Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers

Public and anecdotal interest in microdosing lysergic acid diethylamide (LSD) has grown because users report improved mood, greater energy and enhanced cognition after taking very low doses at multi-day intervals. Earlier work has established LSD’s serotonergic pharmacology—principally partial agonism at 5-HT2A and related receptors—and controlled studies of much higher doses (100–200 mg) have shown acute changes in emotion processing and long-lasting effects on mood in some clinical contexts. However, most data on microdosing come from naturalistic surveys and open‑label reports; few double‑blind, placebo‑controlled laboratory investigations have tested the acute effects of very low doses on mood, cognition and affective processing in humans. Bershad and colleagues set out to characterise the acute subjective, behavioural and physiological effects of single very low doses of LSD in healthy young adults under double‑blind, within‑subject conditions. The primary aim was to identify threshold doses that produce detectable subjective effects and to evaluate whether these doses alter mood, cognitive performance or emotional responses to valenced stimuli—information intended to guide future studies of repeated dosing and clinical populations.

The study used a double‑blind, within‑subject crossover design with four 8‑hour laboratory sessions separated by at least 7 days. Twenty healthy volunteers (N = 20; 12 women), aged 18–40 years, attended sessions in counterbalanced order and received sublingual administrations of placebo (water), 6.5 mg, 13 mg or 26 mg of LSD. Screening excluded current psychiatric disorder, recent substance dependence, pregnancy and several other medical or behavioural conditions; subjects had to abstain from drugs and alcohol for specified windows before and after sessions and comply with urine and breath testing. Participants were told they might receive placebo, stimulant, sedative or hallucinogen. Doses were prepared in solution by the investigational pharmacy and held under the tongue for 60 seconds. Baseline subjective and cardiovascular measures were taken and repeated at 30–90‑minute intervals; peak‑effect testing occurred around midday. Behavioural testing at the expected peak included affective tasks and cognitive measures: the dual n‑back (working memory), digit symbol substitution (processing speed), cyberball (simulated social exclusion), an emotional images task using the International Affective Picture System, and a Remote Associates Test (convergent creativity). The Profile of Mood States (POMS) was prespecified as a primary outcome and was administered at baseline and at 120 and 360 minutes; participants also completed the 5D‑ASC (altered states) and the Drug Effects Questionnaire, and heart rate, blood pressure and temperature were monitored. A follow‑up mood questionnaire was emailed 48 hours after sessions. Statistical analyses used repeated‑measures analysis of variance (ANOVA) with dose and, where relevant, time as within‑subject factors; planned contrasts compared each active dose with placebo. Missing data were handled with listwise deletion, which reduced sample sizes for some analyses. The paper reports demographic averages (mean age ~25 years; mean ~3 years post‑high‑school education) and that most participants had moderate prior drug experience.

Subjective drug effects were dose‑related across the three active doses. On the Drug Effects Questionnaire, both 13 mg and 26 mg increased ratings of “feel drug,” with the 26‑mg dose producing the largest effects (e.g. 26 mg vs placebo, p < .001 at 120 and 180 minutes). The 26‑mg dose also increased ratings of “feel high” (p < .001 at 120 and 180 minutes) and “like drug” (p < .01 at 120 minutes), and it increased ratings of “dislike drug” at later time points (p < .05 at 240 minutes). There was a trend for a dose×time interaction on “want more” (p = .09). On the Addiction Research Center Inventory (ARCI), the ARCI LSD subscale increased after 26 mg compared with placebo (p < .05 at 120 minutes; p < .01 at 180 minutes); other ARCI subscales showed no significant effects. Mood ratings on the POMS showed a significant main effect of dose for Vigor, with 26 mg increasing Vigor relative to placebo (p < .05). A main effect of dose was seen on Friendliness but follow‑up tests were not significant, and there was a trend for increased Anxiety at the highest dose (26 mg vs placebo, p = .051). No significant effects were observed on POMS Elation, Depression, Anger, Fatigue or Confusion. On the 5D‑ASC, several subscales increased dose‑dependently: Experience of Unity and Blissful State were higher after 13 mg and 26 mg versus placebo (p < .05), and Impaired Control and Cognition and Changed Meanings of Percepts also showed dose effects with the 26‑mg dose differing from placebo; measures of Spiritual Experience, Insightfulness and Complex Imagery showed trends (p values in the .06–.08 range). Several 5D‑ASC subscales (Disembodiment, Anxiety, Elementary Imagery, Audiovisual Synesthesia) were unchanged. The 48‑hour follow‑up questionnaire showed no significant dose effects, but only 11 of 20 participants completed all emailed follow‑ups. Physiologically, systolic blood pressure increased with 13 mg and 26 mg (placebo mean ~105.35 mmHg to peaks of 111.5 mmHg at 13 mg and 115.3 mmHg at 26 mg), and 26 mg significantly raised diastolic pressure at 120 minutes (p < .01). Heart rate and core body temperature were not significantly affected. Performance on behavioural and cognitive tasks was largely unaffected: the main task effects were a marginal decrease in positivity ratings for positive images at the highest dose and a marginal increase in attempted trials on the Remote Associates Test; digit symbol and n‑back performance showed no reliable drug effects. Regarding blinding, during the placebo session most participants correctly identified placebo; during the 6.5‑mg session no participants correctly guessed that they had received a hallucinogen.

Bershad and colleagues interpret these results as showing that single very low doses of LSD produce orderly, dose‑related subjective effects in healthy young adults, with 13 mg and 26 mg producing measurable drug effects and 26 mg producing the clearest changes on multiple subjective scales. The investigators note the linear dose–response across the three active doses and that physiological effects (notably modest increases in blood pressure) were detectable at 13–26 mg while heart rate and temperature remained unchanged. They emphasise that these low doses produced alterations on the 5D‑ASC—typically associated with higher doses—albeit at a much smaller magnitude. The authors situate their findings relative to prior work by noting that single high doses of LSD have shown emotion‑processing and mood effects, but that microdosing had primarily been assessed in naturalistic and uncontrolled studies until now. They highlight that, in this healthy sample, single microdoses did not produce robust improvements in mood or cognitive performance; the only consistent POMS change was increased Vigor at 26 mg, and cognitive measures generally showed minimal effects. A surprising finding was a marginal decrease in positivity ratings of positive images at the highest dose, which the authors suggest might reflect altered large‑scale brain connectivity associated with LSD leading to changes in perception of valenced stimuli. Key strengths reported include the double‑blind, within‑subject design, testing of three active doses versus placebo, controlled laboratory conditions, standardised questionnaires and physiological monitoring, and a one‑week washout between sessions. The authors acknowledge limitations: the sample was small and comprised healthy volunteers without mood disturbance, follow‑up response rates were incomplete for emailed questionnaires, and the study tested only single administrations rather than repeated dosing regimens reported by community microdosers. They recommend future studies to collect pharmacokinetic data, to examine repeated dosing schedules used in real‑world microdosing (every 3–5 days), and to test effects in clinical populations reporting low mood or cognitive dysfunction. Concluding, the investigators propose that 13 mg may be an optimal threshold dose for future repeated‑dosing studies because it produced detectable subjective effects while minimising interference with normal function.