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

Title & Introduction

• Paper Title: Acute Effects and Pharmacokinetics of LSD after Paroxetine or Placebo Pre-Administration in a Randomized, Double-Blind, Cross-Over Phase I Trial
• Published In: Clinical Pharmacology & Therapeutics
• Publish date: February 18, 2025
• Authors: Anna M. Becker, Mélusine Humbert-Droz, Lorenz Mueller, Alen Jelušić, Avram Tolev, Isabelle Straumann, Isidora Avedisian, Livio Erne, Jan Thomann, Dino Luethi, Edna Grünblatt, Henriette Meyer zu Schwabedissen, Matthias E. Liechti
• Objective: To assess the pharmacokinetic and pharmacodynamic interactions between LSD and the SSRI paroxetine in healthy participants.
• Importance: As psychedelics like LSD and psilocybin gain attention for treating depression and anxiety, understanding their interactions with common antidepressants like SSRIs is critical for safe therapeutic applications.

Summary & Takeaways

Key Takeaway: Paroxetine pre-administration did not alter the pleasant subjective effects of LSD but significantly reduced negative effects such as "bad drug effect," anxiety, and nausea. Paroxetine increased LSD plasma concentrations by inhibiting its metabolism via CYP2D6.

Practical Application: The findings suggest that discontinuing SSRIs before psychedelic-assisted therapy may not be necessary. However, SSRIs that do not inhibit CYP2D6 might require dose adjustments for LSD.

Key Background Information

• Context: Psychedelics, including LSD, are being studied for their therapeutic potential in mental health treatment. However, many patients already take SSRIs, and little is known about how these drugs interact.
• Hypothesis: LSD will have similar subjective effects with or without paroxetine, but paroxetine will reduce adverse effects and increase LSD blood concentrations by inhibiting CYP2D6 metabolism.

Methodology

• Study Design: Randomized, double-blind, cross-over, placebo-controlled Phase I trial.
• Participants: 23 healthy volunteers (12 male, 11 female, ages 25–55).
• Intervention/Exposure: Paroxetine (10 mg for 7 days, then 20 mg for 35 days) or placebo for 42 days before receiving a single dose of LSD (100 µg).
• Controls: Each participant received both paroxetine and placebo in a cross-over design.
• Duration: 42-day pre-administration period for paroxetine or placebo, with LSD administration on test days and a washout period between conditions.

Key Findings

Primary Outcomes:

• Paroxetine did not alter LSD's "good drug effect."
• Paroxetine significantly reduced negative effects, including "bad drug effect," anxiety, and nausea.
• No differences were observed in overall autonomic effects (e.g., blood pressure, heart rate) between the paroxetine and placebo conditions.
• No significant changes were found in LSD-induced altered states of consciousness (measured by the 5D-ASC scale).

Secondary Outcomes:

• Paroxetine increased peak LSD plasma concentration by 1.4-fold and total exposure by 1.5-fold, confirming the involvement of CYP2D6 in LSD metabolism.
• This effect was most pronounced in normal CYP2D6 metabolizers and least in poor metabolizers.
• No severe adverse events occurred in the study.
• Paroxetine did not significantly alter LSD’s overall duration of effects (~9 hours in both conditions).

Interpretation & Implications

• Conclusion: Paroxetine alters LSD pharmacokinetics but not its overall pleasant effects. It reduces adverse reactions, potentially making LSD therapy more tolerable in patients taking SSRIs.
• Implications: Patients on SSRIs may not need to discontinue them before psychedelic-assisted therapy. However, more research is needed in clinical populations.
• Limitations: The study was conducted on healthy participants, not patients with depression or anxiety. The long-term effects of combined LSD-SSRI use remain unknown.

Researchers & Publication

• Researchers: Anna M. Becker, Mélusine Humbert-Droz, Lorenz Mueller, Alen Jelušić, Avram Tolev, Isabelle Straumann, Isidora Avedisian, Livio Erne, Jan Thomann, Dino Luethi, Edna Grünblatt, Henriette Meyer zu Schwabedissen, Matthias E. Liechti
• Publication Name: Clinical Pharmacology & Therapeutics
• Study URL: https://doi.org/10.1002/cpt.3618