Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study

Microdosing with lysergic acid diethylamide (LSD) — ingesting very low doses roughly every 3–4 days — has become popular amid widespread anecdotal claims of improved mood, cognition and overall functioning. Previous controlled work is limited: some single-dose studies document modest subjective and physiological effects at low doses, a small trial in older adults found altered time perception but no mood benefit, and a large naturalistic double-blind trial suggested expectancy/placebo effects may account for reported well‑being gains. Preclinical data indicate repeated small doses of psychedelics can produce antidepressant-like effects in animals, possibly via repeated 5‑HT2A receptor activation and subsequent receptor regulation, but whether repeated low doses yield measurable psychological benefits in humans remains uncertain. De Wit and colleagues set out to test whether repeated low doses of LSD produce measurable improvements in mood, cognitive performance or emotional processing in healthy volunteers. The investigators administered four sublingual administrations of either placebo, 13 μg or 26 μg LSD tartrate (roughly equivalent to 10 and 20 μg LSD base) at 3–4 day intervals and evaluated subjective, cognitive, emotional and physiological outcomes during dosing sessions and at a drug‑free follow‑up 3–4 days after the final dose. The primary hypothesis was that repeated low‑dose LSD, compared with placebo, would improve mood and cognitive performance and that any benefits would persist to the follow‑up session.

This was a double‑blind, placebo‑controlled, between‑groups experimental study. Fifty‑six healthy adults aged 18–35 who reported at least one lifetime use of a psychedelic or MDMA were randomised to receive placebo (N = 18), 13 μg LSD (N = 19) or 26 μg LSD (N = 19). After screening (including semi‑structured psychiatric interview, physical examination and baseline DASS‑21), participants attended an orientation, practised study tasks and were instructed on abstaining from drugs prior to sessions. Participants completed four 5‑hour laboratory sessions conducted at 3–4 day intervals. At each session they provided urine and breath samples to verify abstinence, completed baseline mood and cardiovascular measures, then received a 0.2 ml sublingual administration of placebo (water), 13 μg or 26 μg LSD tartrate under double‑blind conditions. Subjective measures were collected hourly during sessions; heart rate and blood pressure were monitored hourly. Cognitive and emotional tasks (described in supporting information) were administered at 150 min after dosing on Sessions 1 and 4, coinciding with expected peak drug effects. A drug‑free follow‑up visit (Session 5) occurred 3–4 days after the fourth dose, with urine and breath screens and repetition of the DASS‑21 and the same cognitive/emotional tasks. Primary outcomes were mood ratings and performance on cognitive tasks during drug sessions and at follow‑up. Subjective measures included multiple questionnaires (eg, DEQ, ARCI, POMS, 5D‑ASC), and behavioural tasks included an emotional faces task, an emotional images task, an n‑back working memory task, the Digit Symbol Substitution Test (DSST) and a simulated social rejection task (Cyberball). Heart rate and blood pressure were recorded as physiological measures. The drug was prepared as tartrate solution by the investigational pharmacy and administered sublingually; no pharmacokinetic/plasma LSD measurements were obtained. Statistical analyses used mixed‑model ANOVAs: between‑group factor was drug (placebo, 13 μg, 26 μg), within‑subject factors included session day and time within sessions; behavioural tasks comparing Sessions 1 and 4 used two‑way ANOVA. Follow‑up session data and some mood measures used one‑way ANOVA or mixed two‑way ANOVA as appropriate. Analyses were conducted in SPSS and were not corrected for multiple comparisons.

The randomised groups were similar on demographics, drug use history and baseline DASS scores; overall DASS scores at baseline were in a 'normal' range. DASS scores declined across time from screening to the first session and to follow‑up, but there were no significant differences between drug groups (two‑way ANOVAs: Drug, ns; Session effects significant for depression, anxiety, stress and total DASS scores; Drug × Session, ns). Subjective and altered‑consciousness effects were modest and dose‑related. The 26 μg dose produced small increases in ratings of 'feeling a drug effect' and stimulant‑like effects (ARCI A scale) and increased vigour on the POMS; some LSD‑like effects were detected on ARCI and portions of the 5D‑ASC. A 5D‑ASC subscale (complex imagery) showed a main effect of drug (F2,50 = 3.88, p = 0.027) though post hoc tests did not report a significant pairwise contrast. Subjective effects were most pronounced on the first session and declined across Sessions 1–4, suggestive of tolerance. On the end‑of‑session identification questionnaire fewer than half of participants correctly identified LSD at the higher dose; logistic regression comparing likelihood of correct identification showed that placebo and low‑dose groups differed (GEE z = -2.44, p = 0.0147), with placebo participants about five times more likely to identify their substance as placebo than low‑dose participants were to identify theirs as LSD. Physiological measures were unchanged: heart rate and blood pressure did not differ significantly across drug conditions during sessions. On emotional and cognitive tasks, most comparisons were null. The emotional faces task showed a small reduction in false alarms for fearful faces with 26 μg (main effect F2,52 = 3.26, p = 0.046; 26 μg vs placebo, p < 0.05) without changes in hit rates. The Cyberball social rejection task showed reduced negative mood ratings during rejection with 26 μg (F2,53 = 3.65, p = 0.033; 26 μg vs placebo, p < 0.05); this effect did not differ between Sessions 1 and 4. N‑back performance was unaffected by dose across Sessions 1 and 4. DSST performance improved from Session 1 to Session 4 (main effect of session F1,53 = 45.3, p = 0.001), indicating practice effects; there was a non‑significant trend for a session × drug interaction in the direction of improved DSST performance after drug (F2,53 = 3.02, p = 0.057). On the drug‑free follow‑up (Session 5) there were no group differences on the emotional faces, emotional images, n‑back or DSST tasks. Self‑rated perceived task performance at follow‑up was higher in the 26 μg group compared with placebo (one‑way ANOVA F2,49 = 3.86, p = 0.028; 26 μg vs placebo, p < 0.05). Overall, the 26 μg dose produced modest acute subjective and limited emotional processing effects but no reliable improvements in mood, cognition or cardiovascular measures, and no enduring effects were detected at follow‑up.

De Wit and colleagues interpret their findings as demonstrating that, under controlled double‑blind conditions and with a limited number of administrations, repeated low doses of LSD are well tolerated but produce only modest subjective stimulant‑like effects and negligible changes in mood or most cognitive and emotional measures in healthy volunteers. The 26 μg dose elicited small increases in stimulant‑like subjective ratings and some LSD‑like effects, and it produced small reductions in false alarms for fearful faces and in feelings of social rejection; however, these effects were not present 3–4 days after the final dose. The authors situate these results relative to earlier work showing modest subjective effects at low doses and preclinical evidence for antidepressant‑like effects of repeated low doses in animals. They note consistency with prior human studies that reported stimulant‑like subjective effects at low to moderate doses and point out that the detected emotional‑processing changes are congruent with higher‑dose findings showing altered fear processing and reduced social‑pain responses. At the same time, the lack of mood improvement aligns with other controlled human work that has found little evidence for enduring benefits in healthy participants. Key limitations acknowledged by the investigators include the use of a healthy, non‑clinical sample with low baseline emotional distress, administration of only four doses over approximately two weeks, and assessment largely while the drug was acutely active rather than after longer exposure windows. They emphasise substantial intersubject variability in subjective responses — illustrated by wide ranges on the 5D‑ASC Feeling of Unity scale and by reports from other studies of large variability in plasma LSD concentrations — and the absence of pharmacokinetic measurements in this study. The authors also recognise that standard laboratory tasks and questionnaires may not capture the kinds of meaningful life changes reported by community microdosers. On the basis of these data, the investigators conclude the study demonstrates feasibility of placebo‑controlled experimental microdosing research but provides little support for beneficial effects of repeated low doses of LSD on mood, emotional function or cognition in healthy volunteers. They recommend future research in more symptomatic populations, with longer dosing schedules and pharmacokinetic monitoring, and with outcome measures that more closely map onto subjective changes reported by microdosing practitioners.