In the first qualitative study embedded in a randomised, placebo‑controlled trial, interviews with 40 healthy males who microdosed 10 µg LSD every third day for six weeks identified effects across mood, social life, mindfulness, cognition/creativity and physiology, with overarching themes of increased openness and bidirectional (positive and negative) effects. These findings highlight clinically relevant signals (notably changes in anxiety) that bear on patient and dose selection for mood‑disorder trials and emphasise set, setting and placebo‑related uncertainty as key considerations for psychedelic trial design.
Microdosing psychedelics is an increasingly popular phenomenon where small amounts of psychedelic drugs are taken regularly. Qualitative data have been published regarding the experiences of microdosers, but never in the context of a randomised controlled trial. Semi-structured video interviews with 40 healthy males were conducted following a double-blind placebo-controlled trial of 10 µg of lysergic acid diethylamide every third day for 6 weeks. Data were analysed using content analysis with initial deductive categories derived from the literature populated with inductively derived codes. Drug effects were classified in the following categories: “emotions and mood,” “social life,” “mindfulness,” “cognition, work, and creativity,” and “physiological effects,” with an additional “influences” code for non-drug modifiers of participants experiences in the trial. Themes which spanned these categories were openness to experiences and a bidirectionality of effects. Some identified codes have potential clinical relevance and may support the use of microdosing in treatment of mood disorders. Reports of changes in anxiety suggest important considerations in selecting appropriate patients and doses. Of relevance to psychedelic clinical trial design are participants’ reports regarding set and setting, the uncertainty caused by participating in a placebo-controlled trial, and perceived bidirectionality of effects.
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.
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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.
The present study analyses data from experiences of participants randomised into the LSD group of the MDLSD trial. The placebo group data are not analysed here, given that they do not address the first aim of the study and comparison between groups is better addressed via previously published quantitative data. Participants were randomised into parallel groups (n = 40 in each) prior to an initial drug-free baseline session, then attended a first dosing session one week later in which LSD or placebo was administered under supervision. A subsequent 13 doses were taken in participants' home environments over the following 6 weeks. Qualitative interviews were conducted 2 days after the last microdose. Given that the qualitative data were drawn from a relatively large sample size (n = 40), content analysis was selected over thematic analysis as the qualitative methodology. In this approach, the final coding structure takes quotes from the text corpus in the form of "meaning units," and ascribes these to "codes" which are short labels that define the most condensed summary of the data. These codes are subsumed broader "categories" and "sub-categories" which group codes into related domains based on their manifest content. Additionally, latent "themes" which span these categories can also be defined. In this way, content analysis allows for manifest phenomena to be contextualised within categories and to be quantified to some extent with counts of the prevalence of codes, while more latent meaning is explored through themes. Code counts should be considered suggestive of the prevalence of phenomena within the cohort, rather than definitive, as interviews were semi-structured and not all participants were asked about all codes that were eventually derived from the data. Data was collected in the context of a RCT which was primarily focused on quantitatively testing the effects of microdosing LSD across many different domains, where qualitative interviews were collected at the completion of the dosing period. Participants were aware that they were in a "microdosing" trial and, as such, would have framed their experiences through their own expectations, worldviews, and understandings of the practise. The first author and coders conducted analysis after becoming familiar with the literature surrounding microdosing in both unsanctioned and research settings. Thus, analysis was also structured and influenced by the research team's prior interpretations of reported experiences related to microdosing, expectations, and understandings of the practise. Ethical
Interviews were conducted on the final (drug-free) visit day of the MDLSD trial conducted at the University of Auckland between June 2021 and April 2022. Full descriptions of methods are available in a protocol paper, and a trial narrative is included in the initial results paper. This trial was a double-blind, randomised, placebocontrolled trial of repeated microdoses of LSD in healthy adult males. Most participants included in the present dataset took 10 µg of LSD sublingually every third day for 6 weeks, totalling 14 doses (exceptions are discussed in the results section). All participants in the LSD condition were included in the current analysis. The schedule of every third day popularised by James Fadimanwas chosen as it was the most prevalent regime among community microdosers. Dosage of 10 µg of LSD was chosen based on dosefinding studies demonstrating minimal perceptual effects, which did not reach the threshold for hallucinogenic experiencesin line with Fadiman's designation of microdoses' desired effects. Participants were told that any dose could be LSD or placebo; however, they were randomised into either all LSD or all placebo arms. Participants took their first doses under observation in the study clinic and were discharged after 6 hr. At-home compliance was monitored via mobile direct observation of therapy (MDOT), with participants recording dosing videos that were checked daily by the study team. Participants agreed not to drive or undergo any dangerous activities for 6 hr following every dose. Adverse events were collected and checked via daily questionnaires and any effects of concern were escalated to the study clinicians. All interviews were conducted by R. M. via video conference while participants were either at home or in the clinic, using a semi-structured interview guide co-developed by W. E., L. R., and R. M. with general questions followed by more directed items covering expected psychedelic and microdosing effects (available in the Supplemental Material). Interview preparation involved test interviews with study team members and following guidelines from. At the time of the interview, participants had taken their final microdose 2 days previously. Full inclusion and exclusion criteria are available in the supplement (Tableand).
Interviews were transcribed by five student coders from the School of Pharmacy Honours programme. Each transcript was transcribed by one student and then checked for accuracy by another. During transcription, coders kept collaborative notes on potential categories, codes, and themes.
Analysis followed a recursive and collaborative process between the coders and R.M. Following transcription, through 14 discussion groups attended by all coders and R.M., broad deductive categories of microdosing effects were defined by the coders based on familiarity with the data and the existing literature (Stage 1). On the basis of these discussions additional category investigating the modifiers of the microdosing effects was added, labelled "Influences" in order to address the second aim of the analysis. Each coder then coded 8 transcripts in NVivo 14, extracting quotes as meaning units, first placing them into the broad pre-defined categories, and keeping note of potential subcategories and codes that could be used to categorise this data. Coders discussed edge cases collaboratively with R.M. (Stage 2). Once all transcripts were coded, the coders worked through the meaning units in each category to define inductive subcategories and codes based on the patterns identified (Stage 3). After these subcategories were defined, the coders reviewed each other's transcripts for accuracy, such that each transcript had been coded by two coders in total. Meaning units were allowed to be placed within multiple codes to illustrate links between codes. Following this, R.M. and M.W. revisited the coding matrix as a whole and refined a minority of codes in relation to one another to increase label clarity, and identified relevant but missing codes. Finally, R.M. and M.W. reviewed the transcripts a final time to code according to the final coding structure and review edge cases collaboratively (Stage 4). Relevant themes which bridged categories were noted during this process and revisited and discussed once coding was complete. For publication, participant identification numbers have been re-coded in randomised order from their original study ID to L01 to L40 to prevent identification by household members who may have seen documentation of study IDs such as on drug packaging.
A total of 40 exit interviews from participants in the LSD microdosing group were analysed. Demographics are given in Table. Six participants in this group were offered a titration protocol after the initial doses due to selfreports of unpleasant overstimulating effects (for full description, see. Four were withdrawn from the trial due to heightened anxiety by their own request (n = 2) or at the discretion of the study clinicians (n = 2) based on self-reported experiences in daily questionnaires and follow-up discussions with the study team and clinicians (withdrawn participants took between 5 and 12 doses). These withdrawn and/or titrated participants were included in analysis so as to not exclude these effects. The final coding structure and illustrative quotes are given in Table. The initial deductive categories to address the first aim of assessing microdosing's effects broadly followed the topics of the semi-structured interview guide (see Supplemental Material) and were: "Mindfulness," "Cognition, work, and creativity," "Social life," "Emotions and mood," "Habits and routines," "Physiological effects." A further category to address the second aim of identifying non-drug related modifiers of experiences was "Influences." "Habits and routines" was removed as a category following Stage 3 due to a lack of relevant meaning units. Two themes were found to cut across categories and were defined as "Bidirectionality" and "Openness."
Emotions and Mood. Participants reported general increases in positive mood (n = 26) and positive outlook/mindset (n = 15). Reports of positive mood included uplifts in overall mood, which were felt more on the dose days, and felt, for example, like receiving "a little happy shot" [L14]. Participants also reported more positive outlook and mindset that reflected a reframing of thoughts such as "excitement for things that were coming up instead of dread for tasks that had to be done" [L33] and "I certainly had this moment of just absolute change in my head, which is a bit unusual for me, to be honest. By just going from totally negative to going, 'well just, just be positive about it. In terms of specific moods, participants reported increased calm (n = 26), such as feeling "loose and relaxed and very tension free" [L28], and both increases and decreases in anxiety/stress (n = 10 vs. n = 20) and irritability (n = 3 vs. n = 7). Aside from anxiety and irritability, participants didn't report specific increases in negative mood, but rather reported increased intensities of moods (n = 8) where "the emotions were a little closer to the surface". With respect to the bivalent changes in anxiety, decreased anxiety was described as a decreased tendency towards worry or rumination and in some instances, overlapped with the code of "self-compassion", as participants put less pressure on themselves, for example, "I felt less anxious about getting things right" [L37]. Within this code, participants described a sense of being able to better manage stressors when they arose, and to put them into perspective, for example, having "a better understanding of what I couldn't control" [L14]. Meanwhile, increased anxiety included general feelings of "being slightly on edge" [L25] during the dosing period up to a feeling "that wasn't a panic attack [. . .] but it was definitely the precursor to one" [L06]. In some instances, anxiety was provoked by a feeling of mental disorganisation that made everyday functioning difficult, for example, "I think that's what caused the anxiety -knowing that I've got these things to do. I wasn't able to collect my thoughts how I was previously in terms of having the focus to do it" [L36]. In two cases, the same participants reported both increased and decreased anxiety at different points within the interview. Social Life. Participants' reported changes to their social lives in terms of their behaviour and feelings towards others. Behaviour towards others included increased depth of conversations (n = 8) and increased humour in conversations (n = 5). Participants reported seeking out connections more (n = 11), as well as being more extroverted or "talkative" [L10] in social circumstances (n = 12). Conversely, others reported increased introversion (n = 8). Both extraversion and introversion appeared related to a reduction in social inhibition (n = 11) -in some cases reduced inhibition aided social interactions, while in others it led people to feeling "less filtered" [L25] and as if their responses may be inappropriate, for example thinking "Oh, I'm being a bit different, you know, everyone's gonna notice it, think I'm saying weird things" [L33]. Altered feelings towards others included increased connectedness (n = 21), for example, in feeling more "bonded" [L32], "warmth" [L17], "comfortable" [L37], and "closer". Participants also reported feeling more conscientiousness (n = 15), greater valuing of others (n = 8), and both increases and decreases in patience (n = 16 vs. n = 1). Mindfulness. The category "Mindfulness" captured changes to participants' appreciation of ordinary experiences, awareness of their mental states, and a feeling of presence. Participants reported increased appreciation of exercise (n = 5), music (n = 15), nature (n = 16), other media (n = 9), and other experiences including observing friends or pets (n = 2). In nature, especially, participants seemed to derive pleasure from an increased salience of small details of their surroundings, such as "taking more notice of the colour of plants"or "I appreciate clouds more or like plants, or just the act of going for a walk is a lot more pleasurable than it was" [L07]. Participants reported an increased awareness of their mood in the moment (n = 7), a greater depth to their thoughts (n = 10), and greater self-compassion (n = 17) and self-insight (n = 24). Self-compassion involved both increased appreciation of one's merits ("I was a little bit happier on my achievements" [L29]), and less selfcriticism ("I'm not analysing that sort of stuff where normally I'd be beating myself up" [L34]). A Greater presence was experienced as increased feelings of contentedness in the moment (n = 12), greater absorption in activities (n = 15), and three participants reported more mindful eating (n = 3). Cognition, Work, and Creativity. Participants were probed about creativity, concentration, attention, and work and did not report enhancements to overall cognition, however they reported both increases in creativity (n = 14) and increases in problem-solving ability (n = 15). One person reported a decrease in creativity (n = 1). During artistic processes such as writing music, participants reported experiences such as being "more willing to experiment" [L26] and feeling "less constrained" [L08]. During more practical problem-solving tasks, some participants reported being more able to employ "lateral thinking" [L08, L07], with solutions being "easier to actually visualise it in my head". Participants reported increases and decreases in focus equally. Deficits in focus appeared to stem from a tendency towards disorganised thought ("on occasion, especially when I -when I took the dose, and I was on a work day, I did find at times that I was sort of bouncing around from one sort of -doing one thing and then bouncing to the next and to the next" [L18]). Whereas, increases in focus came from an ability to get absorbed into tasks ("you could get like really into things that you were doing, like you got quite focused in and like really immersed in what you were doing" [L22]). Similarly, both increases and decreases in motivation (n = 23 vs. n = 20) and productivity (n = 5 vs. n = 3) were reported. Physiological Effects. Across all the codes and categories, increased energy was reported by the greatest number of participants (n = 29); however, decreased energy (n = 6) and fatigue (n = 7) were also reported. While increased energy was generally reported as a positive effect, a sense of overstimulation was also frequently reported (n = 19). This feeling was described as a sense of "nervous anticipation" [L18], or "jittery"/"jitteriness" [L18, L16, L38, L33], sometimes accompanied by disorganised thoughts or a need to fidget or move. Participants also described changes to appetite (n = 7), chest tightness (n = 2), dizziness/nausea (n = 5), dry mouth (n = 2), headache (n = 3), mild intoxication (n = 7), improved sleep (n = 5), disturbed sleep (n = 9), vivid dreams (n = 5), and perceptual changes to physical sensation (n = 9), sound (n = 5), taste/smell (n = 3), and vision (n = 8). Influences. Mindset and setting (environment) appeared to affect participants' experiences. Participants observed that the drug appeared to act as an amplifier of underlying mood or mental states "like it enhanced what was already there" [L08] (n = 12). In terms of setting, 14 participants contrasted optimal and sub-optimal settings for the dosing, with relaxed settings such as walking in nature or working on personal projects being preferable to pressured social or work environments. Four participants also noted that the experience of their first dose taken in the clinic felt stronger than for those taken in their naturalistic environments. Participants also gave some insight into their expectations around the experience (n = 19), noting that they were surprised either by the strength of effects ("I honestly expected microdosing to be almost not noticeable" [L38]) or disappointed that it hadn't lived up to the hype as a "wonder drug" [L30]. Participants also frequently expressed uncertainty over whether they had experienced the drug or the placebo (n = 28) and reported self-monitoring to guess their drug condition, in some cases this was a source of intrigue for participants for example, "not knowing if you're having an actual dose, or placebo [. . .] engages my thought processes a bit more" [L05], but in other cases this was disruptive to the overall experience, for example, "I was definitely obsessed with trying to work out if it was LSD or placebo. And I think that . . . impacted my ability just to go with the flow" [L34]. Aspects of the study design that participants reported as affecting their experiences included awareness of being measured via questionnaires (n = 13) and wearable fitness trackers (n = 6), and disruption to routines of the trial's safety rules, such as not driving within 6 hr of dosing (n = 4). Reported external confounds included changes to work (n = 7) and relationship (n = 5) situations, the effect of Covid-19 lockdowns (n = 15), engagement with other psychological interventions such as therapy or books (n = 10), and other influences (n = 3), including moving house, illness, and media consumption. Factors that participants identified as modifying their experience of the dose included food and caffeine intake (n = 3), sleep (n = 1), exercise (n = 1), and a possible tolerance effect or habituation to effects (n = 5).
Openness. Openness emerged as a theme that spanned categories of effects. Participants reported feeling a general openness, for example, feeling "quite responsive to the worldBidirectionality. Participants reported both improvement and worsening of the same domains as a result of microdosing. Both increases and decreases were seen in the domains of creativity (n = 14 vs. n = 1), focus (n = 23 vs. n = 20), motivation (n = 13 vs. n = 5), productivity (n = 5 vs. n = 3), anxiety (n = 10 vs. n = 20), irritability (n = 3 vs. n = 7), energy (n = 29 vs. n = 6), sleep (n = 5 vs. n = 9), patience (n = 16 vs. n = 1), and extroversion (n = 12 vs. n = 8). In some cases, this was context-dependent within the same participant. For example, one participant reported focus being easier or harder depending on the task by being "able to focus more on the things that you are interested in, and I guess you become a bit more . . . more distracted by other things when you are on those that your focus is not in there" [L13].
Content analysis of participants' reported experiences of being in the active arm of an LSD microdosing trial identified changes to mood, social life, mindfulness, and cognition/work/creativity, physiological effects, and identified potential modifiers of these experiences. Themes of openness and bidirectionality of effects which spanned categories were also identified. General positive mood was reported by more than half of participants, and while increases in general negative mood were not reported, increases in anxiety and irritability were reported alongside decreases. This is consistent with daily questionnaire reports from the same sample, where acute positive mood effects (feeling "happy" and "well") were seen; however, the full course of microdoses had no overall effect on mood, but anxiety was elevated for some participants. Acute anxiety has been reported elsewhere in controlled studies, typically after 20 µg. Observed pro-social effects, such as increased extraversion and supportseeking, are congruent with daily questionnaire reports of increased connectedness. Pro-social effects have previously been observed during controlled trials in reduced negative mood responses during a social rejection task, and reduced response to fearful faces, and increased valence ratings in response to happy faces. Community microdosers have displayed lower dysfunctional attitudes to self and others when compared to matched controls, and have reported social benefits to be among their motivations, and perceived benefits of microdosing. Increased energy was the most prevalently reported code. Energy was also observed in previously reported quantitative analysis of self-rated effects of LSD on dose days, remaining significant even when participants were unsure of whether they had taken LSD or a placebo. Previous studies have found that 10 to 20 µg doses of LSD are often categorised as amphetamine-like. In the present study, energy was not always positive, as overstimulation was also reported, which could be related to the reports of increased anxiety, as well as disturbed sleep. Previous analysis of activity tracker data showed that there was no overall reduction in sleep quality on the night of a microdose, however increased sleep duration was observed on the following night. Increased openness has been repeatedly observed following full doses of psychedelicsand has previously been found to be higher in microdosers than matched controls. However, no changes were observed in pre-versus post-microdosing scales in one prospective study, and in another were found in within-group analysis but not in between-groups comparison to a self-blinded placebo. Despite openness being evident as a theme in the qualitative data presented here, no changes in trait openness were observed in the quantitative assessment of this cohort relative to placebo when measured pre-and post-intervention. It may be these experiences were transient and could have been captured if they had been asked about in the questionnaires that were sent to participants daily (as was done with changes to mood), but were not cumulatively strong enough to cause changes to trait openness. Bidirectionality of effects in the simultaneous emergence of benefits and drawbacks along the same factors was identified in a previous qualitative study of people who microdose. In some cases, the relative prevalence of reported effects differed from this previous work, notably reduced anxiety was reported more prevalently in the present study than increased (50% vs. 25% in the present study; 4.2% vs. 6.7% in, and the relatively higher reporting of increased energy was much higher in the present study (72.5% vs. 15% in the present study; 10.5% vs. 7.2% in.discuss two hypotheses for explaining the bidirectionality of effects. Firstly, that the role of placebo and expectancy are crucial in phenomenological reports of microdosing and/or secondly, that effects are moderated by differential sensitivity between individuals to the same dose. The observation of this effect within the present cohort of participants who were dosing in a controlled setting reinforces the need for expectancy assessments in clinical trials of microdosing, and for the exploration of physiological biomarkers and trait-based predictors of individual responses. Beyond this, the present results demonstrate that set and setting were influential here as they are in full-dose contexts. Set and setting are rarely discussed in microdosing papers, and it has been argued that more needs to be done in documenting these variables in order to understand the variable reported effects of microdosing. In the absence of significant differences in pre-and postmicrodosing measures of mood and cognition when compared to placebo, it is possible that self-reported effects may be a matter of placebo, and bidirectional effects a consequence of noise. However, controlled microdosing studies have been limited in sample sizes, populations (primarily healthy), and number of doses, and have found acute self-reported mood and objective biophysiological effect, suggesting that more research is needed in order to reconcile the gap between observational and experimental results as either a matter of placebo or experimental limitations.
While the participants in this trial were psychologically healthy, some of the reported effects may have clinical relevance for the treatment of mood disorders if they are also observable in patient populations. Overall positive mood, calmness, positive outlook, and reduced anxiety were reported by participants but conversely, the bidirectionality of effects discussed above showed some increases in anxiety and irritability. Reduced anxiety was reported at a 2:1 ratio with increased anxiety; however, four participants in the LSD group were withdrawn from the overall trial due to heightened anxiety. Their anxiety responses appeared to be linked to an overstimulation effect which was evident in these qualitative interviews. While increased energy was frequently cited as a positive effect in this and other qualitative research, this feeling of excessive energy has also been discussed in qualitative studies of microdosers as an effect specific to LSD when compared to psilocybin. This finding highlights the need for responsive dosing protocols that use strategies such as titration to identify optimal doses for participants. Titration has been used in comparable studies investigating LSD in large doses, and has subsequently been incorporated as the standard in the Phase 2 trials undertaken by our group. As has been argued in the social science literature on full doses, mindset and setting also played a role in participants' experiences, with the drug acting as a non-specific amplifier of existing states, and pressured work and social environments enhancing negative effects, while relaxed environments enhanced calming effects. The reported influence of set and setting replicates reports from people who microdose outside of sanctioned clinical settings. This finding suggests that clinical microdosing may be best administered within the framework of psychotherapeutic or behavioural interventions to structure and optimise patients' experiences. Pro-social effects reported here may be of clinical relevance. Social disconnection is a common feature of depression, and strong social bonds can be protective against it. Participants here reported pro-social effects, including increased feelings of social connection, compassion, valuing others, and patience, as well as changes to social behavior, including seeking out connections, deeper conversations, and reporting greater extroversion and reduced social inhibition. Effects such as these, if replicable in depressed populations, could offer benefit by increasing protective behaviours such as seeking social and therapeutic support, as well as the therapeutic alliance within -and compliance with -talk therapy. Conversely, there were some reports of decreased patience and increased introversion, which both had links to a lack of social inhibition, causing blunt responses and fear of misspeaking, as well as a sense of being overwhelmed. This is again suggestive of the need for titration and responsive dosing schedules, whereby social inhibition might be lifted enough that patients feel pro-social effects, without these effects being so large that they feel inappropriately unfiltered. Participants also reported altered relationships to self and altered experiences of their environments. Additionally, participants reported increased self-compassion in the form of being less self-critical and more appreciative of their own merits, as well as increased self-insight. These effects are the targets of existing therapeutic interventions such as mindfulnessand acceptance and commitment therapy (ACT;. ACT, in particular, has previously been argued to be a potential complementary therapy to microdosing based on qualitative reports. Participants also reported reframing towards a more positive outlook, which is often a target of cognitive behavioural therapy (CBT;. Additionally, participants reported increased absorption in activities and salience of small external details, especially in nature, which could be indicative of an increased tendency towards externally rather than internally-focused attention. This increased external salience has also been reported in interviews with microdosers. Negative internally-focused attention, such as rumination is a feature of depression, and, indeed, shifting attention externally is another target of mindfulness interventions in the form of "presence". Alongside increased external salience, participants reported enhanced enjoyment of everyday activities such as walking and listening to music, which could serve to reinforce positive behaviours in populations with mood disorders. Behavioural activation, a behavioural therapy which involves scheduling enriching activities that are typically avoided by depressed patients, may be a complementary framework for enhancing these effects in clinical populations, especially those experiencing anhedonia. This cluster of effects (self-compassion, self-insight, external focus, enhanced enjoyment) suggests that microdosing should be investigated as an amplifier of behavioural therapies such as mindfulness, CBT, ACT, and behavioural activation.
Participants discussed several additional features of their experience that warrant consideration for the design of future microdosing trials. Firstly, the experience of being in a placebo-controlled trial and the uncertainty that generates was mentioned frequently; 28 participants expressed uncertainty and second-guessing their experiences, qualifying their reports with statements such as "is that just my mind playing tricks on me?" [L05]. The question of whether microdosing effects are purely the result of placebo-dependent on expectancy has been previously discussed, but these reports also bring up the possibility that participants in a clinical trial of a barely perceptible drug may be invalidating their own experiences because of their awareness of the placebo control. Indeed, the known probability of being in a placebo arm has been shown to have a negative relationship with drug response in trials of antidepressant medications. Participants also expressed an awareness of the process of being measured during the trial via fitness trackers and questionnaires, which could have attuned them further to this self-monitoring. These problems are tied to a fundamental issue with microdosing in the context of a placebo-controlled clinical trial, particularly if set and setting are influential: the placebo condition and context of the trial are inevitably part of the set and setting. It may then be impossible to extricate microdosing's effects from the effects of placebo, expectancy, set, and setting. Possible experimental designs to accommodate this have been proposed, for example, by documenting these features fully and by manipulating set and setting to optimise experiences.
Participants in this trial were healthy adult males, and the majority were New Zealanders of European descent and as such, generalisability to clinical and to more diverse populations is limited. While mood effects were observed, there was likely a ceiling effect in this healthy population. There is some observational evidence that females respond differently to microdosing than malesand gender diverse people's responses are not known. The ethnicity-bias of this sample towards European/White people reflects trends more broadly in microdosing use. Further research on the phenomenological experiences of microdosing in clinical and representative populations is needed. Participants had substantial contact with the interviewer (R.M.) during the process of the trial prior to the exit interviews. While this presents a strength, as the relationship may have led to more open responses, conversely, it may also have led to response bias in participants saying what they believed the interviewer might want to hear. Similarly, participants were aware that they were participating in a microdosing trial and, as such, their existing beliefs about psychedelics may have prejudiced their answers. However, participants did report several negative effects such as increased anxiety (n = 10) and overstimulation (n = 19), which suggests that some were willing to share experiences that were not considered favourable psychedelic effects.
The current work provides qualitative detail to the quantitative data previously published regarding this cohort's experience of microdosing LSD in an RCT. Positive effects on mood, energy, sociability, and enjoyment in externally focused behaviour were observed. These benefits suggest that microdosing may be complementary to behavioural and talk therapy interventions for people with mood disorders. Negative effects of anxiety, reduced focus, and some physiological effects were reported, reinforcing the need for dose titration and the investigation of biomarkers and environmental modifiers of effects. Participants described an awareness of mindset and setting having an impact on their experiences, including both their environments and the environment of the clinical trial. Future microdosing research needs to account for the impact of these variables.
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