This systematic review (2020) of (mostly) observational studies on microdosing psychedelics (LSD & psilocybin) finds that it is experienced both positively and negatively by participants (n=3,619).
“Microdosing psychedelic drugs-that is, taking sub-behavioral doses of lysergic acid diethylamide (LSD) or psilocybin-is a growing practice in Western societies. Taken mainly for creative or mood-enhancing purposes, thousands of users are increasingly being exposed to (micro)doses of psychedelic drugs. In this systematic review, we searched the available evidence from human studies, focusing our results in terms of three main axes: efficacy, safety, and the influence of the placebo effect in microdosing practices. While the available evidence has some strengths (e.g. large sample sizes, robust methodologies) there are also remarkable limitations (e.g. gender bias, heterogeneity of dosing schedules and drugs used). Highly contradictory results have been found, showing both the benefits and detriments of microdosing in terms of mood, creative processes, and energy, among other regards. This review provides a general overview of the methods and approaches used, which could be useful for improving future studies.”
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.
Papers cited by this study that are also in Blossom
Anderson, T., Petranker, R., Christopher, A. et al. · Harm Reduction Journal (2019)
Anderson, T., Petranker, R., Rosenbaum, D. et al. · Psychopharmacology (2019)
Andersson, M., Kjellgren, A. · Harm Reduction Journal (2019)
Benko, J., Vranková, S. · Molecules (2020)
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.
The "psychedelic renaissance"that started in the mid-1990s brought about renewed academic interest not only in psychedelic drugs' mechanisms of action) but also their therapeutic potential. The investigation of psychedelic drugs in experimental settings has been accompanied by increased usage, for various reasons, by the general population. Of particular interest is the periodic use of very low doses of lysergic acid diethylamide (LSD), psilocybin, and other psychedelic drugs, a practice that is popularly known as "microdosing." In pharmacological research, microdosing is understood as an interesting strategy for testing new drugs that consists of "low exposure" or "Phase 0" clinical trials. Those trials are not designed to assess tolerability but to obtain mechanistic information, such as pharmacokinetics in plasma or in drug targets. For this purpose, doses of no greater than 100 μg (for small molecules) or 1/100th of the No Observed Adverse Effect Level (NOAEL) are used. This approach has little, if anything, to do with microdosing psychedelic drugs. In the latter case, very low doses of psychedelic drugs are commonly used (e.g. less than 25 μg in the case of LSD), so no psychoactive effects are observed and, therefore, there are no impairments to the normal functioning of the individual. However, the absence of a psychoactive effect does not mean a total lack of effects, since microdosing practitioners usually report mood-enhancing effects, improved creative thinking, and the relief of various psychological disorders, among other effects. Thus, although subtle, the effects of microdosing psychedelics are noticeable, in contrast to microdosing practices in pharmacological research.
Although using tiny amounts of psychedelic drugs was first proposed by the Swiss chemist Albert Hofmann, the discoverer of LSD, it was not until the 2010s that this practice spread globally. This increased interest in microdosing was partly due to the publication of The Psychedelic Explorer's Guide: Safe, Therapeutic, and Sacred Journeys, in which Fadiman discussed the results of early experiments involving microdoses of psychedelic drugs. Additionally, some press articles appeared about workers in Silicon Valley using microdosing to enhance their creative abilities and efficiency. As more people tried LSD and psilocybin microdosing, it seems that others started to take microdoses of ayahuasca or ibogaine, among other substances. Indeed, there are websites where one can read "protocols" for microdosing with these substances. Given this growing trend, more research is urgently needed in this field in order to assess the safety of this practice and the potential risks it might pose to public health. Beyond potential risks, the possible benefits of psychedelic microdosing should also be assessed. There is evidence that psilocybin, ibogaine, and other psychedelic drugs enhance neural plasticity and neurogenesis through their action on 5-HT2A receptors. In fact, in recent years these substances have been termed "psychoplastogens" in order to emphasize this remarkable ability. The "psychoplastogenic" effect of these substances, including ibogaine especially, along with their neuroprotective and neurotrophic-enhancing effects, are relevant in relation to neurodegenerative diseases. Preclinical research and anecdotal cases have suggested J o u r n a l P r e -p r o o f that microdoses of ibogaine may be effective in reducing Parkinson's disease (PD) symptoms. Other studies have started to expose elderly individuals to low doses of LSD in order to explore the safety of psychedelic drugs for the treatment of neuroinflammation associated with neurodegenerative diseases. Due to the lack of effective treatments for neurodegenerative diseases, this area of study should be explored in depth. With the aim of summarizing the current evidence on microdosing and therefore helping to facilitate future studies, we present a systematic review exploring central concerns, such as: the safety of microdosing, main reported benefits, and what aspects of these benefits might be attributed to a placebo effect. Additionally, the limitations of the available evidence and directions for future research are discussed.
We conducted a search using the electronic databases PubMed, Scopus, and Web of Science, using the terms "psychedelics," "hallucinogens," "lysergic acid diethylamide," "psilocybin," "ibogaine," and "microdosing." These terms were combined using "AND" or "OR". Manual searches were also conducted using Google Scholar and Core (core.ac.uk) to identify other relevant studies.
In order to find all of the relevant research published on the safety of microdosing, its reported benefits, and the possible influence of a placebo effect, the main eligibility criteria were: 1) publication in a peer-reviewed journal, and 2) studies in which microdosing practices were assessed in humans using either a qualitative or quantitative approach.
Recorded variables included author(s), year of publication, sample size, study location (country), study design, questionnaires used, microdosing protocol (if any), drug type and dose (if any), and main findings.
The search of the literature yielded 64 separate references that were reviewed by abstract screening (first pass). Following the first pass and after excluding duplicates, 22 potentially relevant references were identified. Full-text reports of these citations were obtained for more detailed evaluation. Following detailed examination of the reports, 17 citations were finally included in the systematic review. See Figurefor a flow diagram of the selection process.
The included studies are comprised of 10 observational studies; three qualitative studies; and four randomized, double-blind, placebocontrolled clinical trials. The drugs most frequently used in this research were LSD and psilocybin. Although much less common, other drugs, such as cannabis, 1P-LSD, and mescaline have also been reported on in some of the included studies. See Table.
Considering all of the studies selected for inclusion in this review, the practice of microdosing was assessed among a total sample of 3,619 individuals. The preliminary report bydid not specify an exact sample size, since data collection is ongoing. Most samples were gender skewed, with more men than women, so that 69% of the total of 3,619 people was male. The gender ratio was only balanced in clinical trials, where the proportion of males was 40%, 50%, and 56%. Although the study byrecruited an elderly sample (mean age was 62.9 years), the other included studies selected young people between 18 and 35 years of age (mean age was 28.3 years). It must be noted that, since most of the studies used online-surveys to collect data, an unknown number of participants may have participated in multiple studies. J o u r n a l P r e -p r o o f
A study byqualitatively analyzed videos posted on YouTube by individuals who microdosed (using mostly LSD and psilocybin, but also 1P-LSD and O-Acetylpsilocin [4-ACO-DMT]) in which they explained their experiences. Various benefits were reported. They were classified in four categories: 1) enhanced states and heightened senses (more focus; improvement in experiencing the present moment; improved mood; more energy; reductions in stress, sadness, or anger); 2) insights and transformation (augmented self-reflection; thoughtful insights; psychospiritual changes; improvements in personal orientation, priorities, and habits; improvements in self-confidence and self-acceptance; increased sense of empathy and deeper connections in personal relationships; a sense of reconnecting with nature; greater motivation to exercise, eat healthier food, and less habitually use social media; reduced procrastination; and spontaneous impulses to clean the house, tidy drawers, and pay bills); 3) improved abilities and optimal performance (increased creativity; enhanced productivity and effectiveness, especially in cognitively intensive jobs such as software development and music composition; heightened sense of presence, extraversion, attendance, and persuasiveness in social situations); and 4) relief and cure for health conditions (users reported benefits regarding depression, anxiety, posttraumatic stress disorder [PTSD], bipolar disorder, addiction, attention deficit and hyperactivity disorder [ADHD], autism spectrum disorder, paralysis from spinal cord injuries, dyspraxia, and cluster headaches). Survey studies were the most fruitful in terms of revealing potential benefits.conducted a retrospective survey study that recruited 278 J o u r n a l P r e -p r o o f microdosing users of LSD and psilocybin. The main benefits reported were with regards to improved mood (26.6%), improved focus (14.8%), creativity (12.9%), self-efficacy (11.3%), and improved energy (10.5%). Participants also reported a reduction in the use of caffeine (44.2%), alcohol (42.3%), cannabis (30.3%), tobacco (21%), psychiatric prescription medications (16.9%), and illicit substances (16.1%).designed an online-survey to collect data from microdosing practitioners. Users mainly microdosed with LSD and psilocybin (but also cannabis, N,N-dimethyltryptamine or DMT, and 3,4-methylenedioxymethamphetamine) and the main benefits reported were related to improvements in symptoms of depression (71.8%) and anxiety (56.5%), as well as improvements in memory (38.8%), attention (59%), and sociability (66.5%).conducted an international survey and created a sub-sample to examine the results of individuals who reported having microdosed. The main benefits (among these microdosing practitioners who mainly used psilocybin, LSD, and 1P-LSD) were improved mood and reduced anxiety, enhanced connectivity to people and the environment, and enhanced cognition. A different study byrecruited individuals who microdosed through an on-line forum to test previously defined hypotheses. They found that microdosing predicted lower scores for dysfunctional attitudes and negative emotionality, and higher scores for wisdom, openmindedness, and creativity.used an online-survey in order to recruit microdosing practitioners (who mainly used LSD, psilocybin, and MDMA) who had been diagnosed with physical and/or psychological disorders. The study measured the self-rated effectiveness of microdosing for the treatment of various conditions. In general, microdosing was rated as more effective than conventional medications, especially regarding anxiety, ADHD, and pain.conducted J o u r n a l P r e -p r o o f the only prospective, observational study with a sample of microdosing practitioners who were recruited through on-line platforms. Participants used mainly LSD and psilocybin. Baseline, daily, and long-term measures were used. Daily measures showed an increase for all scores (connected, contemplative, creative, focused, happy, productive, well) on days when users microdosed. Long-term improvements (at 6 weeks) were reported for depression and stress. Scores for the scale measuring mindwandering decreased, while scores for the absorption scale increased during the study period. The main benefits that users reported were enhanced mood, increased productivity and creativity, and heightened sociability.conducted individual interviews with participants who microdosed (mainly using LSD and psilocybin) and who were recruited through on-line forums. The main benefits reported were with regards to depression, anxiety, obsessive-compulsive disorder (OCD), PTSD, narcolepsy, migraine symptoms, and pain. Additionally, enhancements in energy, mood, and cognition were also reported.conducted a quasi-experimental study in which assessed creativity and intelligence among users under the effects of microdoses of psilocybin truffles. Improvements in both convergent and divergent thinking were reported. However, this study has important limitations, as subjects performed the same test J o u r n a l P r e -p r o o f before microdosing and while under its effects, so a learning effect could have biased the results. The published randomized, placebo-controlled studies did not specifically assess the potential benefits of microdoses, as they were primarily designed to assess safety and tolerability. However, some scales regarding changes in mood or drug effects were also included.conducted a clinical trial involving microdoses of LSD (6.5, 13, and 26 µg) and a placebo. Microdosing LSD dose-dependently increased participant scores for the scales measuring experience of unity and blissful state, as measured by the 5D-ASC questionnaire. Another study conducted by the same groupreported small and inconsistent mood enhancements using 13 µg of LSD.note that study participants reported several safety concerns.
The authors classified them into 11 categories: illegality (29.5%; leading to unknown dosages, purity concerns, social stigma, etc.), physiological discomfort (18%; disrupted senses, temperature dysregulation, numbing/tingling, insomnia, gastrointestinal distress, reduced appetite, and increased migraines and/or headaches), impaired focus (8.8%; poor focus, distractibility, and absent-mindedness), increased anxiety (6.7%; general, social, and existential), impaired energy (7.2%; restlessness, fatigue, drowsiness, brain fog), impaired mood (6.9%; sadness, discontent, irritability, overemotionality, mood swings, fear, feeling unusual), social interference (2.6%; awkwardness, oversharing, difficulties with sentence-production in social settings), J o u r n a l P r e -p r o o f cognitive interference (2.3%; confusion, disorientation, racing thoughts, and poor memory), self-interference (1.2%; dissociation, depersonalization, rumination, overanalysis), increased symptoms (6.2%; participants reported concerns regarding psychological dependence, substance tolerance, hangover, and adverse psychological events), and others (10.6%; substance-related concerns regarding taste, pupil dilation, duration of effects, and negative drug interactions).explain that some users experienced increased anxiety, panic attacks, physical and gastrointestinal discomfort, cramping, increased body temperature, restlessness, "jitters," over-stimulation (especially when using LSD), insomnia, impulsivity, reduced practical or problem-solving skills, and decreased cognitive performance.found that 4.75% of participants experienced a worsening of their depression symptoms, 13.1% of their anxiety symptoms, 14.6% of their memory, 14.7% of their focus/attention, and 11.1% of their social abilities. They also noted that among the freeform responses regarding physical changes, 31.25% reported negative outcomes, such as occasional "swimmy" vision and sweats. Althoughprovided only anecdotal reports as preliminary results, they mentioned insomnia, uncomfortable physical symptoms, and increased anxiety as common adverse events that follow microdosing.reported that some participants experienced a worsening of conditions or symptoms, including hangovers and mental health problems (unspecified). Other adverse events included insomnia, over-stimulation, and a "bad trip" when an LSD microdose was combined with cannabis.reported that one-fifth of their sample experienced negative effects, including both physical and psychological effects, but the effects are not specified.asked participants to report unwanted effects that occur often/always or at any point in
Only three placebo-controlled studies were found among the search results.found that the LSD condition (13 and 26 µg, but not 6.5 µg) increased ratings for "feel drug" on the Drug Effects Questionnaire. The LSD-26 µg condition also increased ratings for "feel high" and "like drug". LSD (13 and 26 µg) was associated with a higher systolic blood pressure, as it was 105.35 mmHg among those who took a placebo, as compared to 111.5 mmHg at 13 µg of LSD and 115.3 mmHg at 26 µg, and 26 µg significantly increased diastolic blood pressure as well. To summarize, 13 and 26 µg of LSD produced measurable subjective and physiological effects, which were linearly dose related.found that, when given a placebo, 16 out of 20 J o u r n a l P r e -p r o o f participants correctly identified the substance as a placebo. When given LSD (13 µg), eight participants identified the substance as a placebo, seven as a sedative, one as a stimulant, one as an opioid, one as a cannabinoid, one was unsure, and only one subject identified it as a psychedelic drug. Near-significance increases were reported on Drug Effects Questionnaire (DEQ) ratings for "feel high," "want more," and "like drug," as well as regarding the sedation scale of the Addiction Research Center Inventory (ARCI). Yanakieva et al. () recruited older adults. Using four different conditions (placebo, 5, 10, and 20 µg of LSD), no significant differences were found regarding subjective effects, despite the authors reporting "numerical tendencies" for drug effects in the LSD conditions. Although LSD did not produce relevant subjective effects as indicated by selfreport measures, participants showed longer reproduction times in the temporal reproduction task when under the effect of LSD, in contrast to the placebo condition. Thus, the differential temporal reproduction performance across conditions was independent of self-reported drug effects.
This systematic review collected the available evidence regarding microdosing, a growing practice regarding which there are still many unanswered questions. We were interested in providing information regarding three main issues: safety concerns, potential benefits, and the possible influence of the placebo effect. We found three types of studies: observational studies (n=10) mainly conducted through on-line surveys; J o u r n a l P r e -p r o o f qualitative studies (n=3) for which data collected on-line or personal interviews were analyzed; and randomized, placebo-controlled clinical trials (n= 4). While clinical trials are scarce in this area, the strength of the data provided by observational studies is remarkable. These studies were conducted in the period 2017-2020, some of them using very complex and robust methodologies in order to control as many variables as possible. One example is the study byin which the effect of expectation was controlled for. Additionally, these observational studies provide data collected from a sample of over 3000 people who tried microdosing in a naturalistic setting, giving these results high external validity. This is a much larger sample than Phase-I and Phase-II clinical trials commonly use. In fact, the available clinical trials have some limitations. Participants in studies conducted byandwho had previous adverse reactions to psychedelic drugs were excluded, so the results of these studies regarding the safety of microdosing are clearly biased. Additionally, they allowed participants to smoke and drink coffee before and after the studies' experimental sessions, although the effects of caffeine and nicotine could mask some of the subtle effects of microdosing. Among the studies reviewed, the most frequently reported benefit was mood enhancement. In some studies, related concepts regarding mood enhancement suggest mechanisms that might underlie such an effect. For instance,reported that microdosing produced personal and thoughtful insights, improvements in selfconfidence and self-acceptance, deeper connections with other people and with nature, Other studies found a correlation between the intensity or the quality of the psychedelic experience and the therapeutic efficacy of psychedelic drugs. However, in this case there is no psychedelic experience at all and, thus, the effects of microdosing on mood suggest that the subjective experience might not be as relevant as previously thought. Reductions in stress were also reported. It is remarkable that preclinical studies have been published regarding improvements in mood and anxiety among rodents following the administration of microdoses of DMT.provided preliminary evidence regarding the potential mechanisms involved. They found a dampening effect in terms of amygdala activity and connectivity following the acute administration of 13 µg of LSD, a finding consistent with results obtained using higher doses of LSD.
Given the associations between amygdala hyperreactivity and various psychological disorders, the effect of both microdoses and regular doses of psychedelic drugs on this region could partially explain reported mood enhancements. Another frequently reported benefit of microdosing was enhanced creativity. Remarkably, contradictory findings were found between observational studies and the clinical trial performed byin terms of both mood and creativity. While benefits in these areas were frequently reported by microdosing practitioners,found that none of the LSD doses (6.5, 13, and 26 µg) modified mood nor convergent thinking, an aspect of creativity. Most of the observational studies collected data using online surveys, so evidence of improvements to mood and creativity was obtained through subjective reports. However, regarding creativity, an observational study involved the administration of validated measures in an open-label, naturalistic setting. The authors found improvements in both convergent and divergent thinking among participants who microdosed and were under the effects of "magic truffles" (psilocybin). However, this study has several limitations, including the lack of a control group and a possible learning effect. In light of this, we can conclude that the evidence regarding improvements to mood and creativity is weak. Notably, research suggests that regular doses of psychedelic drugs can increase some measures of creativity. Some studies included in the review also reported on microdosing in relation to various mental health conditions. Improvements were mainly reported with regards to J o u r n a l P r e -p r o o f symptoms of depression, anxiety, PTSD, ADHD, pain, and cluster headaches. Other less commonly reported disorders regarding which microdosing offered benefits were autism spectrum disorder, paralysis from spinal cord injuries, dyspraxia, and narcolepsy. Improvements in mood disorders are in line with not only the previously mentioned benefits regarding mood and related aspects, but also with the preliminary results of ongoing research on psychedelic drugs at regular doses. Other disorders, such as ADHD, or common symptoms like pain, merit further research in order to clarify the potential mechanisms at work. In the case of pain, the use of regular doses of psychedelic drugs has also proven beneficial, with long-lasting analgesic effects reported in case reports.noted how very small, sub-behavioral doses of 2,5-Dimethoxy-4iodoamphetamine (DOI) are required to induce potent anti-inflammatory effects. The authors suggest that sub-behavioral doses of psychedelic drugs should be tested as potential treatments for asthma, cardiovascular disease, metabolic disorders, inflammatory bowel disease, and other widespread disorders related to inflammatory processes. Among the observational studies collected, several report the use of microdosing as a substitution for prescribed psychiatric medication. Indeed, some subjects reported that the effectiveness of microdosing (mainly with psilocybin and LSD) was greater than that J o u r n a l P r e -p r o o f of conventional medications. Given their well-known lack of efficacy and the side effects associated with psychiatric medications, innovative strategies are needed in order to discover new treatments. Therefore, the use of psychedelic drugs in both regular and microdoses should be further explored. Reduced use of caffeine, alcohol, cannabis, and tobacco was also associated with microdosing, and thus additional research on microdosing as a treatment for addictions is also suggested. This is in accordance with lines of research where regular doses of various psychedelic drugs are employed (Winkelman, 2014). Regarding the safety of microdosing, a remarkable proportion of study participants reported adverse events. We can classify these adverse events, detailed above, into five categories. The most common category concerned negative effects on mood, including increased anxiety, sadness, irritability, and worsening of symptoms of depression. The second category concerns physical discomfort, including overstimulation, disrupted senses, and temperature dysregulation. The third category concerns adverse events related to cognitive functioning, such as distractibility, absent-mindedness, and decreased performance on cognitive tasks. The fourth category concerns mental health issues, including insomnia, dissociation, depersonalization, and rumination or overanalysis. The fifth and final category concerns impaired social skills, including feelings of awkwardness, oversharing, and difficulties with sentence production. The most commonly reported issues were increased anxiety and insomnia. Most of the studies did not provide percentages regarding the proportion of participants who reported these adverse effects. However, in the case of anxiety,found that 6.7% J o u r n a l P r e -p r o o f of participants reported this effect, whilefound this to be the case among 13.1% of their sample. A "bad trip" was also reported, involving a microdose of LSD that was combined with a regular dose of cannabis. This supports the need for further research, specifically regarding potential drug-drug interactions between microdoses and other psychedelic drugs, cannabis, and even prescribed medications, since it seems that psychoactive effects can be potentiated. Some of these adverse events might be explained by overdosing, where a small-to medium-sized dose was taken rather than a microdose. This is particularly likely given the small amounts required for microdosing. Regarding the worsening of anxiety and symptoms of depression, users should be extremely cautious when microdosing as a self-medication strategy, since undesired effects can occur and occasionally result in fatalities. The current evidence regarding the efficacy of psychedelic drugs to treat mood disorders comes from using regular doses, and the effect of small or microdoses in this regard is unknown. From a psychodynamic point of view,has stated that mediumsized to large doses are preferable in psychotherapeutic settings. According to him, low doses of LSD and other psychedelic drugs can start an "emergence" process of material coming up from the unconscious, but these low doses are insufficient for the process to be completed. This would result, rather, in a kind of stagnation, in which symptoms of anxiety are common. According to both Hutton et al. (2019a) and, one-fifth of microdosing practitioners experience some type of adverse event. Given this high proportion, practitioners should be cautioned. Despite the apparent safety of extremely low doses of psychedelic drugs, such doses can entail significant risks, so more controlled studies are necessary in order to elucidate their safety profiles. Additionally, appropriate risk-benefit assessments will need to be conducted not only J o u r n a l P r e -p r o o f with samples recruited from a healthy population but also with people who have mental health conditions. Even when this information becomes available, we should remember that microdosing practitioners will be still exposed to the risk of overdosing and other uncertainties linked to informal markets. This high frequency of adverse events contrasts with their scarcity in the clinical trials in which regular doses of psychedelic drugs are administered. Some authors suggest that those studies do not implement appropriate methods for reporting adverse eventsIn recent years, it has been suggested that, given the small amounts of psychedelic drugs that are commonly used when microdosing, the alleged benefits could be attributed to a placebo effect. Only the four randomized, placebo-controlled trialsJ o u r n a l P r e -p r o o f 2019) could assess the potential influence of a placebo effect. In LSD sessions, Yanakieva et al. () found a delayed time perception in the absence of self-rated effects on perception. This suggests that even when no psychoactive effects are shown there can be alterations in certain parameters, so the dose would have pharmacological effects.found no differences in mood, cognition, nor physiological parameters, while subjects reported notable subjective effects. This again suggest that the desired effects of microdosing would not depend on the psychoactive effects, as the benefits in that case were not significant.reported increases in various rating scales following the administration of 13 µg of LSD, suggesting that at least some subjects noticed psychoactive effects, although only one identified them as hallucinogenic. The four clinical trials used LSD in similar doses (5-20 µg, 6.5-26 µg, and 13 µg). Despite being preliminary, these studies suggest that individuals can avoid psychoactive effects that might disturb normal functioning by taking less than 20 µg of LSD, and obtain noticeable benefits as well. However, we should not forget that the mean age of the sample recruited byandwas 62.9 years, as that study focused on elderly adults. This limits our ability to make comparisons between studies and the generalizability of the results. It should also be noted that, beyond the placebo effect, a nocebo effect in naïve subjects is also reasonably likely to exist, given the social stigma around and illegality of psychedelic drugs. For instance, Family et al. (2020) found a higher number of adverse events in the placebo group. The authors suggested that participants may have had expectations about the adverse events associated with the drug, as they were told that LSD could be given in the study. Further placebo-controlled studies should examine these hypotheses.
While more controlled clinical trials should be performed, more naturalistic, non-gender biased, prospective observational research, in which subjects are evaluated in-person, is also necessary in order to overcome the limitations of survey-based studies. Asstated, intense positive experiences with a substance motivate individuals to use that substance in the future. Thus, microdosing practitioners who have previous experience with regular doses of psychedelic drugs may be especially motivated to try microdosing and may evaluate its benefits more positively. Researchers should be aware of this limitation and determine the safety and efficacy of microdosing by recruiting naïve users. Microdosing with drugs other than LSD and psilocybin represents a novel, vast, and promising field of research. As stated above, anecdotal reports suggest that microdosing with ibogaine could be effective for the treatment of PD (European Ibogaine Forum, 2017), since it has been shown that ibogaine increases neurotrophic factors. Analogs with similar properties are also being explored. Notably, this potential use of ibogaine is gaining early support through preclinical research. Harmalines (compounds present in ayahuasca) have been shown to increase the proliferation of human neural progenitorsand stimulate adult neurogenesis. Recently, the potential role of ayahuasca as a treatment for PD and other neurodegenerative diseases has been revived. DMT has also been shown to produce neurogenesis and neuroprotection in cell cultures. Using metabolomics, a recent study found that ayahuasca contains compounds with highly neuroprotective properties. Psilocybin also induces J o u r n a l P r e -p r o o f neurogenesis, and it has been suggested that it is geroprotective. Thus, a future clinical application of microdosing may be the treatment of neurodegenerative diseases, one of the greatest threats to public health. Microdosing non-psychedelic drugs such as suboxone has led to other successful results in terms of helping individuals to overcome opioid dependence. Thus, we may be witnessing the beginning of an entirely new paradigm in pharmacological research and therapy. In most of studies included in this review, the majority of participants used LSD and psilocybin, although the use of other psychedelic and non-psychedelic drugs was also reported to a much lesser degree, adding complexity to the results. No differential or specific effects of these other drugs were reported, so future studies should assess the effects and safety profile of various drugs in order to offer reliable information for each of them. The doses used ranged from 5 to 50 µg of LSD and from 0.1 to 0.5 g of dried mushrooms (psilocybin). There were very heterogeneous samples and most of the participants in observational studies did not know the exact dose they were taking. Regarding the clinical trials, it should be noted that a dose of less than 20 µg of LSD would be recommended, but we are lacking clinical trials involving microdosing with psilocybin. The most commonly used protocol was the one developed by Fadiman (2011) of one day microdosing and two days off, but there were six studies in which the regimen was not specified, and eight others in which other schedules were followed. Future studies should explore the most common dose schedules and try to standardize this as much as possible. In addition, future naturalistic, observational studies would benefit from the inclusion of technology in their methods, such as the use of mobile Several contradictory results have been found regarding risks and benefits. For instance, it seems that while some people benefit from microdosing in terms of mood, creative processes, and energy, other people experience a worsening of these and other dimensions. Regarding the latter, apart from subjective reports from observational studies regarding impaired energy,found an increase in sedation following the administration of 13 µg of LSD in a controlled setting. These contradictory findings could be the result of the different study designs used. For instance, clinical trials are specifically designed to find small effects in controlled settings. However, paradoxically, these effects are commonly restricted to those settings, whereas the same intervention may produce distinct effects in the general population, which is why some clinical trials are regarded as having poor external validity. Observational methods, while controlling fewer variables and therefore being more subject to bias, have enhanced external validity. So, the effects observed when different methodological approaches are followed will always differ to some extent and, thus, In addition, making comparisons between studies is challenging, since the various samples were only matched by age and show a remarkable gender bias, with males making up 69.5% of the total sample. The presence of gender bias in the observational but not the controlled studies might explain some of the differences observed between these different kinds of studies.
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