AdultCytochrome P-450 CYP2D6Selective Serotonin Reuptake InhibitorsHallucinogensCytochrome P-450 CYP2D6 InhibitorsDrug InteractionsMiddle Aged