Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review

The paper frames microdosing—the periodic use of very low doses of classical psychedelics such as LSD and psilocybin—as a distinct phenomenon from pharmacological "microdosing" or Phase 0 trials. Whereas Phase 0 uses sub-therapeutic exposures to obtain mechanistic information, recreational and self-administered microdosing typically employs doses (for example <25 µg LSD) that do not produce overt psychoactive impairment but are reported by users to produce subtle effects on mood, cognition and wellbeing. The authors note growing public interest since the 2010s, popularised accounts and online protocols, and emerging preclinical data that psychedelics can enhance neural plasticity and neurogenesis via 5-HT2A signalling, which has prompted interest in possible applications ranging from mood disorders to neurodegenerative disease.

Ona and colleagues performed a systematic review using PubMed, Scopus and Web of Science with search terms including "psychedelics," "hallucinogens," "lysergic acid diethylamide," "psilocybin," "ibogaine," and "microdosing," supplemented by manual searches on Google Scholar and Core. Eligible studies were peer-reviewed reports in humans that assessed microdosing using qualitative or quantitative methods. Extracted variables comprised authorship, year, sample size, country, design, questionnaires, microdosing protocol, drug type and dose (when reported), and main findings. The flow of selection began with 64 references at abstract screening, 22 potential records were identified after de-duplication, and 17 citations met inclusion after full-text review. The included corpus comprised 10 observational studies (mostly online surveys), three qualitative studies (online data or interviews), and four randomized, double-blind, placebo-controlled clinical trials. Across the included studies the total assessed sample was 3,619 individuals, although one preliminary report did not specify its sample size and the authors note that online recruitment raises the possibility of participant overlap between studies. Demographic reporting was heterogeneous: overall the pooled samples were male biased (about 69% male), though clinical trials had more balanced gender ratios, and most participants were young adults (mean age ~28.3 years) except for one elderly sample (mean age 62.9 years). The extracted text does not indicate that a quantitative meta-analysis was performed; results were synthesised narratively.

The systematic review synthesised three broad domains of findings: reported benefits, safety/adverse events, and evidence regarding placebo or expectancy effects. Reported benefits: Across observational and qualitative reports the most frequently reported benefit was mood enhancement. Qualitative analysis of user videos yielded four categories of benefits: heightened states/greater presence and mood improvements; insights and personal transformation; improved cognitive and occupational performance (notably creativity and productivity); and relief of various health conditions. Survey data provided numerical estimates in some studies: a retrospective survey of 278 users reported improved mood (26.6%), focus (14.8%), creativity (12.9%), self-efficacy (11.3%) and energy (10.5%), plus reductions in caffeine (44.2%), alcohol (42.3%), cannabis (30.3%), tobacco (21%), psychiatric prescriptions (16.9%) and illicit drugs (16.1%). Another survey found self-reported improvements in depression (71.8%) and anxiety (56.5%), and gains in memory (38.8%), attention (59%) and sociability (66.5%). A prospective naturalistic study that collected baseline, daily and long-term measures reported within-day increases in connectedness, creativity, focus, happiness and productivity on microdosing days and 6-week reductions in depression and stress, together with reduced mind-wandering and increased absorption. Experimental evidence on cognitive enhancement is mixed: an open-label study with psilocybin truffles reported improvements in convergent and divergent thinking but lacked a control group and may be confounded by practice effects. The published randomized trials were primarily safety and tolerability studies and did not uniformly demonstrate robust improvements in mood or creativity; one LSD trial (6.5, 13 and 26 µg) increased 5D-ASC ratings for unity and blissful state dose‑dependently, while others reported small or inconsistent mood effects. Safety and adverse events: The review catalogued a wide array of adverse experiences reported in observational data. These included eleven categories (for example illegality-related harms, physiological discomfort, impaired focus, increased anxiety, impaired energy, impaired mood, social interference, cognitive interference, dissociation/self-interference, increased symptoms including tolerance and dependence concerns, and miscellaneous issues). Reported problems ranged from increased anxiety, panic attacks, gastrointestinal and thermoregulatory symptoms, restlessness and overstimulation (notably with LSD), to insomnia, impulsivity, reduced problem‑solving and decrements on cognitive tasks. Where percentages were provided, one study reported worsening of depression in 4.75% of participants and worsening of anxiety in 13.1%; impairments in memory (14.6%), focus/attention (14.7%) and social abilities (11.1%) were also reported. Freeform physical complaints were reported by 31.25% in one sample. A "bad trip" was noted when a microdose of LSD was combined with cannabis. The authors emphasise risks related to imprecise dosing, illicit markets and potential drug–drug interactions. Placebo and expectancy: Only four randomized, placebo-controlled trials were identified. Findings were mixed. In one trial LSD at 13 and 26 µg (but not 6.5 µg) increased self-ratings of "feel drug" on a Drug Effects Questionnaire and raised systolic (placebo 105.35 mmHg, 13 µg 111.5 mmHg, 26 µg 115.3 mmHg) and diastolic blood pressure at 26 µg, indicating dose‑related subjective and physiological effects. Another trial reported that 16 of 20 participants correctly identified placebo sessions, and that 13 µg produced only modest and inconsistent subjective effects with near-significant increases on some DEQ items and ARCI sedation. Yanakieva et al. studied older adults with doses up to 20 µg and found no significant self-reported subjective effects, but detected longer temporal reproduction times under LSD relative to placebo, suggesting objective pharmacological effects despite absent self-report. The reviewed trials therefore suggest that doses ≥13 µg can produce measurable effects, yet expectancy and identification of placebo versus drug varied and may influence outcomes; one trial reported more adverse events in the placebo group, raising the possibility of nocebo/expectation effects.

Ona and colleagues interpret the literature as preliminary and heterogeneous but informative. They highlight three study types: observational surveys (n=10), qualitative reports (n=3) and randomized placebo-controlled trials (n=4). Observational work supplies large samples (>3,000 individuals) and high external validity but is vulnerable to self-selection, gender bias (69% male overall), online recruitment overlap and lack of dosing precision. The clinical trials are few and limited by exclusion of participants with prior adverse reactions, allowance of caffeine/tobacco around sessions, and small, heterogeneous samples, all of which constrain the generalisability of safety findings. The authors emphasise that mood enhancement is the most consistently reported benefit and propose possible mechanisms, including amygdala dampening observed after 13 µg LSD in one study, which parallels findings with higher psychedelic doses and may underlie anxiolytic or antidepressant effects. Nevertheless, they caution that evidence for creativity and other cognitive enhancements is inconsistent: observational reports commonly claim gains but controlled trials do not uniformly replicate these findings, and uncontrolled designs are susceptible to expectancy and learning effects. Reports of symptom improvement across a range of psychiatric and neurological conditions (depression, anxiety, PTSD, ADHD, pain, cluster headache and others) are mainly self-reported and require rigorous clinical evaluation. Safety concerns receive substantial attention: the review groups adverse events into mood disturbances, physical discomfort, cognitive impairments, mental health issues (for example dissociation, insomnia), and social difficulties. The authors warn of overdosing risks due to imprecise dosing, potential drug–drug interactions (notably with cannabis and prescribed medications), and the consequences of illicit sourcing. They note a discrepancy between the frequency of adverse events in survey studies and their relative scarcity in clinical trials, suggesting differences in reporting methods and sampling biases. Expectancy effects are explored as both placebo and nocebo phenomena: some experimental evidence points to pharmacological effects at modest doses while other outcomes may reflect expectations, and one trial found more adverse events in the placebo arm. For future research the authors call for more randomised, placebo-controlled trials, standardisation of dosing regimens and schedules (many current users follow Fadiman's one day on/two days off protocol but practices vary), recruitment of psychedelic‑naïve participants to reduce expectancy bias, and in-person prospective observational studies to mitigate online survey limitations. They also encourage investigation of microdosing with a broader range of compounds (for example ibogaine, DMT, harmalines) and exploration of potential applications such as neurodegenerative and inflammatory conditions in light of preclinical psychoplastogenic findings. Key limitations acknowledged include heterogeneous dosing (LSD ranges 5–50 µg; psilocybin 0.1–0.5 g dried mushrooms), uncertain or unreported doses in many observational studies, sample heterogeneity and gender imbalance, and the small number of RCTs, particularly with psilocybin. The authors conclude that controlled, standardised research is necessary to clarify safety, efficacy and the role of expectancy in reported microdosing effects.