This randomized, double-blind, cross-over study (n=23) investigates LSD (100μg) effects after daily paroxetine (SSRI) or placebo administration in healthy participants. It finds paroxetine reduced negative LSD effects (“bad drug effect,” “anxiety,” “nausea”) while maintaining pleasant effects, and caused higher LSD concentrations (1.4-1.5x) due to CYP2D6 inhibition, suggesting no LSD dose adjustment is needed when combined with CYP2D6-inhibiting SSRIs.

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

“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 (100μg) after daily administration of paroxetine (10mg for 7days, followed by 20mg for 35days) or placebo (42days) 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: 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

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

Classic psychedelics like lysergic acid diethylamide (LSD) and psilocybin induce alterations of consciousness primarily through serotonin 5-HT2A receptor activation. These substances are currently being investigated as potential treatments for depressive and anxiety disorders, conditions for which many patients are already being treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs are known to modulate 5-HT2A receptors, potentially including receptor down-regulation. Previous case reports and surveys have suggested that SSRIs might attenuate responses to psychedelics, which led to the discontinuation of SSRI therapy before psychedelic administration in most clinical Phase II trials.

However, discontinuing SSRIs carries risks including symptom relapse and withdrawal symptoms. Studies have shown that mood states before psychedelic administration can influence the acute effects, and unpleasant effects like anxiety during the psychedelic experience might limit treatment efficacy. While one Phase II trial showed lower antidepressant response to psilocybin when SSRI treatment was discontinued, another found psilocybin efficacy unaffected by antidepressant discontinuation. This highlights the uncertainty regarding whether antidepressants should be discontinued prior to psychedelic administration. The present study was designed to investigate whether a 6-week pre-administration of paroxetine alters the acute subjective and adverse effects of LSD in healthy participants.

Materials and Methods

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Find this paper

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

https://doi.org/10.1002/cpt.3618

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Cite this paper (APA)

Becker, A. M., Humbert‐Droz, M., Mueller, L., Jelušić, A., Tolev, A., Straumann, I., ... & Liechti, M. E. Acute Effects and Pharmacokinetics of LSD after Paroxetine or Placebo Pre‐Administration in a Randomized, Double‐Blind, Cross‐Over Phase I Trial. Clinical Pharmacology & Therapeutics.

Study details

Compounds studied
LSD

Topics studied
Healthy Subjects

Study characteristics
Original Placebo-Controlled Double-Blind Within-Subject Randomized

Participants
23 Humans

Institutes

Institutes associated with this publication

University of Basel
The University of Basel Department of Biomedicine hosts the Liechti Lab research group, headed by Matthias Liechti.

Compound Details

The psychedelics given at which dose and how many times

LSD 100 μg | 1x

Linked Clinical Trial

Effects of SERT Inhibition on the Subjective Response to LSD in Healthy Subjects (SERT-LSD)
The aim of the study is to assess whether SERT inhibition reduces expression of the gene coding for the 5-HT2A receptor and the response to LSD.

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