Side Effects of Microdosing Lysergic Acid Diethylamide and Psilocybin: A Systematic Review of Potential Physiological and Psychiatric Outcomes

Research on classic psychedelics has resurged since regulatory restrictions of the late 20th century, and with that has come widespread interest in the practice of microdosing — the repeated administration of sub‑perceptual doses of substances such as LSD and psilocybin. Earlier studies, largely observational or short-term laboratory experiments, report many anecdotal benefits (improved mood, cognition and daily functioning) but provide limited, inconsistent and often non-systematic information on adverse effects. The literature is further complicated by heterogeneous definitions of microdosing, variable preparation methods, and reliance on internet surveys and self-report data. Modzelewski and colleagues set out to systematically collect and characterise reported physiological and psychiatric side effects of microdosing with LSD and psilocybin. The review aimed to describe the nature, frequency, severity and course of adverse events in the existing literature, separating physiological and psychiatric outcomes and highlighting gaps that impede understanding of long‑term risk.

The investigators conducted a systematic review following PRISMA 2020 guidance. Searches of PubMed, Web of Science and Scopus were performed on 3 August 2024, covering publications from 2004 to 2024. Search terms combined concepts for psychedelics, microdosing, and side/adverse effects; initial yields were screened for duplicates and then by two authors independently at title/abstract and full‑text stages. Exclusion criteria included non‑original studies, animal studies, non‑English papers, and studies that did not address microdosing or report side effects. After de‑duplication and screening, 31 studies met inclusion: 15 laboratory or mixed laboratory studies judged higher quality, 14 lower‑quality studies (surveys and exposure studies), and 2 clinical case reports. Two authors independently extracted study characteristics (author, year, study type), details of the psychedelic exposure (substance, dose, schedule), and available adverse‑event data (nature, number affected, severity, duration). The authors did not perform a quantitative meta‑analysis owing to heterogeneity in side‑effect assessment and did not undertake a formal risk‑of‑bias assessment because most studies did not have side effects as a primary outcome. The review protocol is registered in PROSPERO (CRD42024590719).

Thirty‑one studies were included: 15 laboratory or mixed laboratory reports, 14 lower‑quality observational/survey/exposure studies, and two clinical case reports. Across studies, side effects of classic psychedelic microdoses were generally described as mild, transient and often dose‑dependent, though reporting was heterogeneous and frequently qualitative. Physiological effects: Gastrointestinal complaints (nausea, vomiting) were reported in several studies. In laboratory work, one psilocybin study recorded nausea in 1 of 52 participants (dose unspecified), while LSD studies reported nausea variably (one small study reported 1 of 12 participants reporting nausea across several dose conditions; another reported 7 of 40 participants at 10 μg versus 2 of 40 on placebo). Diarrhoea and broader “gastrointestinal discomfort” were reported but uncommon. Headache appeared across laboratory and survey studies; in one LSD laboratory dataset incidence by dose was 16.7% at 5 μg, 50.0% at 10 μg, and 25.0% at 20 μg, typically mild to moderate and often occurring after the active phase. Cardiovascular monitoring in 12 of 15 laboratory studies found small, transient increases in blood pressure (a few mm Hg) during the active phase of dosing; psilocybin doses around 1–3 mg/70 kg and LSD doses at the higher microdose equivalent (approximately 20 μg) were the most consistent correlates of modest systolic and, at times, diastolic increases; some studies also reported small heart rate rises. Body temperature changes were not observed in the few studies that measured them. Psychiatric and CNS effects: Anxiety was commonly recorded. Four psilocybin and ten LSD laboratory studies addressed anxiety; some reported slight increases, particularly at higher microdose equivalents (20 μg LSD), and in one 6‑week trial four of 80 participants discontinued because of anxiety. Large online samples reported that mild anxiety as an adverse effect affected about 25% of respondents, with severe anxiety in about 4.6% in one survey. Cognitive effects were mixed: of five laboratory studies using specific cognitive tests, the psilocybin study reported no impairment, while LSD studies produced mixed findings — three showing no deficit and two small negative effects (e.g. on psychomotor vigilance and Digit Symbol Substitution Test), with reduced processing speed reported in some cases. EEG studies noted reduced oscillatory power at low doses but not always linked to measurable cognitive decline. Hallucinatory and dissociative phenomena were generally minimal at 10 μg LSD and at typical microdoses of psilocybin; small increases in visual distortions, derealisation and other mild perceptual changes were occasionally observed, more often at 20 μg LSD and usually transient. Mood changes tended to be transient during the active phase; several studies reported small positive effects on mood or no effect, while a subset reported worsened mood, feeling overwhelmed, or amplified emotions. Sleep findings were inconsistent: some reports of insomnia or sleep disturbance and others (one study) indicating a 24‑minute increase in sleep duration versus placebo. Reports of agitation, irritability or impulsivity were infrequent and often embedded within broader anxiety measures. Other domains: Evidence for tolerance, withdrawal or addiction was limited. Laboratory studies did not report frank dependence, although some measures (Drug Effects Questionnaire) showed small increases in “want more” in a minority of participants. Serious adverse events — HPPD, psychosis, suicidal behaviour, persistent perceptual disturbances — were not observed in the laboratory studies reviewed, but most trials excluded participants with pre‑existing psychiatric vulnerability, limiting generalisability. Additional sporadic complaints across studies included tinnitus, muscle pain or tightness, decreased appetite, diaphoresis, pupil dilation and fatigue. Reporting and data quality: The reviewers emphasised that many studies did not systematically report adverse events, frequently grouped diverse symptoms under general labels (e.g. “challenges,” “physiological discomfort”), and that most laboratory studies assessed only single or a few doses, limiting insight into long‑term or cumulative harms.

The study team interprets the assembled literature as indicating that microdosing classic psychedelics is associated with mostly mild, transient and dose‑dependent side effects. Physiological complaints such as short‑lived increases in blood pressure, nausea and headaches were the most commonly documented, while psychological effects most often involved elevated anxiety and occasionally small, transient cognitive changes. Where measured, adverse effects tended to be no greater than placebo in many trials, although some studies and large‑scale surveys report non‑trivial frequencies of mild anxiety and other complaints. The authors position these findings against several important limitations of the evidence base: heterogeneous and non‑transparent adverse‑event reporting, predominance of short‑duration laboratory studies or self‑selected survey samples, and routine exclusion of participants with cardiovascular disease or psychiatric vulnerability. These factors limit conclusions about cumulative or long‑term risks, applicability to clinical populations, and the true incidence of rarer but serious events. The reviewers highlight additional methodological issues: variable microdose definitions, differing preparation and administration methods outside laboratory settings, and the potential for placebo effects or biased self‑report in observational data. As practical implications for future research, the authors recommend standardised, transparent adverse‑event reporting (using explicit questionnaires and presenting side‑effect data in the main text), longer follow‑up, inclusion of more clinically representative populations, and stratified or pre‑screened designs that account for metabolic and psychiatric heterogeneity. They stress that while serious harms were not observed in the included laboratory studies, the exclusion of at‑risk individuals and the short follow‑up periods mean that absence of evidence is not evidence of absence for long‑term or rare harms.

Modzelewski and colleagues conclude that reported side effects of LSD and psilocybin microdosing are generally minor, transient and dose‑dependent, most commonly including short‑term increases in blood pressure, mild anxiety, occasional headaches, nausea and small, often temporary cognitive effects. These effects are typically not dangerous in otherwise healthy individuals but the current literature is limited by inconsistent adverse‑event reporting, short study durations and selective study populations. To resolve remaining uncertainties, the authors recommend that future microdosing studies adopt standardised adverse‑event instruments, report side effects transparently in the main text, and include longer, more representative evaluations to assess cumulative and clinically important risks.