Participant Experiences of Microdosed Lysergic Acid Diethylamide in a 6-Week Randomised Controlled Trial

Microdosing is the practice of taking repeated sub-hallucinogenic doses of a psychedelic with the aim of improving mood, cognition, creativity or general well-being. Despite widespread anecdotal reports and a growing “grey literature,” there have been few randomised, placebo-controlled studies and no published qualitative data collected within such trials. The authors note concerns with external validity of community reports (unknown dose, purity, expectancy) and highlight the importance of documenting contextual factors such as set (mindset and expectations) and setting (physical and social environment) when interpreting variable outcomes in the microdosing literature. J. and colleagues report qualitative data collected within the Microdosing LSD (MDLSD) randomised controlled trial to address two related aims: (a) to describe participants’ subjective effects of repeated microdoses of LSD administered in the trial, and (b) to identify non-drug modifiers of those experiences, including expectancy and environment. The trial attempted to replicate common community practice (approximately 10 µg LSD every third day for 6 weeks, the “Fadiman protocol”) while retaining a placebo-controlled, double-blind design to increase ecological and experimental validity.

The qualitative study analysed exit interviews from participants randomised to the active LSD arm of the MDLSD trial. The parent trial was a double-blind, randomised, placebo-controlled study in healthy adult males. For the qualitative dataset, all participants in the LSD condition who completed the trial were included (n = 40 analysed here). Participants took 10 µg LSD sublingually every third day for six weeks (target of 14 doses), with the first dose administered under supervision in clinic; subsequent at-home dosing was monitored using mobile direct observation of therapy (MDOT) with daily dosing videos and daily questionnaires for adverse events and compliance. Participants agreed to safety restrictions (for example, no driving for 6 hours following dosing). Some participants were offered a titration protocol after initial overstimulation reports; four participants were withdrawn from the trial because of heightened anxiety (they had taken between 5 and 12 doses). The extracted text does not clearly report the full demographic breakdown here beyond noting participants were healthy adult males and that demographics are given in a Table. Qualitative data were collected via semi-structured video interviews conducted two days after the final microdose. Interviews used a guide co-developed by study team members; the full guide and inclusion/exclusion criteria are reported in supplemental material referenced but not reproduced in the extracted text. Transcription was performed by five student coders with cross-checking for accuracy and collaborative note-taking. Given the sample size (n = 40), the analysts employed content analysis rather than thematic analysis. Analysis followed a staged, collaborative workflow: initial deductive categories were defined from the literature and interview guide (Stage 1); coders coded meaning units into these categories in NVivo 14 and discussed edge cases (Stage 2); inductive subcategories and codes were generated from patterns in the data and cross-checked (Stage 3); and the coding matrix was refined and transcripts re-reviewed to finalise coding (Stage 4). Meaning units could be assigned to multiple codes. The authors emphasise that code counts should be taken as suggestive of prevalence rather than definitive because interviews were semi-structured and not all participants were asked about every eventual code.

Forty exit interviews from participants randomised to the LSD microdosing arm were analysed. Six participants were offered titration after initial overstimulating effects; four participants were withdrawn from the overall trial for heightened anxiety (two by request, two by clinician decision). Titrated and withdrawn participants were retained in the qualitative analysis. The content analysis yielded a final coding structure with primary categories addressing drug-related effects: "Emotions and Mood," "Social Life," "Mindfulness," "Cognition, Work, and Creativity," and "Physiological Effects," plus an "Influences" category for non-drug modifiers. Two cross-cutting themes were identified: "Openness" and "Bidirectionality." Key findings within categories (with code counts reported by the authors) include: - Emotions and mood: General increases in positive mood were reported by 26 participants, and increased positive outlook/mindset by 15. Increased calm was reported by 26 participants. Reports of anxiety and stress were bidirectional: decreases in anxiety were reported by 20 participants while increases were reported by 10. Irritability showed both increases (n = 7) and decreases (n = 3). Some participants described emotions as more intense or closer to the surface (n = 8). - Social life: Participants described behavioural and affective social changes. Increased connectedness was reported by 21 participants. Behavioural changes included seeking social contact more often (n = 11), increased depth of conversation (n = 8), and increased humour (n = 5). Changes in sociability were bidirectional: increased extroversion/talkativeness in 12 participants and increased introversion in 8. Reduced social inhibition was reported by 11 participants and sometimes produced concerns about being "less filtered." - Mindfulness: Participants reported greater appreciation of ordinary experiences (music n = 15, nature n = 16, exercise n = 5), increased self-insight (n = 24) and self-compassion (n = 17), greater present-moment absorption (n = 12) and increased task absorption (n = 15). A few participants reported mindful changes such as more mindful eating (n = 3). - Cognition, work and creativity: Participants reported increased creativity (n = 14) and improved problem-solving (n = 15), though one person reported decreased creativity. Changes in focus, motivation and productivity were variable and often bidirectional: the authors report increases and decreases in focus (reported elsewhere as n = 23 vs n = 20), increases and decreases in motivation (n = 23 vs n = 20 in one section), and mixed reports of productivity (n = 5 increased vs n = 3 decreased). Some participants described enhanced lateral thinking or willingness to experiment in creative tasks; others reported disorganised thought on dosing days that impaired task focus. - Physiological effects: Increased energy was the most frequently reported physiological effect (n = 29), though decreased energy (n = 6) and fatigue (n = 7) were also mentioned. Overstimulation or "jitteriness" was reported by 19 participants and was linked to some anxiety reports. Other physiological reports included disturbed sleep (n = 9), improved sleep (n = 5), vivid dreams (n = 5), mild intoxication (n = 7), headaches (n = 3), dizziness/nausea (n = 5), chest tightness (n = 2), dry mouth (n = 2), and perceptual changes in vision (n = 8), sound (n = 5), taste/smell (n = 3) and physical sensation (n = 9). - Influences: Participants frequently described the drug acting as an amplifier of pre-existing mood or mindset (n = 12). Setting mattered: 14 participants contrasted optimal settings (nature, personal projects) with pressured settings (work, social obligations); four participants found their first clinic dose felt stronger than at-home doses. Expectancy and uncertainty were prominent: 19 participants discussed expectations (surprise at strength or disappointment), and 28 participants reported uncertainty about whether they had received LSD or placebo, sometimes leading to preoccupation with guessing. Aspects of being measured (questionnaires n = 13; wearables n = 6), life changes (work n = 7; relationships n = 5), Covid-19 lockdowns (n = 15), concurrent psychological interventions (n = 10) and other factors (food/caffeine n = 3; sleep n = 1; exercise n = 1; possible tolerance n = 5) were also described as modifying experiences. - Themes: "Openness" was described as a general increased responsiveness to experience. "Bidirectionality" captured the frequent pattern in which the same domain displayed both improvements and deteriorations across participants (or within individuals across contexts), with enumerated opposing counts for many domains (creativity, focus, motivation, anxiety, energy, sleep, patience, extroversion). The authors note that in some participants directionality depended on context or task.

J. and colleagues interpret the qualitative findings as providing granular, participant-level detail that complements previously published quantitative data from the same trial. They highlight congruence between qualitative reports and daily questionnaire findings from the cohort: acute positive mood on dose days (feeling "happy" and "well") and reports of increased energy on dose days, but no overall difference in mood across the full course when compared with placebo. Anxiety emerged as elevated in some participants, and the qualitative data illustrate that such anxiety was sometimes linked to overstimulation and disturbed sleep. The prominence of increased energy and occasional overstimulation maps onto prior reports that low doses of LSD may produce stimulant-like subjective effects. The authors emphasise two interpretive possibilities for the frequent bidirectionality of effects. One is that placebo and expectancy effects are important determinants of subjective reports in microdosing; the other is individual variability in sensitivity to a fixed low dose, such that the same dose can produce beneficial effects for some and adverse effects for others. They argue these hypotheses are not mutually exclusive and that both expectancy assessment and exploration of physiological or trait-based predictors of response are necessary in future work. The data also reinforce the role of set and setting in shaping microdosing experiences; participants frequently described the drug as amplifying pre-existing mood and noted that relaxed environments tended to produce more positive effects while pressured contexts exposed or amplified negative reactions. In clinical terms, the authors propose that some reported effects—positive mood, calm, increased self-compassion and self-insight, greater external focus and enjoyment of everyday activities, and social connectedness—could potentially be relevant for treating mood disorders or as adjunctive to psychotherapies (for example, behavioural activation, mindfulness, cognitive behavioural therapy, acceptance and commitment therapy). However, they caution that negative effects (increased anxiety, reduced focus in some cases, overstimulation) and the trial withdrawals indicate the need for responsive dosing strategies such as titration, and for monitoring biomarkers and environmental modifiers. For trial design, the authors raise concerns about the difficulty of disentangling drug effects from placebo, expectancy, and the measuring context in microdosing RCTs—participants frequently second-guessed their experiences and reported that awareness of being measured or the known probability of placebo affected their responses. They recommend more systematic documentation of set and setting and consideration of experimental designs that manipulate or control these factors. Acknowledged limitations include the sample being limited to healthy adult males (predominantly New Zealanders of European descent), which restricts generalisability to clinical populations and more diverse groups; potential response bias from interviewer familiarity; and participants' pre-existing beliefs about psychedelics. The authors note that reporting of negative effects in the dataset suggests some candour in participant responses. They conclude that further research is needed in clinical and representative samples, with attention to expectancy, titration, biomarkers and environmental variables to reconcile observational and experimental findings.

The authors conclude that the qualitative analysis enriches quantitative trial findings by describing a range of reported effects of repeated low-dose LSD in a controlled trial setting: positive changes in mood, energy, sociability and enjoyment of externally focused activities, alongside negative reports including anxiety, reduced focus and various physiological effects. These mixed findings support the need for titration and personalised dosing strategies, the investigation of biomarkers and trait predictors of response, and careful attention to set and setting in both clinical application and research design. Future microdosing studies should explicitly account for expectancy and contextual variables when evaluating efficacy and safety.