The emerging science of microdosing: A systematic review of research on low dose psychedelics (1955 - 2021)

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.

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.