Acute Effects and Pharmacokinetics of LSD after Paroxetine or Placebo Pre‐Administration in a Randomized, Double‐Blind, Cross‐Over Phase I Trial
Lorenz Mueller, Alen Jelusic, Avram Tolev, Isabelle Straumann, Isidora Avedisian, Livio Erne, Jan Thomann, Dino Luethi, Edna Grünblatt, Anna M Becker, Mélusine Humbert‐droz, Henriette E. Meyer zu Schwabedissen, Matthias E. Liechti
Clinical Pharmacology & Therapeutics February 28, 2025 DOI: 10.1002/cpt.3618 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial, crossover Peer reviewed |
|---|---|
| Sample size | 23 |
| Population | Healthy participants |
| Interventions | LSD Paroxetine |
| Dose | 100 μg LSD; 10 mg paroxetine for 7 days, then 20 mg for 35 days |
| Duration | 42-day intervention |
| Topics | LSD |
| Keywords | Pharmacokinetics Placebo Double blind Pharmacology Crossover study Paroxetine Cross over Randomized controlled trial Anesthesia |
| Citations | 15 |
| Key findings | Daily paroxetine did not diminish the pleasant subjective effects of LSD but reduced negative effects and increased LSD exposure via CYP2D6 inhibition, suggesting LSD can be safely added to SSRI treatment without dose adjustment when the SSRI inhibits CYP2D6. |
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 μg) 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.
Comparable studies
Other randomized controlled trials on LSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated With Life-threatening Diseases Patients with anxiety associated with life-threatening diseases | 2014 | Randomized controlled trial | n = 12 |
| Dose-Response Study of N,N-Dimethyltryptamine in Humans Experienced hallucinogen users | 1994 | Double-blind, saline placebo-controlled, randomized study | n = 12 |
| Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects Healthy subjects (8 women, 8 men) | 2014 | Double-blind, randomized, placebo-controlled, crossover study | n = 16 |
| Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor Healthy human participants | 2018 | Double-blind, randomized, counterbalanced, cross-over study | n = 24 |
| LSD-induced entropic brain activity predicts subsequent personality change. Healthy adults | 2016 | Balanced-order, placebo-controlled study | n = 19 |
Citations in the library
Cited by 13
- Psilocybin in alcohol use disorder and comorbid depressive symptoms: Results from a feasibility randomized clinical trial Addiction July 24, 2025
- Implementing psychedelic-assisted therapy: History and characteristics of the Swiss limited medical use program Neuroscience Applied 2025
- The 3D-ASCr scale: A revalidation of the core dimensions of the Altered States of Consciousness Rating Scale 5D(11)-ASC for psychedelic research. Journal of Psychopharmacology December 26, 2025
- Concomitant use of antidepressants and classic psychedelics: A scoping review Journal of Psychopharmacology September 12, 2025
- Liquid chromatography-tandem mass spectrometry-based pharmacokinetic and metabolic analysis of 4-bromo-2,5-dimethoxyphenethylamine and its metabolites in human plasma. Drug Metabolism and Disposition April 28, 2025
and 8 more in the library
Cites 35
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Psychopharmacology July 7, 2006
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 30 more in the library