Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study

LSD is a classical psychedelic that produces marked alterations of waking consciousness at full doses (100–200 mcg) and has been investigated for therapeutic uses such as depression and anxiety. In parallel with interest in full-dose research, the practice of repeated low-dose ‘‘microdosing’’—commonly described as about one-tenth of a typical recreational dose—has become popular and is reported anecdotally to improve mood and cognitive performance. Prior analyses of blotter contents and user surveys suggest that typical microdoses range broadly (commonly ~6–10 mcg tartrate but reported between 1.4–50 mcg), and earlier controlled studies at low doses (6.5–26 mcg tartrate) have shown some subjective and neurophysiological effects but little evidence for changes in higher-order cognitive performance after a single administration. Hutten and colleagues designed a placebo-controlled, within-subject dose-finding study to determine the minimal oral dose of LSD that alters mood, subjective experience, and cognitive processes in healthy volunteers. Using three low base doses (5, 10, and 20 mcg) plus placebo, the study aimed to measure acute effects up to 6 hours after administration, and to explore inter-individual variability in cognitive and subjective responses. The investigators hypothesised, based on anecdotal reports and earlier work, that low doses would enhance attention, cognitive control, and positive mood.

The study used a double-blind, placebo-controlled, within-subject crossover design with four dosing sessions per participant: 0 (placebo), 5, 10, and 20 mcg LSD base (dissolved in 1 mL ethanol), administered on separate days in randomised order with at least a five-day washout. Twenty-four healthy recreational psychedelic users (12 male, 12 female; mean age 22.8 years, SD = 3.0) completed the study. Inclusion criteria included age 18–40, prior psychedelic experience but not in the previous three months, good physical and mental health, and BMI 18–28 kg/m2; standard medical and drug screening procedures were applied. Participants were trained on tasks before testing and completed each testing day in a controlled clinical room from 9 AM; drug administration occurred at 10 AM and assessments ran from 30 minutes to 6 hours post-dose. Primary cognitive and subjective outcome measures comprised the Psychomotor Vigilance Task (PVT) for sustained attention (mean reaction time and number of lapses), the Digit Symbol Substitution Test (DSST) for information processing (number correct and ratio), a Cognitive Control Task (CCT) assessing goal-directed versus habitual responding (devaluation ratio), the Profile of Mood States (POMS) for mood subscales, Visual Analogue Scales (VAS) for immediate subjective drug states, the 5-Dimensional Altered States of Consciousness (5D-ASC) scale, and the Ego Dissolution Inventory (EDI). Blood samples were collected for LSD plasma concentration analysis using UHPLC-MS/MS with a lower limit of quantification of 2.5 pg/mL after re-extraction when needed. Statistical analyses were conducted in SPSS. POMS and VAS data were baseline-corrected. General Linear Model (GLM) univariate ANOVAs and repeated-measures GLM were used to test main Dose effects and Dose-by-Time or Dose-by-Participant interactions. In the event of a main Dose effect, Bonferroni-corrected contrasts versus placebo were performed. Where Dose-by-Participant interactions emerged, placebo–LSD difference scores were examined with binomial tests to assess whether the proportion of observations showing improvement exceeded chance (50%). Missing data handling and sphericity corrections (Greenhouse-Geisser) are described; an alpha of p = 0.05 was used for significance.

Objective attention on the PVT showed no main Dose effect in ANOVA, but significant Dose-by-Participant interactions for attentional lapses and mean reaction time (interaction F statistics reported; partial ƞp2 large). Binomial analyses of observations that changed from placebo indicated fewer attentional lapses after 5 mcg (76% of changed observations; p < 0.01) and 20 mcg (74%; p < 0.01), whereas 10 mcg did not produce a significant change (38%; p = 0.19). Reaction time reductions after LSD were not statistically significant in binomial tests (e.g. 65% after 5 mcg, p = 0.06). On the DSST there was a main Dose effect and a Dose-by-Participant interaction for total correctly encoded digits. Pairwise contrasts showed participants encoded fewer digits after 20 mcg than after placebo (p < 0.01). Binomial testing indicated a reduction in correctly encoded digits after 20 mcg in 79% of changed observations (p < 0.01); 5 and 10 mcg showed no systematic directional change. When scores were expressed as a ratio of correct to total responses, no Dose effect emerged, indicating decreased speed at 20 mcg without loss of accuracy. Cognitive control as measured by the CCT (devaluation ratio) did not show a significant main Dose effect, and baseline performance across dosing days was comparable. Mood results (POMS) revealed Dose-by-Participant interaction effects across subscales but no consistent main Dose effect or Dose-by-Time interaction. Binomial analyses of changed observations showed mixed effects: significant increases in anxiety (5 and 20 mcg), arousal (5 mcg), confusion (10 mcg), friendliness (5 and 20 mcg), and positive mood (20 mcg); decreases in anger (10 mcg) and depression (20 mcg) were observed but only half of observations showed any change from placebo for those scales. On the VAS, 10 and 20 mcg increased self-reported states of feeling 'under the influence', feeling 'high', and ratings of both 'good drug effect' and 'bad drug effect', and 'liking' (all p < 0.01 in contrasts). Concentration ratings increased after 10 mcg (59% of changed observations; p = 0.04) but decreased after 20 mcg (63%; p < 0.01); productivity decreased after 20 mcg (61%; p < 0.01). The 5 mcg dose produced no reliable VAS changes. The 5D-ASC total score and four of five main dimensions (oceanic boundlessness, anxious ego dissolution, visionary restructuralization, reduction of vigilance) showed a main Dose effect; contrasts indicated higher scores after 20 mcg versus placebo (all p < 0.01). The 10 mcg dose increased anxious ego dissolution only (p = 0.04). Subscales with significant main Dose effects included insightfulness, impaired control and cognition, anxiety, complex imagery, and changed meaning of percepts, but after correction only some subscale contrasts (insightfulness, impaired control and cognition, changed meaning) remained significant for 20 mcg. The EDI showed no main Dose effect. The authors also report large inter-individual variability in LSD plasma concentrations and note too few samples to relate PK to behavioural outcomes.

Hutten and colleagues interpret the results as evidence that single low oral doses of LSD produce selective effects on mood, subjective state, and cognition, with considerable inter-individual variability. The investigators highlight that low doses (particularly 5 and 20 mcg) improved sustained attention in the majority of changed observations, while a higher low dose (20 mcg) slowed speed on a more complex information-processing task (DSST) without reducing accuracy. Cognitive control (CCT) was not affected. Subjectively, 10 and 20 mcg increased self-rated drug effects and produced measurable but small changes on the 5D-ASC; the profile of altered consciousness resembled that of full psychedelic doses but at much smaller magnitude (total 5D-ASC scores at low doses were roughly one tenth of typical full-dose scores). The authors position these findings relative to earlier work by noting concordance with some prior reports of subjective and physiological effects at low doses, and disagreement with anecdotal claims of universal cognitive enhancement: objective sustained attention improved in many observations, yet some higher-level processing speed and subjective concentration worsened after 20 mcg. Inter-individual variability is emphasised as an important feature; the study observed large between-subject differences in blood concentrations and behavioural responses, and the investigators suggest future work should examine pharmacokinetic, genetic, or receptor-level factors that might explain this variability. Key limitations acknowledged include the relatively small sample size and the limited set of cognitive modalities tested, which restricts generalisability and the ability to probe dose–response relationships in detail. The authors also note an insufficient number of pharmacokinetic samples to robustly link LSD plasma levels to behavioural effects. Finally, they emphasise that while some positive mood and attention effects were observed in many changed observations, unwanted effects such as increased anxiety or confusion also occurred in a substantial proportion of changed observations. Implications discussed by the study team include the need for more placebo-controlled research across a broader cognitive battery and in clinical populations with attentional deficits (for example ADHD), and for studies designed to identify biological markers of individual sensitivity. The authors caution that although participants reported subjective drug effects and measurable alterations of consciousness at 10–20 mcg, these effects were small relative to full psychedelic doses and exhibited meaningful inter-individual variability.