This preprint (2021) review is one of the most comprehensive reviews on microdosing to date. The reviewers report effects across six categories; mood and mental health; wellbeing and attitude; cognition and creativity; personality; changes in conscious state; and neurobiology and physiology. Studies showed a wide range in risk of bias and argue that the idea that the effects of microdosing are due to expectancy is possibly wrong.
The use of low doses of psychedelic substances (microdosing) is attracting increasing interest. This systematic review summarises all empirical microdosing research to date, including a set of infrequently cited studies that took place prior to prohibition. Specifically, we reviewed 44 studies published between 1955 and 2021, and summarised reported effects across six categories: mood and mental health; wellbeing and attitude; cognition and creativity; personality; changes in conscious state; and neurobiology and physiology. Studies showed a wide range in risk of bias, depending on design, age, and other study characteristics. Laboratory studies found changes in pain perception, time perception, conscious state, and neurophysiology. Self-report studies found changes in cognitive processing and mental health. We review data related to expectation and placebo effects, but argue that claims that microdosing effects are largely due to expectancy are premature and possibly wrong. In addition, we attempt to clarify definitional inconsistencies in the microdosing literature by providing suggested dose ranges across different substances. Finally, we provide specific design suggestions to facilitate more rigorous future research.
Microdosing refers to the repeated ingestion of very low doses of psychedelic substances, most commonly LSD and psilocybin, typically practised with the aims of improving wellbeing, cognition, mood, or social functioning. Polito and colleagues note that microdosing has become substantially more visible in recent years through mainstream media, anecdotal reports, and commercial interest, yet the empirical literature remains fragmented and of variable quality. The authors highlight three practical difficulties that have complicated prior work: uncertain dose definitions across substances and individuals, variability in subjective thresholds for perceptual effects, and the use of unregulated substances by naturalistic microdosers. This paper sets out to systematically review all empirical human research on microdosing from 1955 through 18 April 2021. Rather than summarising only contemporary studies, Polito and colleagues include earlier pre‑prohibition research in which doses that would now be considered microdoses were administered. Their aim is to catalogue study characteristics, tabulate reported effects across key domains (mood and mental health; wellbeing and attitude; cognition and creativity; personality; changes in conscious state; neurobiology and physiology), assess risk of bias with a tailored tool, and offer design recommendations to strengthen future research.
Papers cited by this study that are also in Blossom
Anderson, T., Petranker, R., Christopher, A. et al. · Harm Reduction Journal (2019)
Anderson, T., Petranker, R., Rosenbaum, D. et al. · Psychopharmacology (2019)
Andersson, M., Kjellgren, A. · Harm Reduction Journal (2019)
Andersson, M., Persson, M., Kjellgren, A. · Harm Reduction Journal (2017)
The review protocol was pre-registered (PROSPERO and OSF) and a comprehensive search was completed on 18 April 2021 across five bibliographic databases: Scopus, PsycINFO, Embase, PubMed and Web of Science. The search strategy combined terms for psychedelic substances with terms indicating very low dose use (for example, “microdose”, “sub-perceptual” or “low dose”) and also incorporated studies identified in relevant book chapters and bibliographies to capture pre‑prohibition literature. Initial de-duplicated references numbered 387; after title/abstract screening 83 full texts were assessed and 44 papers met inclusion criteria. Inclusion required human empirical data on classical (serotonergic) psychedelics, doses within a plausible microdose range or reports of sub-hallucinogenic/no functional impairment effects, psychological or neurobiological outcomes, and peer‑reviewed publication. Both authors independently screened records, extracted data (one author extracted with corroboration by the other), and performed independent risk of bias (RoB) assessments; disagreements were resolved by consensus. Because reviewed studies were highly heterogeneous in design and vintage, the authors developed a tailored RoB tool rather than applying standard instruments. Studies were rated low/medium/high risk across ten domains covering selection, exposure and outcome ascertainment, validation of measures, causal inference (including dose–response and follow-up), and transparency (reporting, preregistration, data availability). The reviewed studies were organised into four methodological groups: qualitative (n=7), retrospective surveys (n=9), prospective studies (n=5), and laboratory studies (n=23). Where available the authors summarised dosing ranges across substances and noted whether studies tested single acute doses or repeated administrations.
A total of 44 studies from 1955–2021 were included; sample sizes ranged from 4 to 1,116 participants, and 30 of the 44 studies were published in 2018 or later. Most studies examined multiple psychedelics (21 studies), with LSD-only studies numbering 13 and psilocybin-only studies numbering 7; a small number investigated other substances such as DMT and ibogaine. Study aims and designs spanned motives for use, subjective experiences, psychometric outcomes, cognitive tasks, and a small number of neurobiological and physiological measures. Motives and general patterns: Across qualitative, survey and prospective work, respondents reported varied motives for microdosing including performance and mood enhancement, curiosity, self‑treatment of health conditions, personal development, and social connection. Many microdosers reported confidence that microdosing fulfilled these aims and some reported reducing or substituting conventional medications. Mood and mental health: Self‑report and qualitative studies frequently described improved mood and reductions in depressive symptoms, but findings were mixed. Some surveys linked microdosing to lower depression scores, whereas at least one survey found higher depressive symptoms among microdosers. Three controlled lab studies reported no acute changes in depression or affect on the dosing day. Anxiety and stress findings were inconsistent across studies, with reports of decreases, increases, and bidirectional effects. A small clinical trial reported reduced OCD severity in the microdosing condition, but the authors caution that intensive psychotherapeutic support and expectancy could have contributed to pre–post changes in some studies. Wellbeing and attitudes: Several qualitative and retrospective studies reported increased wellbeing, self‑fulfilment, resilience, insight and related gains; one prospective 4‑week study showed wellbeing increases partially accounted for by expectation. Evidence from lab studies on wellbeing is lacking or null for acute effects. Cognition and creativity: Results were heterogeneous. Some open‑label and naturalistic studies reported increases in convergent and divergent thinking and self‑reported creativity. In contrast, several controlled lab studies found no acute changes on many cognitive tasks. The most consistent lab finding in cognition relates to time perception: two well‑controlled experiments (LSD and psilocybin microdoses) found shortened reproduced durations, indicating faster subjective time perception. Evidence for attention and working memory is mixed, with isolated improvements in selective attention in some studies and null or negative effects on working memory or concentration in others. Personality and social functioning: Reports of changes in the Big Five traits were inconsistent. A more reliable pattern was increased interpersonal feelings and sociability reported in qualitative and survey studies, though some controlled studies found no acute change in social sensitivity or connectedness. Conscious state: Contrary to the common claim that microdosing is sub‑perceptual, many studies documented subjective alterations. Video analyses and self‑reports described heightened presence and perceptual clarity, while some participants reported unwanted psychedelic experiences (for example, feeling 'mildly tripping' or vivid dreams). Controlled lab measures of subjective drug intensity typically found higher ratings for microdoses than placebo (microdose intensity around 30% of scale maxima vs <10% for placebo), and several controlled studies reported dose‑dependent increases on dimensions of the 5D‑ASC (altered states scale). Neurobiology and physiology: Only one imaging study assessed neurobiological change following microdosing and reported altered resting‑state connectivity between the amygdala and several regions implicated in depression (increased connectivity with right angular gyrus, right middle frontal gyrus and cerebellum; decreased connectivity with postcentral and superior temporal gyri). Physiological and somatic reports included reductions in perceived pain across qualitative and survey studies and a well‑controlled lab study in which 20 µg LSD increased cold tolerance and reduced pain/unpleasantness ratings relative to placebo. Autonomic changes (galvanic skin, pupil changes, blood pressure) were reported in some studies, while others found no autonomic effects. Common adverse or unpleasant physical reports in self‑reports included headache, insomnia, fatigue and nausea; one survey estimated about 6% experienced negative physiological effects. Risk of bias and blinding: RoB ratings varied widely. First‑generation pre‑1974 studies in the sample generally scored below the median RoB, while many contemporary laboratory studies scored above the median in this tailored assessment. Prospective designs tended to have lower RoB than retrospective surveys, which in turn tended to have lower RoB than qualitative studies. Less than half of included studies were placebo‑controlled (17 of 44); only five assessed the success of blinding and only two (from the same lab) achieved reasonable blinding. Eight modern placebo‑controlled laboratory studies specifically targeting microdosing exist, six of which tested multiple microdose levels; these lab studies nevertheless consistently reported dose‑dependent changes on some measures. Expectancy/placebo considerations: Two recent large studies argued for a predominant role of expectancy: one prospective study found baseline expectations predicted positive outcomes, and a self‑blinding citizen science study (Szigeti et al.) found little difference between microdose and placebo across many outcomes. Polito and colleagues present seven reasons for caution in interpreting a dominant placebo explanation, including generally poor blinding in the literature, asymmetric guessing rates favouring detection of microdoses, modest variance explained by expectancy in some studies relative to overall effect sizes, possible reverse causation of guesses and outcomes, bidirectionality of drug effects obscuring group means, self‑selection of motivated microdosers in key studies, and the likelihood that some participants received ineffective doses. The authors therefore conclude that expectation contributes but evidence is currently insufficient to declare microdosing effects chiefly placebo-driven.
Polito and colleagues interpret the assembled evidence as indicating that microdosing produces measurable psychopharmacological effects, while also acknowledging substantial uncertainty about clinical or optimisation benefits. They highlight three findings that are supported by both controlled lab and self‑report research: alterations in time perception, reductions in pain sensitivity, and subjective changes in conscious state. These, together with a single preliminary imaging study showing altered amygdala connectivity, are framed as the strongest evidence that microdosing engages neurocognitive mechanisms. At the same time, the authors stress important caveats. Contemporary evidence is heterogeneous in quality and design, many findings come from self‑selected samples and retrospective reports, and placebo control and blinding have been weak or unassessed in most studies. They note a recurrent pattern of bidirectional effects—some individuals improve on a given measure while others worsen—and argue this could reflect contextual moderators or stable responder subtypes. The disparity between lab studies (which have mostly assessed acute single doses) and naturalistic reports (which often describe cumulative effects after prolonged microdosing) is emphasised as a key reason for apparent inconsistencies, for example regarding mood outcomes. Several limitations are acknowledged explicitly: the review relied on studies that vary widely in methodological rigour and historical context; dose definitions are inconsistent and many naturalistic studies cannot verify substances or doses; blinding integrity is often untested; and long‑term safety has scarcely been studied. The authors flag a specific safety concern that merits targeted investigation: chronic activation of serotonin 2B receptors, implicated in cardiac valvulopathy, could pose a risk with long‑term frequent microdosing. To move the field forward the authors offer concrete recommendations. These include accurate measurement of substance and dose (and substance‑specific dose ranges), systematic variation and reporting of dosing frequency and schedules, reframing microdosing as frequently supra‑perceptual (and thus routinely measuring acute subjective effects), rigorous control for expectancy using active placebos and validated blinding indices, exploration of predictors to distinguish responders from non‑responders, focus on specific lower‑level cognitive measures (for example time perception) rather than broad ill‑defined constructs, investment in clinical trials for putative therapeutic indications such as depression, recruitment of more representative samples, long‑term longitudinal safety and efficacy studies, and improved open science practices including preregistration and data sharing. Overall, the authors position microdosing research at an inflection point: an initial exploratory phase dominated by qualitative and survey work has yielded hypotheses and shown substantial public uptake, and the field is now beginning to produce controlled lab studies. With better controls for expectancy, clearer dosing standards, and longitudinal clinical research, Polito and colleagues argue the discipline can resolve whether microdosing offers reliable benefits, identify who might benefit, and characterise potential harms. They caution that current evidence is insufficient to settle these questions and call for methodologically rigorous confirmatory studies.
Microdosing is the practice of regularly ingesting very low doses of psychedelic substances, usually for the purpose of improving wellbeing, cognition, mood, or interpersonal processes. Over the past five years, the popularity of microdosing has increased rapidly in Western societies. Whereas illicit drug use of all kinds has often been considered a taboo topic, microdosing is now positively discussed in mainstream news stories, documentaries, books, moviesand entertainment television. After describing what microdosing entails and providing context for the sudden popularity of this practice, this review outlines and summarises scientific findings on the effects of microdosing from both the first and current waves of psychedelic research. We draw out the most robust findings to date, examine the methodological quality of the included studies, and discuss patterns across the literature that may shed light on the possible actions and effects of microdosing. We conclude with several open questions for the field, and provide a list of recommendations for a robust science of microdosing.
Microdosing can refer to the ingestion of a wide range of psychedelic substances at very low doses: lysergic acid diethylamide (LSD) and psilocybin are the most common, but people also report microdosing with mescaline, dimethyltryptamine (DMT), amphetamines, salvia divinorum and other research chemicals. Critically, unlike other forms of psychedelic use, microdosers usually consume these substances regularly or semi-regularly (for example, a common schedule is to dose every 3 days;. The emerging science of microdosing 4
The precise quantity that constitutes a microdose is difficult to define, and to date there have been no consistently accepted criteria amongst researchers. The most commonly reported definition is that a microdose is a dose between approximately one tenth and one twentieth of a typical recreational dose, although this range is uncomfortably imprecise for scientific purposes. There are perhaps three key reasons for uncertainty in defining dosing criteria. First, as microdosing typically involves taking unregulated substances, users cannot be confident about the identity of their drugs, or quantities of the active constituents they contain. Second, there is considerable variation in pharmacological and subjective effects within and across substances, and also across individual responses to a given substance. That is, it is difficult to establish equivalent dose ranges for different classes of drug (e.g., LSD vs. psilocybin), for variants of a given class (e.g., different species of psilocybin-containing mushrooms), for different methods of preparation (e.g., identical mushrooms dried or fresh), or for different people (e.g., individual differences in subjective effects to an identical dose and substance can vary widely). Third, there is no consensus regarding the subjective effects (or lack of effects) that should be associated with microdosing. In popular reports and guides, microdosing is often referred to as 'sub-perceptual', meaning that users should take a dose so low that they cannot identify any drug effects (e.g.,. Many microdosers claim anecdotally that this is the case (i.e., that they notice no effects of microdosing). Yet, in qualitative studies, participants often describe alterations of consciousness) and in lab-based studies, participants frequently report some acute effects following ingestion of microdoses (see. This suggests that individuals who are microdosing often have insight into subtle subjective changes. Considering this, it may be that the effects of microdosing are The emerging science of microdosing 5 not truly sub-perceptual, and instead may better be described as sub-hallucinogenic (e.g.,. As a consequence of these difficulties, not all microdosing studies have specified explicit dose ranges. Based on doses and associated subjective effects that have been reported, we summarise plausible ranges for microdosing various substances in Table. Note: PO, per oral; IV, intravenous; IM = intramuscular; LSD, lysergic acid diethylamide; # = depends on infusion rate. 1 Griffiths et al. (2016, 2018);. 2 Abramson and Rolo (1965) ;. 3 Fanciullacci (1974);;;;. 4 Hasler;. 5 Hasler et al. (1997). 6;;;;;;. 7;;;;;;. 8 Strassman et al. (1994). 9 Riba et al.. 10 Lea (2020b). 11. 12. 13 Forsyth et al. (2016);.
The current wave of interest in microdosing can be traced back to 'The Psychedelic Explorers Guide', a book by James, which popularised the term and led to a subsequent boom in anecdotal reports of psychedelic microdosing, media stories, and scientific research. This interest in microdosing coincides with a broader positive shift in attitudes to psychedelics over the past few years, evidenced by dramatic increases in reported lifetime use of hallucinogens, the easing of legal restrictions around personal use, and the establishment of high-profile psychedelic research centres. These changes have been largely driven by a reinvigoration of scientific interest in the therapeutic potential of psychedelics. However, whereas the bulk of research involving 'high dose' psychedelics has focused on their clinical potential, an additional theme in microdosing research has been the capacity of these substances to enhance cognition and wellbeing in healthy individuals. With a wide range of benefits ascribed to microdosing, a considerable uptake of the practice in the community, the recent emergence of commercial interests, and almost no controlled science until a few years ago, microdosing is a curious phenomenon. Given this level of public, scientific, and industry interest in microdosing, it is important to establish what has been empirically demonstrated, and separate scientific data from anecdote and hype.
This study reviews all scientific research to date on the effects of microdoses of psychedelics (referred to as "very low dose" in some reports;. Most research on microdosing has been published in the last three years (i.e., since 2018); however, there exists an additional under-reported set of relevant scientific publications from before the The emerging science of microdosing 7 prohibition of psychedelic use in 1970. Although the contemporary practice of microdosing was not the specific focus of any pre-prohibition scientific studies, a subset of early studies administered doses that would today be considered microdoses, either within dose escalation studies or as control conditions in high-dose psychedelic studies. The results of many of these studies were summarised in a book, 'The science of microdosing psychedelics' by Torsten. Passie also reports popular experimentation with microdosing in earlier decades, and in one intriguing example describes the availability of pre-packaged microdoses of LSD -branded 'Clearlight'in Berkeley in the 1980s (see Figure). However, despite these records, few contemporary microdosing studies refer to any research or popular use of very low dose psychedelics prior to the 2010s (although see. The emerging science of microdosing 8 and cover both treatment and optimisation studies (including an additional 12 papers published since the last review). We outline the key details of each study (Table), tabulate their effects across domains of interest (Table), and evaluate the strength of evidence for each study (Table).
The search procedure and terms were pre-registered on PROSPERO (; ID:171236) and OSF (). The final search was completed on 18 th April 2021 across five databases (Scopus; PsycINFO; Embase; PubMed; Web of Science). Our broad search strategy was to identify papers that included a term related to any psychedelic substance in the title, plus a term indicating very low doses in the title, abstract or keywords. The full search terms (Scopus syntax example) were: TITLE (psychedelic OR hallucinogen OR lsd OR psilocybin OR psilocin OR "Lysergic acid diethylamide" OR "Magic mushroom" OR dmt OR mescaline OR trimethoxyphenethylamine OR peyote OR "San pedro" OR dimethyltryptamine OR "2C-B" OR "2, 5-dimethoxy-4bromophenethylamine" OR iboga OR ibogaine) AND (TITLE-ABS-KEY( "low dose" OR microdose OR microdosing OR "Mini dose" OR "Small dose" OR "Sub-threshold" OR "Subperceptual" OR "Sub-acute") or TITLE (dose)). In addition, to ensure that we captured pre-prohibition research, we included eligible studies reported in Chapter 7 of 'The Science of Microdosing Psychedelics'. Finally, we scanned key bibliographies for any additional eligible studies. The emerging science of microdosing 10 Inclusion criteria were: 1) use of 'classical' or serotonergic psychedelics; 2) doses within a microdose range (see Table) OR if the dose was not ascertained, reports of effects that were sub-hallucinogenic and/or involved no functional impairment; 3) inclusion of psychological or neurobiological data; 4) reporting of primary empirical data; 5) use of human subjects; and 6) peer reviewed publications. All screening rounds were conducted independently by both authors. Reference lists across the five databases,, and manual bibliography searches were imported into Covidence, duplicates removed, and titles and abstracts were screened for eligibility (n=387). Full text screening was conducted on the remaining articles (n=83), leading to a final sample of 44 included papers (see Figure). Data were extracted by one author and corroborated by the other, with independent Risk of Bias (RoB) assessment conducted by both authors. Any disagreements during screening were resolved through discussion and consensus.
Because of the highly heterogeneous nature of reviewed studies, including early studies that employed outdated methodologies, we were unable to use common Risk of Bias assessments such as the Cochrane Collaboration tool. Instead, a tailored risk assessment methodology was developed, based on. Studies were ranked (low, medium, high risk) on the following ten domains: 1) Selection: were selection criteria clear, and were participants selected without bias? 2) Reliability: was the exposure adequately ascertained? 3) Reliability: was the outcome adequately ascertained? 4) Reliability: were outcome measures well validated and reliable? 5) Causality: were alternative causes that may explain the observation ruled out? 6) Causality: was there a doseresponse effect? 7) Causality: was follow-up long enough for outcomes to occur? 8) Transparency: was the study described with sufficient details to allow other investigators to The emerging science of microdosing 11 replicate the research? 9) Transparency: were the study design, analyses, and hypotheses preregistered? and 10) Transparency: was the data made publicly available? Each rank within each domain was precisely operationalised with specific criteria (available at). Both authors independently assessed Risk of Bias and any discrepancies were resolved through discussion and consensus. The emerging science of microdosing 12 Investigates the effects of a microdose on time perception (temporal reproduction) by reproducing tone durations (1.5 to 5 seconds; order randomised), and on subject reports (mood and ASC). Investigates changes in mood and cognitive performance (Pro, Anti, Pro/Anti, Simon, Flanker, and 2-back) following ibogaine dosing, and whether SSRI pre-treatment (which inhibits the enzyme that converts ibogaine to its active form) modulated the effects of ibogaine, compared with placebo pre-treatment.
Psilocybin (Note: Doses in italics are considered higher than a microdose. 1 = Escalating doses with randomised microdose. Papers marked by *, #, and ^ describe the same or overlapping datasets. 'Multiple doses' = a study where participants received a drug on multiple occasions (usually at different doses) but measurement focused on acute effects. 'Longitudinal' = a study where participants received a drug on multiple occasions but measurement focused on enduring effects (i.e., changes from baseline to study endpoint). BS = between-subjects comparison. WS = withinsubjects comparison.
Tablesummarises the design and aim of all studies. Studies were organised in four categories based on their methodology: a) Qualitative studies, which involved interviews, free response questionnaires, and analyses of internet forums or videos (7 studies); b) Retrospective survey studies, which involved online questionnaires that asked participants to report on past microdosing experiences (9 studies); c) Prospective studies, which collected measures related to microdosing at multiple timepoints either online or in a naturalistic setting (5 studies); and d) Laboratory studies, which investigated the acute effects of microdoses administered in a controlled setting (23 studies). Sample size ranged from 4 to 1116 microdosing participants. Most studies explored multiple different psychedelics (21 studies), LSD only (13 studies), or psilocybin only (7 studies). A minority of studies focused on other psychedelics like DMT (1 study) and ibogaine (1 study). The vast majority of studies specifically exploring microdosing were published in the last few years, with 30 of the 44 reviewed studies published in 2018 or later.
Several studies assessed respondents' reasons for microdosing. A wide variety of motives were reported, including performance enhancement, mood enhancement, and curiosity; treatment of health conditions; selffulfilment, coping with negative situations, and increasing social connection; improving mental health, personal/spiritual development, and enhancing cognitive performance. In general, participants reported confidence that microdosing fulfilled these aims (e.g.,. There were also indications that microdosing is being used as an adjunct The emerging science of microdosing 20 or substitute to conventional medications for mental and physical health issues by a considerable proportion of individuals. The emerging science of microdosing 21 were not found to relate to microdosing. Many studies deployed large batteries of tasks and did not always report on variables that were unaffected by microdosing. Accordingly, any impression of consistency may be inflated. Lack of findings may be important for characterising the effects and limitations of microdosing, and so we have summarised relevant null findings from recent lab-based studies in the following sections.
Improved mood during or following microdosing was found across numerous qualitative, retrospective survey, prospective, and lab studies. Microdosing was also frequently linked with lower depression scoresThe emerging science of microdosing 27 & Stevenson, 2019). However, one survey study found higher levels of depressive symptoms associated with microdosing, and three controlled lab studies that found no acute changes in depression, negative affect, or positive affect scores on the dosing day. Findings related to anxiety and stress were mixed, with reports of decreased anxiety or stress in six of the reviewed studies, increased anxiety or stress in four studies, and both increases and decrease in anxiety found in three studies. Improvements in substance misuse was another recurrent finding, although this was assessed in only a minority of studies. Qualitative studies showed microdosing was thought by respondents to be linked to reductions in smoking, and substance use. Additionally, one retrospective survey study found that microdosers reported lower levels of substance use disorders yet higher rates of recreational substance use. No lab studies have assessed substance misuse effects yet. Microdosing was also linked to improved general mental health in two qualitativeand two retrospective survey studies. Microdosing was associated with reduced OCD severity in a small clinical trial, and with increased dissociation in a lab study with healthy volunteers. Some of these results need to be treated with caution; for example reduced pre-post depression scores linked to the microdosing condition inand lower prepost OCD scores in the microdosing condition in, may be attributable to The emerging science of microdosing 28 substantial psychotherapeutic support and expectancy effects associated with the administration of the microdose (which was used in these studies as the 'placebo' group). Also, higher depression scores in the microdosing group inmay be attributable to self-medication motivations, relative to controls. Notably, most survey studies did not probe the duration of effects following microdosing, so it is unclear whether the above findings relate to fleeting or sustained changes in mood and mental health.
Three qualitative studies, and one retrospective survey studyshowed increases in the overlapping constructs of wellbeing, self-fulfilment, self-efficacy, and resilience. Additionally, one prospective study showed increases in reports of wellbeing and resilience over the course of a 4-week period of microdosing, with this finding partially accounted for by expectation. No lab-based studies have investigated wellbeing yet. Other findings relevant to wellbeing included two qualitative studies that found increases in themes of self-insight; one retrospective survey study that showed increases in wisdom, and decreases in a measure of dysfunctional attitudes, and two qualitative studies that showed improved physical health and other habits. Findings related to energy levels were somewhat mixed. Microdosing was linked to reports of increased energy in a qualitative studyand in a placebo controlled prospective study. In two retrospective survey studies from the same group, 11-45% of respondents reported that microdosing was related to increased energy, while 8-10% reporting decreases in energy. Finally, two lab studies found no evidence of group level changes in vigour, arousal or fatigue. The emerging science of microdosing 29
There are several indications that microdosing may lead to an increase in creativity. In a quasi-experimental, open-label study,reported increases in both convergent and divergent thinking following ingestion of psilocybin-containing truffles in a retreat setting. Similarly, in an online study byparticipants who microdosed scored higher on a divergent thinking task compared to a non-microdosing control condition. There were also six accounts of self-reported increases in creativity following microdosing. A placebo-controlled prospective studydid find an increase in creativity, however, another prospective studyand one lab-based studyfound no effects. Several studies have shown changes in neurocognitive behavioural tasks following microdosing. Specifically, evidence from two well-controlled lab studies have shown that both LSDand psilocybinimpact time perception, with participants systematically generating shorter responses in a time reproduction task (i.e., microdoses led to faster subjective time perception). In another labbased study,investigated the effects of microdoses of ibogaine on a large battery of cognitive tasks but found only slight improvements in selective attention. Similarly,found that some participants improved performance on a psychomotor vigilance task (indicating improved selective attention), but that both performance on a working memory task and self-rated concentration were reduced following microdoses of LSD. Two contemporary controlled lab studies found no acute changes in concentration on dosing day, and one controlled The emerging science of microdosing 30 lab study found no acute change in working memory, visuospatial processing, attention, and convergent thinking. Psychometric measures also indicated various changes in cognition. In studies collating microdosers' self-reports, claims of increased attention, mindfulness, and ability to focus were common. Similarly, in a prospective study by, reports of mind wandering decreased following six weeks of microdosing. Participants administered microdoses of DMT (.04 -.05 mg/kg) instudy rated cognition items on the Hallucinogen Rating Scale higher than placebo. However, in an early lab studyreported reductions in alertness, control and thought that persisted over the course of a day when participants were administered 20 g of LSD, and for several hours when given 7 g LSD (although these results were based on just 4-6 participants).
Although there have been reports of positive personality change following ingestion of psychedelics at high doses, this was less consistent in studies of microdosing. With regards to changes in the classic big five personality traits, one qualitative study, and two retrospective survey studies reported increases in openness, whereas four prospective studiesand one lab studychanges. An exception is, who reported that participants taking LSD in a lab setting frequently showed acute neurotic signs. Much more consistent were increases in interpersonal feelings, attitudes, and behaviours (coded as sociability in Table). One early lab study, one prospective study, three survey studies, and nearly all of the qualitative studies reported improved relationships and interpersonal connection. However, one controlled lab study found no increase in sensitivity to social rejection during acute effectsand one prospective study found no increase in social connectedness compared to placebo. Finally, one cross sectional studyand one prospective studyfound an increase in absorption, although a second prospective study reported no change.
Despite the common anecdotal claim that microdosing is sub-perceptual (e.g.,, there was consistent evidence that microdosing did lead to changes in subjective awareness. In a qualitative analysis of videos about microdosing, Andersson and Kjellgren (2019) described a change in psychophysiological state characterised by heightened presence and perceptual clarity, which they claimed was a prerequisite for the beneficial effects of microdosing. However, changes in conscious state were not always linked to benefit:reported that unwanted psychedelic effects were the primary negative outcome associated with microdosing, with over 70% of microdosers in that study reporting that they The emerging science of microdosing 32 sometimes felt like they were 'mildly tripping', and a similar proportion reporting unusually vivid dreams. A focus of several of the older lab studies was to investigate whether participants and/or researchers could distinguish very low doses of psychedelics from placebos or other non-psychedelic substances. Four of these studies found evidence of drug effects in the microdosing condition. More recent lab studies have included self-ratings of overall drug intensity (or positive and negative drug effects), and have consistently found higher scores for microdoses compared to placebo, with two controlled lab studies reporting non-significant trends. Based on these findings, it appears that microdoses led to ratings of approximately 30% of scale maxima for drug intensity ratings, compared to ratings of < 10% for placebos. By comparison,reported that 100ug of LSD was rated at 87% of the scale maximum for subjective drug effects. In addition to increased intensity, Strassman et al. (1994) also reported increased somaesthesia (i.e., interoceptive and tactile sensations) and reduced volition following DMT microdoses.used a microdose of psilocybin as a control condition in a study of psychedelic induced mystical experiences. Although the outcomes reported in this condition were minimal, therapist ratings of participants' behaviour indicated some drug effects. Finally, self-rated intensity of drug effects was the only measure that differentiated between microdoses and placebo, after controlling for expectation inself-blinded prospective study. Some studies have used the 5D-ASCas a more detailed psychometric measure of alterations in consciousness.showed a dose- The emerging science of microdosing 33 response effect across four out of the five primary dimensions of this scale, with 20g of LSD leading to significant increases on each dimension (apart from auditory alterations) compared to placebo, and 10g of LSD only increasing the anxious/fearful dimension. Similarly,found increases in the blissful state and experience of unity sub-dimensions following 13g of LSD, and Family et al. () found a dose dependent relationship in the reduction in vigilance subscale (i.e., drowsiness and reduced alertness) following LSD microdosing. However, another lab study found no acute changes in 5D-ASC scores following 13g of LSD. Finally, in one lab study,found that headache patients were considerably more likely to have acute psychological, affective and perceptual alterations following microdoses of both psilocybin and LSD, compared to healthy controls. This finding is intriguing in the context of reports that high dose psychedelics may offer relief for otherwise difficult to treat headache symptoms.
Only one study assessed neurobiological changes following microdosing. In a detailed exploration of the effects of microdoses of LSD on the brain,found changes in resting state connectivity between the amygdala and a series of brain regions that have been associated with depression (i.e., increased connectivity with the right angular gyrus, right middle frontal gyrus, cerebellum; and decreased connectivity with the postcentral gyrus and superior temporal gyrus). Although this is a single preliminary finding, these results are compatible with both findings from research on the effects of high dose psychedelics, and potential mechanisms for the efficacy of traditional antidepressants (S. E.. Although we did not specify somatic changes as inclusion criteria for this review, a range of effects from psychophysiological to somatic were reported in the reviewed studies. The emerging science of microdosing 34 The most consistently reported of these was reduction in perceived pain. This has been found in a qualitative studyand two survey studies. However, the clearest evidence comes from a well-controlled lab study by, who found that 20g of LSD led to significant increases in the duration that participants could tolerate aversive exposure to cold, and that participants rated the experience as significantly less painful and unpleasant compared to placebo. Relatedly, there was also one qualitative report of increased sensory acuity. Notably, two large scale survey studiesfound that microdosers rated the effectiveness of very low dose psychedelics as greater than conventional treatments for physical disorders (e.g., migraines, chronic pain). This led some users to reduce or entirely cease standard medications (e.g., Lea et al. reported that 27.5% of affected respondents stopped taking pain medication). Despite these positive reports, negative physical outcomes were also relatively common during or following microdosing in self reports. Qualitative accounts noted insomnia, physical discomfortand other unwanted physiological effects (e.g., headache, fatigue, nausea;. In a survey study,found that approximately 6% of microdosers experienced negative physiological effects. Similarly,found relatively common reports of trouble sleeping, overstimulation and headache. Finally,found that physiological discomfort was common among psilocybin microdosers, but not among microdosers using LSD (or similar substances). Five reviewed studies showed autonomic changes following microdoses (e.g., increased galvanic skin responses, pupil changes, increased blood pressure;.The emerging science of microdosing 35 2018) also reported findings suggestive of increased cardiovascular response following microdosing, but these were not formally compared to a no drug condition. However,found no autonomic changes associated with microdoses of psilocybin.andadditionally reported minor unpleasant physical symptoms such as somatization and dizziness. Finally, in a study of the impact of LSD on sleep,suggest that low doses of LSD may lead to prolonged REM phase sleep, although doses were inconsistently grouped together in that paper and it is not clear if the reported outcomes are truly representative of effects in the microdose range.
The reviewed studies showed a wide range of Risk of Bias (RoB) scores (Table). There were several patterns related to study type and year of publication. All studies from the first generation of psychedelic research (in our selection, from 1955 to 1974) scored lower than the median for RoB, whereas all contemporary laboratory studies scored higher than the median RoB. Prospective studies tended to have lower RoB scores than retrospective survey studies, which in turn tended to have lower RoB scores than qualitative studies. Several of the included studies were aimed at investigating the effects of high dose psychedelics and used a microdose condition as a placebo. Despite being rigorously designed for their intended purpose, these studies did not include any additional comparator conditions that could be used to evaluate the effectiveness of microdosing, and so these studies scored higher for risk in our assessment (this is not a comment on their overall study quality, only on suitability for evaluating microdosing specifically). In A correlation investigating the association between number of citations (Google scholar citations as of 3 June 2021) and RoB scores indicated that papers with lower risk of bias were more cited (r = -0.32, p = .040). This was also the case when controlling for year of publication (r = -0.37, p = .017). This indicates that more rigorous microdosing studies were more likely to be cited. The emerging science of microdosing 37 reported a large number of outcomes. There were several themes that stood out across these studies.
Although there are emerging questions about the degree to which microdosing effects can be explained by expectation (see 4.3), several lines of evidence indicate direct drug effects in the microdose range. In particular, multiple studies indicated beneficial changes in cognitive processing, and improved indicators of mental health. Here we summarise the most promising evidence from both lab and self-report studies (see Table).
Some of the clearest evidence for changes in cognition from lab-based microdosing research relates to alterations in time perception. This has been demonstrated in two wellcontrolled lab studies. Although on its own, a finding of altered perception of time does not have immediately obvious clinical or optimisation benefits, reliable changes in this capacity do typically imply the involvement of attention and working memory. However, lab findings directly related to attention and working memory are mixed.found no evidence The emerging science of microdosing 42 of changes to working memory (n-back task). Similarly, bothfound no changes in general cognitive functioning using a digit span substitution task. Hutten et al. did find that the majority of participants showed improved attention in a psychomotor vigilance task following 5g and 10g of LSD, but not after 20g. In any case, untangling the mechanisms that underlie temporal processing following microdosing is a promising avenue for future research. Reduced pain perception is another finding that has been demonstrated in a wellcontrolled lab study, and several self-report studies. Reduced sensitivity to physiological pain is likely also a factor driving other self-reported physical and mental health outcomes. A further common finding, particularly in lab studies, was that microdosers report a variety of acute subjective alterations to their conscious state when microdosing (e.g.,. This contradicts the popular narrative that microdosing is a subperceptual phenomenon. Beyond questions of accurately defining the practice of microdosing, this finding calls into question the veracity of blinding in placebo-controlled trials (see 4.3). Although time perception, pain reduction, and changes in conscious state are not commonly mentioned in popular reports, these are consistent findings from controlled lab and self-report studies, and together provide good evidence of direct neurocognitive effects of psychedelics taken in the microdose range. Further evidence of neuropharmacological effects of microdosing comes from the only imaging study to date, which found evidence of altered neural connectivity that was associated with affective changes after microdosing with LSD. The emerging science of microdosing 43
There were a wide range of promising findings from self-report studies that have not been well explored in lab settings. Most notably, there have not yet been any clinical trials of microdosing. There is strong and consistent evidence from qualitative, survey, and prospective research that microdosing may improve mental health (particularly depression and anxiety), including reports that microdosing is perceived by users to be more effective than existing treatments. Microdosing was also commonly reported to relieve physical discomfort, and reduce substance use. The possible clinical impact of microdosing is an underexplored area with considerable potential impact for future research to address. Other promising findings that have not yet been explored in well-controlled lab studies relate to the potential for microdosing to optimise or enhance functioning in healthy individuals. In particular, self-report studies have indicated: beneficial changes in specific attentional capacities, such as increases in absorption and decreased mind wandering; increased wellbeing and insight; positive personality changes; and greater connection to nature.
There were several promising self-report findings that, so far, have not been confirmed in lab studies. These include improved mood, sociability, cognition, creativity, and emotional processing. However, a critical factor to consider when evaluating the current microdosing literature is that all lab studies to date have focused on acute changes following a single dose, or a small number of doses. By contrast, many of the findings reported in qualitative, survey and prospective studies are accumulative effects that result from lengthy periods of microdosing. This means that it is prudent to be cautious when interpreting null findings from current lab studies. For example, two well controlled studies by Bershad et al. The emerging science of microdosing 44 (2019, 2020) reported no acute change in mood following microdoses of LSD, whereas multiple self-report studies indicate marked improvements in mood (see Table). It may be the case the microdosing has no immediate, acute effect on mood but that regular microdosing does lead to sustained, gradual mood improvements. By way of comparison, traditional antidepressant medications often take a month or more to have any effect. It would not be very informative to assess the effectiveness of fluoxetine after a single dose. Well controlled lab studies that investigate the long term effects of microdosing are needed to properly test sustained impacts (and there is at least one such study currently underway; R. J.. Sociability is another finding commonly shown to improve in self-report studies but that was not supported bylab study. Again, a state-based measure tapping immediate responding after a single exposure to microdosing may not be informative regarding enduring trait-like changes that might result from repeated exposures. We suggest that although mood and social connection have not yet been confirmed in lab-based research, considering the weight of evidence from self-report studies, these are domains where it would be worthwhile to explore enduring changes in controlled studies. Other self-report findings that were not confirmed in lab studies included improvements in cognition, creativity, and emotional processing. The evidence base around these constructs is less consistent and these may be less of a priority for future research. The emerging science of microdosing 45
A recurrent and noteworthy finding, both within and across studies, was opposing or bidirectional effects. That is, in some cases microdosing appeared to be related to both increases and decreases on the same measures. For example,showed that several variables significantly increased in some participants but decreased in others, as a function of drug dose (including attentional lapses, cognitive function, mood, and energy). Some survey studies also showed bidirectional effects (e.g.,, with notable emphasis on this pattern of findings within, who report bidirectional findings associated with anxiety and cognitive effects in particular. This pattern of findings may in some cases be an interaction between drug effects and expectancy or other contextual factors (e.g., anxiety may increase or decrease depending on how conducive the physical environment is), and thereby vary within the same individual in different contexts. In other cases, bidirectionality may be attributed to subtypes of people that respond to microdoses in specific and consistent ways (for example, microdosing may reduce anxiety symptoms in some people, and increase anxiety symptoms in others). For example, The emerging science of microdosing 46 recent research has identified genetic markers that impact on certain individuals' capacity to metabolise LSD. If bidirectionality is explained by contextual factors, future research should attempt to determine contexts that better support beneficial effects. If instead bidirectionality relates to population subtypes, then future research should attempt to ascertain predictive markers for certain responses, conduct subtype analyses, and thereby determine who is likely to benefit from microdosing.
Less than half of the reviewed studies were placebo-controlled (17 of 44 studies). All 17 of these placebo-controlled studies were either single-or double-blind. However, only 5 of these assessed the success of the blind (i.e., 71% did not assess the blind), only two studies (different samples from the same lab) achieved a reasonable degree of blinding, and none used active placebos. In most studies that assessed blinding, participants often correctly guessed the difference between placebo and microdose. As microdosing in the typical dose range often produces noticeable changes to conscious awareness (see 3.3.5) which would cause the blind to be broken, it is possible that many placebo-controlled microdosing studies that did not explicitly assess blinding failed to achieve it. Accordingly, it is difficult to distinguish between the role of expectancy and direct effects of microdosing within the reviewed studies. Despite this, two recent studies have suggested that the effects of microdosing may be wholly or predominately caused by expectation. First,showed in a prospective, self-report study, that baseline expectations predicted positive outcomes. Second,used an innovative 'self-blinding' citizen science design to compare microdosing and placebo conditions, and found little evidence of any difference between the two conditions across many of the commonly-reported effects of microdosing The emerging science of microdosing 47 (e.g., improved mood, well-being, social connectedness, cognitive performance, mindfulness). Szigeti et al. also analysed data according to which experimental condition participants guessed they were in and found that despite the lack of overall group differences, there were significant differences between those who guessed they had microdosed compared with those who guessed they had taken a placebo (regardless of which substance they had taken). The authors of both studies interpret their results to indicate that many of the reported effects of microdosing are driven by expectancy. However, we highlight seven issues that cast doubt on a predominant role of expectancy in these findings. First, blinding in microdosing research has been mostly ineffective. As highlighted above, this is the case for almost all studies to date. In particular, over 70% of all guesses were correct in, and participants accurately guessed they had consumed a microdose at double the rate predicted by chance (i.e., blinding in the microdose condition was limited). This means that we don't have a clear picture of what the real placebo component is from many of these studies. Second, there are likely to have been substantially asymmetric expectations between experimental groups in many microdosing studies. In other words, guessing is not independent of drug effects. Inparticipants correctly guessed the placebo condition only marginally better than chance, but correctly guessed they were in the microdose condition at twice the rate expected due to chance. In addition, correct guesses increased with higher doses, and participants indicated various acute drug effects as the reasons for breaking the blind in the microdose condition. This suggests that correct microdose guesses, in addition to being more frequent, were likely made with higher confidence than correct placebo guesses (given the acute drug effects). If this is the case, it implies considerably different levels of expectancy between the conditions. Moreover, participants who reported acute drug effects inwere more likely to have The emerging science of microdosing 48 had an 'effective dose' that could produce changes in other outcome variables compared with those reporting no acute drug effects (see sixth point below), confounding any distinctions between guess confidence and direct microdosing effects. Third, previous microdosing studies suggest that the magnitude of expectancy effects may be small. Althoughstudy showed that expectancy contributed to changes on each outcome variable, the proportion of variance explained by expectancy was relatively modest (8% for wellbeing; 7% for depressive symptoms; 5% for anxiety). In contrast, the main analyses showed relatively large effect sizes for overall changes from baseline to the end of the study period (wellbeing ηp2 = .18; depressive symptoms ηp2 = .31; anxiety ηp2 = .24). Relatedly, in a controlled lab study,found that although the majority of participants (74%) increased performance on a cognitive attention task, most participants (63%) believed that they had decreased performance. In other words, many participants' beliefs about their change in performance were in direct opposition to their actual change in performance. These findings suggest that although expectation is important, it may not be the main mechanism driving microdosing effects. Fourth, spurious attributions may have impacted participants' guesses in.imply that participants' guesses (or expectations) cause changes on the outcome variables. But it may be that (for at least some participants) observed changes in outcome variables lead to particular guesses. Specifically, in the absence of acute drug effects, any observed effects that occur for unrelated reasons may be misattributed to the study. If a participant notices improved mood they may misattribute this to the being in the microdosing condition (regardless of their actual experimental condition). Similarly, a participant who notices worsened mood may misattribute this to being in the placebo condition. That is, changes due to spurious causes may have led participants to make an incorrect guess regarding experimental condition, which would appear indistinguishable from The emerging science of microdosing 49 the scenario where the condition a participant guesses drives the expected changes. This means that differences between the guessed conditions may have been inflated by causes unrelated to expectancy. Fifth, commonly found bidirectional effects may obscure group differences. As outlined in the previous section, microdosing may affect subgroups of individuals in opposite ways. If a subset of individuals increase on a particular variable but others decrease (e.g.,, potentially interesting patterns of results may be obscured by group level analyses. If the placebo component of a particular effect is consistent across individuals, in the context of strong bidirectional drug effects, this component may survive group aggregation, whereas the highly variable drug effects may not. This would lead to an overestimation of placebo effects. Sixth, participants in bothandwere selfselected and highly motivated microdosers. These individuals presumably undertook legal risks to obtain psychedelic substances and went to considerable effort to prepare these in the appropriate dose for these studies. The majority of participants in both studies rated themselves as strong advocates of psychedelics and most also reported previous experience with high dose psychedelics. As such, these samples were unlikely to be representative of the wider populations, and likely also possessed positive expectations about the effects of low dose psychedelics. Considering this, it is not clear whether claims regarding the role of expectation in these studies might also apply to less motivated populations (more broadly, self-selection biases are a concern for many reported microdosing findings: see 4.6). Seventh, and perhaps mostly importantly, studies that suggest strong expectancy effects may have investigated ineffective doses in a proportion of participants. Bothandrelied on self-reports with uncontrolled and variable doses.found no discernible acute drug effects in about 20% of participants; The emerging science of microdosing 50 and Szigeti et al. reported at least 20% of participants in the microdose condition incorrectly guessed they were in the placebo condition, implying that these participants did not notice any subjective effects. Lab based research has shown that the threshold dose for acute effects on conscious state varies widely across individuals, and also that the dose-response relationship for various putative changes related to microdosing varies widely. This suggests that the intensity of acute subjective effects may provide a proxy indicator of an individual's sensitivity to other microdosing outcomes. If this is the case, it is likely that some proportion of participants not reporting subjective effects did not take effective doses. This means that genuine differences due to the pharmacological effects of microdosing were likely obscured by participants in the microdosing condition who took ineffective doses. Furthermore, ineffective doses would inflate differences between guess conditions, as some participants in the microdose condition would guess they are in the placebo condition due to ineffective dosing rather than expectancy. With these issues in mind, we suggest that claims that microdosing is largely a placebo driven effect (e.g., Siebert, 2021) are premature. The above studies show that expectancy does contribute to the overall effect of microdosing, but we cannot yet be confident about the magnitude of the expectancy effect, or its relative importance compared to the pharmacological effects of microdosing. To confidently resolve these questions future studies should employ active-placebos and assess adequate blinding to tease apart the effects of microdosing (including any that depend on acute drug effects) from those of expectancy. Furthermore, studies could ensure effective doses by titrating the dose to achieve some minimal acute drug effects with no loss of function, and develop methods to identify subtypes of individuals with specific response profiles towards separating 'responders' from 'nonresponders'. The emerging science of microdosing 51
Despite various methodological limitations and possible expectancy effects outlined above, there are reasons to be optimistic about a science of microdosing. There have now been eight modern, placebo-controlled laboratory studies specifically focused on the effects of microdosing, six of which tested multiple doses within the microdose range. Importantly, all of these studies show clear dose-dependent changes across a range of measures (see Table). Another consistent outcome in these lab studies is that participants report subjective effects following doses in the microdosing range. These findings together provide clear evidence of psychopharmacological effects. That is, microdosing is doing something. A key question for researchers is whether the effects of microdosing have clinical or optimisation benefits beyond what might be explained by placebo or expectation. Regardless of whether the effects of microdosing are primarily based on expectation or pharmacology, there is clear evidence that microdosing is having a considerable impact on peoples' lives. Prevalence estimates vary, but a surprisingly high proportion of the population reports microdosing. One study, which did not specifically target psychedelic users, found 17% of respondents had microdosed, whereas approximately 7% of respondents to the 2019 Global Drug Survey reported microdosing. Furthermore, microdosers believe that the practice is more effective than traditional treatments for physical and mental health issues, with a considerable proportion (e.g., more than 50% inceasing traditional medications after commencing microdosing. In this regard, microdosing represents a common practice with significant consequences for health behaviours.
As microdosing science becomes a more established field, the next phase of work must focus on well-controlled confirmatory research. Assessing individual predictors, The emerging science of microdosing 52 expectancies, and contextual factors within active-placebo controlled designs will be key to determining reliable findings and their mechanisms. Indeed, the common finding of bidirectional effects (e.g.,, subgroup differences (e.g., greater sensitivity to LSD in essential headache sufferers inand also substantial individual variability in response (e.g.,suggest that until the field has made some initial progress on individual response prediction, aggregate data will lose many signals in the noise. Furthermore, a general question associated with all microdosing research is whether and to what degree the effects depend on acute subjective experience of the microdose effects, and if they do, how to conduct adequately blinded studies. One key area that has been under-studied is the safety profile of long-term microdosing. Occasional ingestion of much higher doses of psychedelic substances are physiologically safe for most people, and a wellcontrolled microdosing study specifically assessing safety found that six low doses of LSD, taken at 4 day intervals, were well tolerated with no differences in adverse events, vital signs, blood markers, and psychiatric parameters from placebo (only mild to moderate headaches were related to microdosing;. However, safety concerns have been raised regarding chronic administration of very low doses over many months or years, as is common in naturalistic microdosing practice. While these concerns have not been directly tested, chronic administration of serotonin 2B receptor agonists have been shown to cause valvular heart disease, and commonly microdosed psychedelics are known to activate this receptor subtype with high affinity. Future research should investigate this, and other potential health risks associated with chronic and long-term administration of microdoses of psychedelics. The emerging science of microdosing 53
We conclude with nine suggestions to guide the next phase of microdosing research. Accurately measure substance and dose: Researchers should clearly specify the substances and dose ranges that are being investigated. An assumption of some qualitative, cross-sectional, and observational studies of microdosing has been that there are common effects across various serotonergic psychedelics. As outlined above, there has also been some uncertainty as to what dose constitutes a microdose. To increase the precision of microdosing science we need to focus on identifying substance-specific psychopharmacological effects. While we hope that the suggestions for plausible microdosing ranges provided in Tablewill assist with this, further research is required to definitively ascertain perceptual threshold doses, and substance specific outcomes. Distinguish and evaluate frequency and dosing schedule: There is likely a substantial distinction to be drawn between the acute effects of one or a few administrations of a microdose versus the sustained effects of regular and longer-term microdosing practice. Most reviewed survey studies reported on regular and longer-term practice, whereas the reviewed lab studies assessed the acute effects of one to six administrations. Future survey studies should clearly assess the frequency and duration of microdosing practice, and future lab studies should systematically vary these. Relatedly, although a common practice in the wild and in research studies is to microdose approximately every three days, to date there have been no formal comparisons of different dosing schedules and we have no empirical evidence to support the relative efficacy of any particular dosing regimen. This is an important variable to test in future research. Reframe microdosing as frequently supra-perceptual: Given that one of the most consistent findings amongst the papers we reviewed was that microdosing was associated with identifiable subjective drug effects, we suggest that researchers avoid describing The emerging science of microdosing 54 microdosing as sub-perceptual. Instead, we suggest that acute subjective effects should always be measured and microdosing could be defined as sub-hallucinogenic with no loss of functionality. Control for expectancy: It is critical that studies investigating the effects of microdosing control for participant expectations. While many lab-based studies incorporate placebo-controlled designs, many do not assess the integrity of the blind. Given typical microdoses produce noticeable acute subjective drug effects, we suggest future controlled studies incorporate active-placebo controls (e.g., low doses of diphenhydramine or tetrahydrocannabinol) and always assess blinding veracity. Metrics such as the Bang Blinding Index allow sensitive evaluation of the relative blinding efficacy of each experimental condition, and may be particularly suited to microdosing research. Controlling expectancy need not be limited to laboratory research:have demonstrated that it is possible to control for expectancy and implement placebo blinding within observational microdosing studies. Explore response prediction: One clear theme to emerge in the reviewed microdosing literature is bidirectional effects: within and across studies, a large number of variables have been shown to both decrease and increase following microdosing. Whether bidirectional effects are a function of stable individual differences (e.g., some people consistently become more anxious and others less anxious following microdosing) or situational factors (e.g., dose, mindset, physical setting, time of day, etc), future studies should explore the key predictors of subgroup effects. Better response prediction may substantially speed up progress in microdosing science. As discussed above, bidirectional effects may cancel each other in group aggregates, and so it may be productive to investigate changes in variance or absolute shift from baseline in addition to mean score differences. Moreover, better response The emerging science of microdosing 55 prediction may substantially improve the usefulness of microdosing science by determining real and reliable benefits and harms in subgroups of people. Improve specificity of measured effects: Future microdosing research should focus on assessing specific cognitive and other capacities. Early and qualitative reports suggested that microdosing might have a very broad range of positive impacts on individuals' lives. This has led microdosing researchers to investigate relatively broad, ill-defined, or complex constructs such as wellbeing and quality of life. On balance, the studies in this review have not shown strong evidence of changes in these domains. By contrast, there is compelling evidence that microdosing may impact specific cognitive functions such as time perception and pain perception. Promising directions for future research may be to focus on identifying other unexplored lower-level cognitive functions that may be responsive to microdosing, and investigate whether the cognitive capacities that are influenced by microdosing have clinical or practical utility (for example, through clinical trials or ecologically relevant performance-based measures). Explore clinical applications: Reported improvements in mental and physical health were some of the most common findings across all types of self report studies. The potential application of microdosing as a clinical tool, particularly as a treatment for depression has been identified previously, but no clinical study has yet taken place. The original reports from Fadiman that catalysed the current popularity of microdosing were clearly focused on the clinical utility of low dose psychedelics (e.g.,, yet this has not been a major focus of most empirical research. This is an obvious gap that should be addressed. Recruit representative samples: Most microdosing research to date suffers from selection bias, with samples comprised of enthusiastic microdosing volunteers. This may The emerging science of microdosing 56 have had a considerable impact on research findings to date. Future research would benefit from large, demographically diverse samples. Conduct long-term longitudinal studies: To date there has been little longitudinal research on the effects of microdosing. Only four prospective studies were identified in this review, and these all looked at effects over a time span of six weeks or less. Moreover, most of the controlled microdosing-specific studies tested different doses once each on the same volunteers, which does not resemble recurrent or sustained microdosing practice. Two controlled studies randomised participants to a specific dose that was administered six times, which goes some way to exploring repeat dosing, yet still does not resemble naturalistic practice. As long-term safety and efficacy remain unknown, and regular long-term use is already the de facto approach to microdosing in the community, carefully controlled studies that investigate the impacts of microdosing over longer time spans are needed. Assess safety: More research is needed into the safety of microdosing. Although psychedelics in general have a very good safety profile, the usage pattern associated with microdosingi.e., regular, ongoing useis quite different to the way that high dose psychedelics are typically consumed. One study has shown that microdosing appears to be safe for older individuals, however this study focused mainly on acute effects. Little is known about potential risks related to long term chronic use, with some notable concerns regarding cardiac valvulopathy associated with chronic serotonin 2B receptor activation. Definitively assessing these risks may require investigation of very long term microdosing. Practice open science: Despite specific calls for transparency in psychedelic research, the microdosing literature to date has not been particularly open. As microdosing science moves beyond the initial exploratory phase, it is The emerging science of microdosing 57 necessary for the field to shift toward emphasising scientific rigour and replication. To facilitate this, we encourage researchers to pre-register their hypotheses, methods, and analytic plans, and to share de-identified data at the time of publication. Microdosing research appears to be at an inflection point. As might be expected, the initial studies that arose in response to the recent popularisation of microdosing were qualitative or survey-based, cross sectional, retrospective investigations, in which people already engaged in the practice have reported on their motives and experiences. Such studies are exploratory in nature, with minimal experimental control. This hypothesis-generating phase of research has led to a large body of knowledge about the characteristics of microdosers and the perceived effects of this practice. A consistent theme from these studies is that microdosers report considerable and varied benefits, and that microdosing can lead to behaviour change. This phase of research is now being followed by well-controlled lab studies and research that places a greater emphasis on teasing apart the influence of expectation and drug effects. Alongside widespread practice in the community and some early signals in the data, a more rigorous science of microdosing is now emerging to investigate acute and long-term benefits and risks, mechanisms of change, response prediction, and differences across substances, doses and dosing regimens. With the above recommendations in mind, microdosing science is set to mushroom into a productive field of enquiry over the coming years.
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