- The pharmacokinetics of LSD microdosing was characterized using a one-compartment pharmacokinetic model, showing a mean elimination half-life of 3.08 hours.
- Participants exhibited minimal physiological effects, with heart rate changes remaining below 15%, and no significant alterations in peripheral brain-derived neurotrophic factor (BDNF) levels were observed.
- The presence of certain CYP enzyme genotypes might affect LSD metabolism and could lead to variability in individual responses to microdoses.
Re-analysis of LSD Microdosing
This re-analysis focused on a Phase I randomised controlled trial involving 80 healthy adult males to explore the pharmacokinetics and pharmacodynamics of microdosing lysergic acid diethylamide (LSD). This study involved a dosage of 10µg of LSD administered sublingually for a duration of six weeks, intending to understand how the body processes the drug and its minimal physiological effects. The researchers constructed a one-compartment pharmacokinetic model that indicated a mean elimination half-life of 3.08 hours. The findings report minimal physiological changes in participants, characterised by heart rate modifications of less than 15% from baseline, along with indications that cytochrome P450 (CYP) enzymes might influence the metabolism of LSD. Additionally, no significant changes in peripheral BDNF levels were detected.Study Design and Methods
The trial was designed as a Phase I double-blind placebo-controlled study where 80 male volunteers, aged between 25 and 60, were split equally to receive either LSD or a placebo. Exclusions were noted for participants with cardiovascular, renal, or hepatic issues, among other criteria. This careful selection aimed to encompass a non-comorbid and healthy population. Participants were required to self-administer a one-millilitre solution of LSD or a placebo held sublingually for half a minute before swallowing. Additionally, some participants underwent dose adaptations while monitoring vital signs and subjective assessments using visual analogue scales (VAS) throughout the study.Sample Collection and Pharmacokinetic Assessment
Blood samples were taken at different time intervals post-administration to assess plasma LSD levels and monitor participants’ physiological responses. The study employed an advanced liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying both the LSD and its metabolite levels from plasma samples. The aim was to secure sensitivity, allowing detection of low concentrations reflective of microdosing. The statistical analysis leveraged linear mixed-effects models to understand the interactions between time and treatment group effectively.Results on Pharmacodynamics and Genotyping
The trial determined a one-compartment model as the best representation for LSD pharmacokinetics. The mean peak plasma concentration was recorded at 0.20 µg/L, signifying the substance’s responses at microdose levels. The researchers noted that the pharmacodynamic effects on heart rate and subjective “feel effect” scores were notably minimal, further limiting robust estimations pertaining to pharmacodynamic parameters. Genotypic analysis of the participants revealed variations in CYP metabolism, especially with regard to liver enzymes that may determine LSD concentration within the body. This insight points towards potential considerations for personalized dosing based on genetic predispositions.Discussion of BDNF Measurements and Conclusions
Importantly, the study did not find evidence supporting an increase in peripheral BDNF levels post-LSD microdosing, which stands in contrast to some earlier findings. High variability in baseline BDNF levels across the population tested suggests that peripheral BDNF may not serve as a reliable biomarker for neuroplasticity induced by psychedelics. In essence, the authors validated a high-sensitivity assay for sublingual LSD and emphasized the need for further studies to enhance the understanding of individual metabolic differences and pharmacodynamic responses. They advocated for a larger pool of genotyped participants and urged future studies to focus on diverse populations, potentially including females while taking menstrual cycles into account.See also our coverage of Safety and Efficacy of Repeated Low-Dose LSD for ADHD, and our explainers on side effects. Read the full paper summary on Blossom.
