This systematic review (s=14) compiles double-blind, placebo-controlled studies on microdosing LSD (5-20μg) under laboratory conditions. It reports that acute low doses of LSD affect blood pressure, sleep, neural connectivity, mood, social cognition, and perceptions of pain and time, with noticeable effects at 10-20 μg but not at 5μg. While no serious adverse effects were noted, repeated microdosing did not significantly change mood or cognition.
Taking regular low doses of psychedelic drugs (microdosing) is a practice that has drawn recent scientific and media attention for its potential psychotherapeutic effects. Yet, controlled studies evaluating this practice have lagged. Here we review recent evidence focusing on studies that were conducted with rigorous experimental control. Studies conducted under laboratory settings using double-blind placebo-controlled procedures and investigator-supplied drug were compiled. The review includes demographic characteristics of the participants and dependent measures include physiological, behavioural, and subjective effects of the drug(s). Fourteen studies met the review criteria, all of which involved acute or repeated low (5-20 μg) doses of lysergic acid diethylamide (LSD). Acute microdoses of LSD dose-dependently altered blood pressure, sleep, neural connectivity, social cognition, mood, and the perception of pain and time. Perceptible drug effects were reported at 10-20 μg but not 5 μg. No serious adverse effects were reported. Repeated doses of LSD did not alter mood or cognition on any of the measures studied. The findings suggest that low doses of LSD are safe and produce acute behavioural and neural effects in healthy adults. Further studies are warranted to extend these findings to patient samples and to other psychedelic drugs, and to investigate microdosing as a potential pharmacological treatment for psychiatric disorders.
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.
Papers cited by this study that are also in Blossom
Bershad, A. K., Schepers, S. T., Bremmer, M. P. et al. · Biological Psychiatry (2019)
de Wit, H., Molla, H. M., Bershad, A. K. et al. · Addiction Biology (2022)
Yanakieva, S., Polychroni, N., Family, N. et al. · Psychopharmacology (2018)
Family, N., Maillet, E. L., Williams, L. T. J. et al. · Psychopharmacology (2019)
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.
Microdosing psychedelic drugs is a medically unapproved practice that has been the subject of recent controlled trials. The term 'microdosing' is typically used to refer to doses that produce minimal, or no perceptible subjective or behavioural effects. The practise involves self-administration of very low doses of psychedelic drugs, particularly lysergic acid diethylamide (LSD) and psilocybin, at regular intervals for a sustained period of time. Individuals who engage in microdosing report that the drug improves their mood and wellbeing, as well as reducing symptoms for depression, anxiety, PTSD, ADHD, and substance misuse. As a potential psychotherapeutic, microdosing presents an appealing alternative to the full doses of psychedelic drugs that induce substantial alterations in J o u r n a l P r e -p r o o f with mean 61-64 years. No analyses were stratified by age. Notably, none of the trials in this review sampled clinical populations, although one paper included participants with high but subclinical depression symptomatology. Most participants reported some previous psychedelic drug use (lifetime or past year) but rates were generally low. Most trials were reasonably balanced between male and female participants, but several had more males than females and one included only males because of concern about fluctuations in primary measures over the menstrual cycle. No analyses were stratified by sex, and cycle phase was not controlled. In general, the participants were relatively homogeneous, recruited from healthy, educated participants in New Zealand, the Netherlands, and the USA. Where reported, most participants had at least a bachelor's degreeand, where reported, most were Caucasian/European.
Four trials used crossover (within-subject) designs, and four used parallel groups (between-subject) designs. Despite often including multiple measures of related constructs, correction for multiple comparisons between measures was only reported in seven papers. Because of this lack of correction, some reported results are potentially false positives. Study design is discussed further in the Supplementary Materials.
All of the studies that met our criteria used LSD and an inactive placebo. LSD base was used in three of the eight trials reported, and LSD tartrate in the remaining five. For ease of comparison, we have reported tartrate doses as their base equivalent ie. 6.5 µg tartrate ≈ 5 µg base; 13 µg tartrate ≈ 10 µg base; 26 µg tartrate ≈ 20 µg base. All trials included doses of 5, 10, and 20 µg vs placebo or 10 or 20 µg vs placebo. One study comparing repeated 10 µg doses to placebo also included a titration protocol in which a subset of participants who experienced undesirable effects J o u r n a l P r e -p r o o f could subsequently take a reduced dose (5 µg) and titrate up to a tolerable dose (up to the original 10 µg).
The studies varied in the instructions given to participants about what drug(s) they might receive and in how blinding data was recorded. Participants in trials at the University of Chicago were told they could receive a placebo, cannabinoid, hallucinogen, opioid, stimulant, or sedative, and were invited to guess which they had received (Table). In most cases, participants correctly identified placebo, and after 5 and 10 µg guesses were divided between placebo and hallucinogen. After 20 µg, participants guessed they had received various drugs but did not identify the drug consistently as a hallucinogen. In the University of Auckland trial, participants were told that they might receive LSD or placebo each dose, and they were asked to guess ('LSD', 'Placebo' or 'Don't know') at the end of each session. In contrast with the Chicago studies, participants who received placebo correctly identified it as such on 36% of doses, whereas participants who received LSD were correct on 61% of doses. In this trial, LSD produced some subjective effects even in participants who were uncertain of their allocation. The remaining two trials did not report data about unblinding.
Two papers reported some pharmacokinetic data, examining doses of 5, 10, and 20 µg over 6and 8 hours. Doses of 5 µg, 10 and 20 µg all increased plasma levels, at comparable times of peak concentration and terminal half-life. Pharmacokinetics are discussed further in the Supplementary Materials.
No serious or severe adverse events were reported in any of the trials reviewed. Detailed adverse event reports were provided for the acute effects of six repeated doses, and six-weeks of 14 repeated doses. In these trials, LSD increased reports of headacheand jitteriness. One paper also reported incidents of anxiety that necessitated the withdrawal of four out of the 40 participants J o u r n a l P r e -p r o o f in the drug condition. This anxiety appeared to be related to subjective overstimulation or jitteriness and led the investigators to introduce a titration protocol to mitigate this risk. The titration protocol was initiated for one participant out of 40 in the placebo group and six participants out of 40 in the LSD group. Notably, some other studies also reported that LSD increased ratings of anxiety (discussed further below).
The studies reviewed demonstrated that microdoses of LSD affected several physiological measures (Table). LSD increased systolic blood pressure (SBP) in most trials, and increased diastolic blood pressure (DBP) less frequently. It did not alter either ECG, heart rate or body temperature. The one trial that examined sleep duration found that LSD increased sleep duration one day after the dose (but not the night of the dose), which included an increase in REM sleep duration. In a different trial, LSD (5 and 20 µg but not 10 µg) increased plasma brain derived neurotrophic factor (BDNF) 4-6 hours post-dose. Using functional magnetic resonance imaging (fMRI), LSD (10 µg) increased connectivity in thalamic and amygdala regions, and amygdala connectivity was positively correlated with increases in positive mood. In that study, the drug did not alter cerebral blood flow (CBF). On electroencephalography (EEG) measures, LSD (20 µg but not 10 µg) decreased oscillatory power across theta, beta, and gamma bands. The drug also decreased event related potential (ERP) amplitudes in response to an emotional face oddball task, and increased ERP responses to rewards and positive feedback. Thus, low doses of LSD do affect brain function as measured by EEG and fMRI, but these effects have only been studied after single doses.
The effects of low doses of LSD on behaviour have been studied using measures of cognition, social perception, and creativity (Table). On measures of social perception, LSD (20µg) increased ratings of positivity in response to happy faces, decreased the likelihood of falsely rating a face as fearful, and decreased negative mood during a social rejection task(but this was not replicated in).
On a measure of time perception, LSD (5, 10, and 20 µg) dose-dependently increased estimates of suprasecond time intervals independent of subjective effects. On a measure of pain tolerance (cold pressor test), LSD (20 µg) increased tolerance to pain. On measures of cognition, neither single nor repeated doses of LSD (5, 10, and 20 µg) had consistent effects with the Cambridge Cognition (CANTAB) toolbox acutelyor with the National Institute of Health (NIH) toolboxafter 6 weeks. These doses of LSD also had little effect on measures of cognitive controlor working memory. Using a broad measure of information processing (Digit Symbol Substitution Test (DSST)), LSDreduced the number of correct answers in one trial, but not others. In contrast, LSD (5 and 20 µg) reduced attentional lapses in the Psychomotor Vigilance Task, consistent with improved function. Creative performance was not altered in either of the instances where it was measured. Thus, low doses of LSD produce modest changes in social function such as recognition of positive emotions, but they have little effect on cognitive performance or creativity on the measures used thus far.
Subjective effects have been measured at three different intervals: during dosing sessions, retrospectively at the end of the session, and after repeated days of dosing (Table). On drug effects questionnaires, 10 and 20 µg LSD (but not 5 µg) increased ratings of feeling the drug's effects (both good and bad), liking it, and feeling 'under the influence' or 'high'. Only 20 µg increased ratings of 'want more', 'dislike drug', and reduced 'concentration'. On a measure of momentary mood states (POMS), 5 and 20 µg (but not 10 µg) increased ratings of anxietyand friendliness. LSD (20 µg only) increased confusion, elation, and vigor, and decreased fatigue. In one study, 20 µg increased scores of elation and vigour only in individuals who scored high on a measure of depression. On a measure of drug-specific effects, LSD (10 and 20µg) increased scores on stimulant-like scales, the LSD scale and, in one case it also increased scores on a sedative-like scale. On a retrospective measure of altered states of consciousness (5D-ASC) 5 µg again had no effect, and higher doses produced increases in 'blissful state' (10 and 20 µg)J o u r n a l P r e -p r o o f 6, 7] and 'impaired cognition and control' (20 µg). LSD did not produce either auditory hallucinations or audio-visual synesthesia, but occasionally affected vision and altered the meaning of percepts at 20 µg only. In the study with mildly depressed participants, 20 µg LSD increased scores on 'blissful state' and 'spiritual experience' in depressed but not in non-depressed participants. Taken together these results indicate that single low doses of LSD above 5 µg produce mild alterations in mood and subjective state in healthy volunteers. These effects appeared to be mainly stimulant-like (e.g., decreased fatigue and increased vigor). One paperalso provided important information about the context in which the drug is taken: the effects of the drug appeared to be more pronounced in participants' natural environment compared to its effects in the laboratory. The trials with repeated doses reveal whether effects of the drug either increase or decrease with time. In one study participants completed single item visual analogue scales (VAS) during 14 repeated administrations of 10 µg. The drug reduced anger and irritability, and increased self-reported connectedness, creativity, energy, happiness, and wellness on the dose days, and visual inspection suggested that the effects were most pronounced during early sessions. There were no lasting effects of the repeated doses. In another study, the effects of LSD on ratings of vigor declined across the four days of administration, and there were no lasting effects on measures of emotion, behaviour or personality.
This review of controlled trials reveals that low doses of LSD (10 and 20 µg) produce modest subjective, physiological and behavioural effects when given under double-blind conditions. No trials investigating laboratory-supplied psilocybin microdoses were found. On subjective ratings, single administrations of 10 and 20 µg LSD increased ratings of feeling high, liking the effect and increased vigor, elation and psychedelic-like effects. However, the drug also increased feelings of anxiety in some instances. On physiological measures the drug changed neural activity, sleep, and J o u r n a l P r e -p r o o f plasma BDNF. On behavioural measures the drug enhanced emotion recognition, and increased pain toleranceand time perception. The drug had no effect on creativity and minimal effect on cognitive performance. None of the studies involving repeated administration of the drug reported lasting effects on mood or cognition. The findings provide limited support for users' claims that low doses of LSD improve mood and cognition and suggest that the drug is safe. However, the findings provide no support for lasting beneficial effects of repeated doses. These findings with healthy volunteers set the stage for future studies investigating the effects of the drug in individuals with significant psychiatric symptomatology.
The studies reviewed here reveal that the threshold dose at which subjective or behavioural effects can be detected is between 5 and 10 µg LSD, and that responses to the drug tend to be linearly dosedependent. We note, however, that subjects vary in their sensitivity to the drug. It remains to be determined whether this variability is related to pharmacokinetic variables or to pharmacodynamic variation related to receptor number or sensitivity, or uncontrolled contextual variables. Future studies will shed light on the mechanisms underlying tolerance to repeated doses, as well as individual variation in either tolerance or sensitization to certain effects. Another important question for future studies is whether repeated ingestion of a dose that produces no detectable subjective effects can nevertheless produce lasting beneficial effect. As noted above, some users claim to experience improved mood after taking individual doses that have no discernible effect.
Because expectancies are known to influence the subjective effects of drugs, it is important to both minimize expectancies before drug administration, and monitor the extent to which participants identify the drug they received. Expectancies derived from either instructions or from subtle early effects could influence further responses to the drug. The present review indicates that doses of 10 µg and above yield detectable subjective effects, raising the possibility that expectancies J o u r n a l P r e -p r o o f stemming from these effects contribute to the overall responses. This makes it unlikely that complete blinding of microdosing trials will be possible. However, it is still not clear whether low doses without detectable subjective effects can change mood with repeated administration. This remains to be explored in future studies with larger samples of participants. One way to minimize expectancies in microdosing studies is to manipulate instructions to participants. For example, presenting a trial as a 'microdosing' study may bias participants to report expected effects, whereas presenting a trial as a generic drug study in which participants might receive a range of drugs, as has been done in the Chicago studiesmay minimize this bias. Another approach may be to include active placebo conditions. For example, in view of the stimulant-like effects reported following LSD microdoses, stimulant drugs such as caffeine or methylphenidate might be appropriate active placebos. It is important that researchers assess and control for expectancies and unblinding, for example by analysing data in terms of correct identification of the drug. If the drug produces similar behavioural or cognitive effects in subjects who do or do not correctly identify the substance as a psychedelic, then expectancies may play a minor role. However, the contribution of expectances would be difficult to rule out if the effects are detected only in participants who correctly identify the drug. There is some evidence that doses below the threshold of subjective detection may have subtle effects, and more is needed to determine if these could be reliable or clinically significant.
One important issue in reviewing the findings from microdosing studies is whether the outcome measures that have been used are sensitive to the drug's effects, and whether the drug alters mood or behaviour in ways that are not detected by current measures. For example, the questionnaire used to assess psychedelic drug effects (5D-ASC) is designed to detect effects of full doses and may not be sensitive to some effects of microdoses. Items such as "I felt like I was in a wonderful other world" may not be relevant to low dose effects. Similarly, other standard drug questionnaires ask participants if they "feel high", which may not apply to this category of drugs. A challenge to researchers is to identify and measure the relatively subtle psychological effects that are reported by community J o u r n a l P r e -p r o o f microdosers. It would be useful to have a questionnaire specifically designed to detect the apparently unique effects of microdoses. Such a questionnaire might be developed using items that were most sensitive to the drug in existing studies, or based on the natural microdosers' anecdotal reports of the drug's effects. Some users claim that microdoses of psychedelic drugs increase creativity. However, creativity is a complex construct which has been measured in various ways including both objective and subjective measures. It is not clear whether objective tasks designed to assess creativity measure the same underlying construct as self-reported feelings of creativity. Low doses of LSD increased selfrated feelings of creativity in one trial, consistent with the findings of two prospective trials. However, the drug did not significantly increase the objective measures of creativity in the controlled studies reviewed here. There is a need for better definitions of creativity, as well as sensitive and valid tasks assessing the construct(s).
Participants in the studies reviewed here were demographically homogeneous. They were screened for physical and psychiatric wellbeing, lived in Western countries, and most were young, educated, male, and Caucasian. These studies are an important first step, but the research needs to be expanded into clinical populations and more heterogeneous groups to identify predictors of drug response. One paper reported that volunteers with depressive symptoms reported different subjective responses to a low dose of LSD on certain subjective measures. Volunteers with depressive symptoms reported greater increases in 'vigor', 'elation', 'spiritual experience', 'blissful state', after LSD, but not did not differ from non-depressed participants on ratings of 'feeling' a drug effect, or on depression. This differential response depending on baseline symptomatology is consistent with preclinical evidence which has shown anxiolytic effects in stressed, but not non-stressed animals. A greater response in symptomatic volunteers could also explain why the existing trials, which only include healthy volunteers, have failed to replicate the widespread changes to mood and cognition J o u r n a l P r e -p r o o f reported in the community. Taken together there is evidence that low doses of LSD acutely improve mood in a healthy population, and that these effects may be stronger in individuals with negative mood at baseline. These findings call for future clinical trials of mood disorders. Variability in responses to low doses of LSD may be related to either pharmacokinetic or pharmacodynamic factors. Pharmacokinetic modelling has shown moderate variability in plasma concentration of the drug doses, which could explain some variance in effect. Polymorphisms of the CYP2D6 gene, which affect the liver's ability to metabolise LSD, predict pharmacokinetics and the intensity of LSD's subjective effects at full doses, it is not known if these play a role at low doses. Other possible sources of variance in subjective effects include age, sex, bodyweight/BMI, lifetime and recent use of drugs (prescription or recreational), current psychiatric symptomatology, and genetic variation in receptor function such as 5HT2A receptor gene polymorphisms and mRNA expression. Future studies should aim to identify predictors of the quality and magnitude of responses to low-dose LSD. The studies reviewed here indicate that microdosing with LSD in healthy adults is safe. Safety in clinical populations, or with more prolonged administration of the drug has yet to be addressed (see the Supplementary Materials for further comments on safety).
Many questions remain unanswered. Little is known about sources of individual differences in acute response to the drug, and what other variables influence responses to low doses of LSD on mood, time perception, reward response, and pain tolerance. The lasting effects of repeated doses have not been studied. There are also important questions about the neurobiological mechanisms by which low doses produce behavioural effects, which might be addressed using selective antagonists of known LSD binding sites (5HT2A or dopamine receptors). Another understudied area is the effects of low doses on social function. Several of the studies reviewed here suggest that LSD microdoses increase behavioural and neural responses to social stimuli, as J o u r n a l P r e -p r o o f well as subjective ratings of feeling connected. This enhanced social function is consistent with survey and interview data from community microdosers who report social benefits, and with preclinical evidence of increased acute pro-social behaviour of animals after repeated low doses of LSD. Although there is currently little evidence that low doses of LSD lead to sustained improvements in social satisfaction, this construct remains to be operationalized, and studied in symptomatic volunteers. The increase in feelings of connectedness during acute drug administration might be of therapeutic benefit in mood disorders, and may enhance the efficacy of therapy if it aids therapeutic alliance. As such, we recommend that pro-sociality scales be developed and included as secondary measures of clinical trials. An important issue is whether very low doses of LSD produce beneficial effects through processes that are similar to effects seen at higher doses. High doses psychedelic drugs are thought to produce their therapeutic effects by inducing a profoundly altered state, of "psychedelic experience". That is, the lasting therapeutic benefits of full-dose psychedelic effects are greatest in patients who experience the most pronounced altered states. This suggests that the therapeutic value, if there is one, of microdoses, is likely to be mediated by different processes. It remains to be determined whether microdosing of LSD or other drugs might have a place in mainstream clinical practice, such as in patients with mood disorders. The approval process through regulatory agencies presents unique challenges with regard to assessment of efficacy and safety. Alternatively, making the drug available as a relatively unregulated dietary supplements would also present difficulties. At present, it needs to be demonstrated whether microdosing psychedelic drugs has any potential benefit, and any risks, and what symptoms the drug might relieve.
The existing psychopharmacological trials of microdosing LSD in healthy volunteers demonstrate mild effects of LSD on mood, sleep, social cognition, reward response, and pain perception. Some of these effects might facilitate treatment of psychiatric disorders, but the findings need to be replicated and J o u r n a l P r e -p r o o f extended to clinical and more diverse populations. Thus far, there has been little support for claimed benefits of improved cognition and creativity, but these negative findings are limited by the sensitivity of the measures available. Future clinical trials to support the users' anecdotal claims and to explore clinical applications are needed. Additional trials with healthy volunteers would also be useful to elucidating the mechanism and sources of variability of the drug's effects. TablesDemographics of participants included in each trial.
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