Microdosing psychedelics: Current evidence from controlled studies

Microdosing refers to the repeated self-administration of very low doses of classic psychedelics, most commonly LSD and psilocybin, intended to produce minimal or no overt subjective intoxication while purportedly improving mood, cognition, or wellbeing. Despite widespread anecdotal reports and media attention, controlled laboratory studies of microdosing have been limited, and the evidence base remains uncertain. Earlier narrative reviews and community reports suggest possible benefits for mood, creativity and cognition, but rigorous experimental data have lagged behind these claims. Murphy and colleagues set out to survey recent laboratory-based trials that used rigorous experimental control to assess the acute and repeated effects of microdoses. Specifically, the review focused on randomised trials published after 2010 that used investigator‑supplied drugs, included a non‑psychedelic placebo, and were conducted in laboratory settings. The authors aimed to describe physiological, behavioural and subjective effects under controlled conditions, identify gaps in the literature, and highlight methodological limitations to guide future research. The review covers 14 papers derived from eight separate trials run by four laboratory groups, all involving LSD microdoses in healthy volunteers.

The review included randomised, laboratory-based trials published after 2010 that met three key criteria: investigator‑supplied psychedelic drug, inclusion of a non‑psychedelic placebo, and controlled experimental settings. The authors compiled studies that used double‑blind or similar procedures and extracted demographic details, dosing regimens, physiological, behavioural and subjective outcome measures. Fourteen papers corresponding to eight distinct trials were identified; several trials yielded multiple publications and the authors distinguished between "trial" (cohort) and "paper" (publication). Designs among the trials varied: four used within‑subject crossover designs and four used between‑subject parallel group designs. Correction for multiple comparisons was only reported in seven papers. Participant samples were predominantly healthy, young-to-middle‑aged adults (mean ages generally 22–38 years), recruited in New Zealand, the Netherlands and the USA; one trial sampled older adults (mean 61–64 years). Trials typically excluded psychiatric and major medical conditions and therefore did not include clinical patient populations, although one paper included participants with elevated but subclinical depressive symptoms. Where reported, most participants had at least a bachelor's degree and were majority Caucasian/European. All included studies tested LSD only, with doses expressed as LSD base equivalents. Trials used low doses commonly described as 5, 10 and 20 µg (with tartrate-to-base conversions applied where necessary). Some protocols compared single acute doses to placebo, while others examined repeated administrations (for example, daily or multiple doses over several days or weeks). Blinding procedures and the information provided to participants varied across trials; in several studies investigators asked participants to guess their allocation. Two papers reported pharmacokinetic sampling over 6–8 hours. Safety monitoring and adverse event reporting were included in the trials; details of these procedures were described variably across papers. The review synthesised outcomes across physiological measures (vital signs, neuroimaging, EEG, biomarkers), behavioural tests (cognition, social perception, pain tolerance, time perception, creativity), and subjective questionnaires administered during and after dosing.

The review found consistent features across the controlled trials: all studies involved LSD microdoses (5–20 µg) and none tested laboratory‑supplied psilocybin. In total, 14 papers from eight trials were synthesised. Participant samples were demographically homogeneous (young, educated, mainly Caucasian), with most having some prior but generally low lifetime psychedelic experience. No trials recruited clinical patient populations. Physiological effects: Low doses of LSD produced measurable acute physiological and neural effects. Systolic blood pressure increased in most trials; diastolic blood pressure increased less consistently. Heart rate, ECG and body temperature were not reliably affected. One trial reported increased sleep duration (and REM sleep) on the day after dosing. Two studies provided pharmacokinetic data showing dose‑related increases in plasma concentrations with similar times to peak and terminal half‑life across 5, 10 and 20 µg. Biomarker data in one trial showed increased plasma BDNF at 5 and 20 µg but not 10 µg at 4–6 hours post‑dose. Neuroimaging revealed that 10 µg increased thalamic and amygdala connectivity, with amygdala connectivity correlating with positive mood changes; cerebral blood flow was not altered in that study. EEG data showed that 20 µg (but not 10 µg) decreased oscillatory power across theta, beta and gamma bands and altered event‑related potentials (reduced ERP amplitudes to emotional oddballs, increased ERPs to rewards). Behavioural effects: On social perception tasks, 20 µg increased positive ratings of happy faces, reduced false fearful attributions, and in one study reduced negative mood during social rejection (a finding not always replicated). Time perception was dose‑dependently altered: 5–20 µg increased estimates of suprasecond intervals. Pain tolerance (cold pressor test) increased at 20 µg. Cognitive testing showed minimal and inconsistent effects: neither single nor repeated doses produced robust changes on the CANTAB or NIH Toolbox; measures of cognitive control and working memory were largely unaffected. On the Digit Symbol Substitution Test, one trial found reduced correct responses while others did not; psychomotor vigilance performance showed reduced attentional lapses with 5 and 20 µg in one study. Objective measures of creativity were unchanged in the controlled trials. Subjective effects: Subjective drug effects were detectable at 10 and 20 µg but not reliably at 5 µg. On drug‑effect questionnaires, 10–20 µg increased ratings of feeling the drug, liking the effect and feeling "under the influence"; only 20 µg raised items such as "want more" and "dislike drug" and decreased concentration. Momentary mood measures (POMS) showed increased anxiety and friendliness at 5 and 20 µg (but not consistently at 10 µg); 20 µg also increased confusion, elation and vigour and reduced fatigue in some samples. Retrospective measures of altered states (5D‑ASC) detected increases in 'blissful state' at 10 and 20 µg and 'impaired cognition and control' at 20 µg; classic perceptual hallucinations were not produced. In participants with elevated depressive symptoms, 20 µg produced greater increases in 'blissful state' and 'spiritual experience' compared with non‑depressed participants. Repeated dosing studies reported transient self‑reported improvements on dose days (reduced anger, increased connectedness, creativity, energy and happiness) but found no lasting effects on mood, cognition or personality after the dosing period. Safety and tolerability: No serious adverse events were reported across trials. Common adverse reports included headache and jitteriness. One paper reported anxiety events that led to withdrawal of four out of 40 participants in the LSD condition; this prompted a titration protocol (reducing dose to 5 µg and titrating up) that was used for six of 40 participants in the LSD group and one of 40 in the placebo group. The authors noted instances of increased anxiety in some studies, but overall concluded low short‑term risk in screened healthy volunteers. Blinding and expectancy: Blinding was imperfect. In some trials participants were told they might receive a range of drugs, and guesses after 5 and 10 µg were split between placebo and hallucinogen; at 20 µg guesses varied. In the University of Auckland trial, participants identified placebo correctly on 36% of doses and LSD correctly on 61% of doses. Only two trials reported pharmacokinetics. The review highlighted that doses ≥10 µg commonly produce perceptible effects, raising the possibility that expectancies contributed to outcomes.

Murphy and colleagues interpret the controlled trial literature as indicating that low doses of LSD (especially 10 and 20 µg) produce modest acute physiological, neural, behavioural and subjective effects in healthy volunteers, while 5 µg generally falls below the threshold for detectable subjective effects. They regard the evidence as providing limited support for some user claims (acute mood enhancement, altered time perception, increased pain tolerance, and enhanced social/emotional processing), but note little evidence for improvements in objective cognitive performance or creativity in the measures used to date. The authors emphasise that none of the reviewed trials sampled clinical populations, so generalisability to patients remains untested. Several methodological caveats and limitations are highlighted. Trials tended to recruit demographically homogeneous, screened, Western participants, limiting external validity. Blinding was often imperfect and participant expectancies could therefore have influenced outcomes; the authors recommend manipulating instructional sets and considering active placebos (for example stimulants) in future trials to better control expectancy effects. They also point out that many standard psychometric instruments (including the 5D‑ASC) were developed for full psychedelic doses and may lack sensitivity to subtle microdose effects, arguing for the development of microdose‑specific measures. Other sources of variability requiring study include pharmacokinetic differences, genetic polymorphisms (for example CYP2D6 and 5‑HT2A receptor variants), age, sex, bodyweight and prior drug use. On safety, the authors report no serious adverse events in healthy volunteers but caution that safety in clinical populations and with more prolonged administration is unknown. Mechanistic questions remain open: it is unclear whether microdoses act through the same neurobiological processes thought to underlie therapeutic effects of full psychedelic doses, which are often linked to profoundly altered subjective experiences. The review highlights a potentially interesting signal for pro‑social effects that could be therapeutically relevant, and recommends inclusion of social functioning measures in future clinical trials. Overall, the authors conclude that controlled trials so far support short‑term safety and mild acute effects of LSD microdoses in healthy adults, but do not support claims of lasting cognitive or creative benefits; they call for replication, extension to clinical and more diverse samples, improved blinding and expectancy control, more sensitive outcome measures, and mechanistic investigations.

Controlled psychopharmacological trials of LSD microdoses in healthy volunteers demonstrate mild, dose‑dependent acute effects on mood, sleep architecture, social cognition, reward processing and pain perception, with detectable subjective effects typically arising at 10–20 µg. Repeated low doses produced transient self‑reported benefits on dosing days but yielded no consistent lasting improvements in mood, cognition or personality in the trials reviewed. The evidence to date provides limited support for some user claims but does not substantiate durable cognitive or creative enhancement. The authors recommend further rigorous clinical trials in symptomatic populations, broader and more diverse samples, development of measures sensitive to microdose effects, stronger blinding or active placebo controls, and studies of mechanisms and predictors of individual variability.