The emerging science of microdosing: A systematic review of research on low dose psychedelics (1955 – 2021)

This preprint (2021) review is one of the most comprehensive reviews on microdosing to date. The reviewers report effects across six categories; mood and mental health; wellbeing and attitude; cognition and creativity; personality; changes in conscious state; and neurobiology and physiology. Studies showed a wide range in risk of bias and argue that the idea that the effects of microdosing are due to expectancy is possibly wrong.

Abstract

“The use of low doses of psychedelic substances (microdosing) is attracting increasing interest. This systematic review summarises all empirical microdosing research to date, including a set of infrequently cited studies that took place prior to prohibition. Specifically, we reviewed 44 studies published between 1955 and 2021, and summarised reported effects across six categories: mood and mental health; wellbeing and attitude; cognition and creativity; personality; changes in conscious state; and neurobiology and physiology. Studies showed a wide range in risk of bias, depending on design, age, and other study characteristics. Laboratory studies found changes in pain perception, time perception, conscious state, and neurophysiology. Self-report studies found changes in cognitive processing and mental health. We review data related to expectation and placebo effects, but argue that claims that microdosing effects are largely due to expectancy are premature and possibly wrong. In addition, we attempt to clarify definitional inconsistencies in the microdosing literature by providing suggested dose ranges across different substances. Finally, we provide specific design suggestions to facilitate more rigorous future research.”

Authors: Vince Polito & Paul Liknaitzky

Summary

This systematic review summarises all empirical microdosing research to date, including a set of infrequently cited studies that took place prior to prohibition. It found that microdosing effects were varied, but largely due to change in pain perception, time perception, conscious state, and neurophysiology.

Microdosing is the practice of regularly ingesting very low doses of psychedelic substances with the goal of improving wellbeing, cognition, mood, or interpersonal processes. This review outlines the most robust findings on the effects of microdosing from both the first and current waves of psychedelic research.

Microdosing can refer to the ingestion of a wide range of psychedelic substances at very low doses. It is usually done regularly or semi-regularly.

To date there have been no consistently accepted criteria amongst researchers for defining a microdose. This is because it is difficult to establish equivalent dose ranges for different classes of drug, different variants of a given class, different methods of preparation, and different people. There is no consensus regarding the subjective effects of microdosing, but many microdosers claim anecdotally that they notice no effects. However, in qualitative studies, participants often describe alterations of consciousness, and in lab-based studies, participants frequently report some acute effects.

Microdosing has become popular due to a renewed interest in the therapeutic potential of psychedelics, and a growing body of scientific research demonstrating that these substances can enhance cognition and wellbeing in healthy individuals. Microdosing is a curious phenomenon that has been ascribed a wide range of benefits. It is important to separate scientific data from anecdote and hype. This study reviews all scientific research to date on the effects of microdoses of psychedelics, including studies from before the prohibition of psychedelic use in 1970. However, few contemporary microdosing studies refer to any research or popular use of very low dose psychedelics prior to the 2010s.

Three previous reviews have investigated evidence for the effects of microdosing. The current review provides a comprehensive overview of the largest number of microdosing studies to date, and evaluates the strength of evidence for each study.

We searched five databases for studies on very low doses of psychedelics, including Scopus, PsycINFO, Embase, PubMed, and Web of Science. We also included studies reported in Passie (2019) and scanned key bibliographies for additional eligible studies.

The emerging science of microdosing 10 included studies that used ‘classical’ or serotonergic psychedelics, were dosed within a microdose range, and reported psychological or neurobiological data. The risk of bias was assessed by both authors, and a tailored risk assessment methodology was developed.

The authors ranked the studies on ten domains, including selection, reliability, outcome, causality, transparency, and alternative causes. The authors independently assessed the risk of bias, and any discrepancies were resolved through discussion and consensus.

Multiple doses and longitudinal studies are considered, as are studies that compare between-subjects and within-subjects effects.

The emerging science of microdosing was reviewed in 19 studies. They were divided into four categories: qualitative studies, retrospective survey studies, and prospective studies.

Most studies explored multiple psychedelics, LSD only (13 studies), or psilocybin only (7 studies), and most were published in the last few years. Participants reported confidence that microdosing fulfilled their aims, and many were also using it as an adjunct considerable proportion of individuals.

Table 3 shows the reported outcomes from all studies, separated by study type and six outcome domains. For qualitative studies, we have included only statistically significant results, and for cross-sectional studies we have included only the themes and outcomes emphasised by the authors. This table does not show variables that were not found to relate to microdosing. However, improved mood was found across numerous lab-based studies, and lower depression scores were frequently found.

There are mixed findings regarding the effects of microdosing on depression, anxiety, and stress, with reports of decreased anxiety or stress in six studies, increased anxiety or stress in four studies, and both increases and decreases in anxiety found in three studies. Microdosing was thought by respondents to be linked to reductions in smoking and substance use, as well as improved general mental health. No lab studies have assessed substance misuse effects yet. Microdosing was associated with reduced OCD severity in a small clinical trial, and increased dissociation in a lab study with healthy volunteers.

The emerging science of microdosing 28 has shown substantial psychotherapeutic support and expectancy effects, and higher depression scores may be attributable to self-medication motivations. Three qualitative studies, one retrospective survey study, and one lab study showed increases in wellbeing, self-fulfilment, self-efficacy, and resilience in participants who took microdosing, while one lab study found no evidence of group level changes in vigour, arousal, or fatigue.

There are several indications that microdosing may lead to an increase in creativity. A quasi-experimental study, an online study, a placebo-controlled prospective study, and one lab-based study have all reported increases in creativity following microdosing. Several studies have shown that microdosing LSD or psilocybin affects neurocognitive behavioural tasks. These studies have shown that participants generate shorter responses in a time reproduction task and that their concentration is reduced following microdoses.

Microdosers reported increased attention, mindfulness, and ability to focus, and decreased mind wandering following six weeks of microdosing. However, in an early lab study, participants reported reductions in alertness, control, and thought.

Although some studies have found positive personality changes following ingestion of psychedelics, this has not been consistently found in studies of microdosing. Most lab studies have focused on acute rather than persisting changes, and most have reported increased interpersonal feelings, attitudes, and behaviors. However, one controlled lab study found no increase in sensitivity to social rejection during acute effects, and one prospective study found no increase in social connectedness compared to placebo.

Despite the common anecdotal claim that microdosing is sub-perceptual, there is consistent evidence that microdosing does lead to changes in subjective awareness. However, these changes are not always linked to benefit.

In older lab studies, participants could distinguish very low doses of psychedelics from placebos or other non-psychedelic substances. More recent lab studies have included self-ratings of overall drug intensity, and have consistently found higher scores for microdoses compared to placebo. Griffiths et al. (2018) used a microdose of psilocybin as a control condition, and Szigeti et al. (2021) used the 5D-ASC as a more detailed psychometric measure of alterations in consciousness.

The emerging science of microdosing 33 has shown significant increases on four out of the five primary dimensions of the 5D-ASC compared to placebo, and a dose dependent relationship in the reduction in vigilance sub-dimension. One study assessed the effects of microdosing LSD on the brain. They found increased connectivity between the amygdala and the right angular gyrus, right middle frontal gyrus, cerebellum, and decreased connectivity with the postcentral gyrus and superior temporal gyrus.

Microdosing psychedelics has been found to reduce perceived pain, increase sensory acuity, and increase duration of tolerance to aversive exposure to cold. This has led some users to reduce or entirely cease standard medications. Despite positive reports, negative physiological outcomes were also relatively common during or following microdosing in self reports. These outcomes included insomnia, physical discomfort, headache, fatigue, nausea, and other unwanted physiological effects.

There have been several reports of minor unpleasant physical symptoms following microdosing, including somatization and dizziness. However, it is not clear if the reported outcomes are truly representative of effects in the microdose range. The reviewed studies showed a wide range of Risk of Bias scores, with several patterns related to study type and year of publication. Prospective studies tended to have lower RoB scores than retrospective survey studies, which in turn tended to have lower RoB scores than qualitative studies. Most studies had clear selection criteria and random samples, and reliability and causality bias was mixed. Transparent research practices were an area of high risk.

Although reporting methods were typically rigorous, very few studies followed open science practices. Only two studies were formally pre-registered and only six provided open datasets.

A correlation between number of citations and risk of bias indicated that more rigorous microdosing studies were more likely to be cited.

Table 4 shows the risk of bias for studies that were assessed for the following: clear selection criteria, adequate ascertained exposure, well validated outcome measures, dose-response effect, follow-up long enough for outcomes to occur, and public availability of data.

This systematic review considered all empirical research on microdosing psychedelics from 1955 to 2021. It found that the older lab studies were consistent with contemporary research, and that there were several themes that stood out across these studies.

The clearest evidence for changes in cognition from lab-based microdosing research relates to alterations in time perception. However, lab findings directly related to attention and working memory are mixed.

Microdosing LSD does not appear to affect working memory or general cognitive functioning. However, participants did show improved attention in a psychomotor vigilance task. Several lab studies and self-report studies have shown that microdosing with psychedelics reduces pain perception, increases sensitivity to physiological pain, and alters the conscious state. This contradicts the popular narrative that microdosing is a sub-perceptual phenomenon.

There were promising findings from self-report studies that have not been well explored in lab settings, including that microdosing may improve mental health (particularly depression and anxiety), relieve physical discomfort, and reduce substance use.

There have been several promising self-report findings that have not been confirmed in lab studies, including improved mood, sociability, cognition, creativity, and emotional processing. However, it is prudent to be cautious when interpreting null findings from current lab studies.

The emerging science of microdosing indicates no immediate effect on mood, but multiple self-report studies indicate marked improvements in mood. Well controlled lab studies are needed to properly test sustained impacts, and at least one such study is currently underway.

In some studies, microdosing appeared to be related to both increases and decreases on the same measures. This pattern of findings may be an interaction between drug effects and expectancy or other contextual factors, or may be attributed to subtypes of people that respond to microdoses in specific ways.

Research shows that certain genetic markers impact on the capacity to metabolise LSD, and future research should attempt to determine which population subtypes are more likely to benefit from microdosing. Most studies that used placebos were single- or double-blind, and only 5 of these assessed the success of the blind. In addition, many studies that did not explicitly assess blinding failed to achieve it, making it difficult to distinguish between the role of expectancy and direct effects of microdosing.

The emerging science of microdosing 47 has found that many reported effects of microdosing are driven by expectancy. However, blinding in microdosing research has been mostly ineffective, and participants accurately guessed they had consumed a microdose at double the rate predicted by chance. In many microdosing studies, participants were likely to have substantially different expectations between experimental groups, and correct microdose guesses were likely made with higher confidence than correct placebo guesses.

Although expectancy contributes to changes in wellbeing, depressive symptoms and anxiety, the magnitude of expectancy effects may be small, and participants’ beliefs about their change in performance may be in direct opposition to their actual change in performance. Fourth, spurious attributions may have impacted participants’ guesses in Szigeti et al. (2021). Changes in outcome variables due to spurious causes may have led participants to make an incorrect guess regarding experimental condition.

The emerging science of microdosing may obscure group differences by affecting subgroups of individuals in opposite ways, and by causing the placebo component of a particular effect to survive group aggregation. Participants in Kaertner et al. (2021) and Szigeti et al. (2021) were self-selected and highly motivated microdosers, who likely possessed positive expectations about the effects of low dose psychedelics. Additionally, both studies relied on self-reports with uncontrolled and variable doses.

At least 20% of participants in the microdosing condition incorrectly guessed they were in the placebo condition, implying that these participants did not notice any subjective effects. This suggests that ineffective doses may have obscured genuine differences due to the pharmacological effects of microdosing. Studies should employ active-placebos and adequate blinding to tease apart the effects of microdosing from those of expectancy, and should identify subtypes of individuals with specific response profiles towards separating ‘responders’ from ‘nonresponders’.

Eight modern, placebo-controlled laboratory studies specifically focused on the effects of microdosing have shown clear dose-dependent changes across a range of measures and consistent subjective effects following doses in the microdosing range. Microdosing is a common practice with significant consequences for health behaviours, with a high proportion of people reporting that the practice is more effective than traditional treatments for physical and mental health issues.

The emerging science of microdosing 52 expectancies, subgroup differences, and individual variability in response suggest that aggregate data will lose many signals in the noise until some initial progress is made on individual response prediction. One key area that has been under-studied is the safety profile of long-term microdosing. While occasional ingestion of much higher doses of psychedelic substances is physiologically safe for most people, chronic administration of very low doses over many months or years has been raised with safety concerns.

We conclude with nine recommendations for the next phase of microdosing science. These include accurately measuring substance and dose, identifying substance-specific psychopharmacological effects, and determining perceptual threshold doses and substance specific outcomes. There is likely to be a substantial distinction between the acute effects of one or a few administrations of a microdose and the sustained effects of regular and longer-term microdosing practice. Future research should clearly assess the frequency and duration of microdosing practice.

We suggest that acute subjective effects should always be measured and that microdosing should be defined as sub-hallucinogenic with no loss of functionality. Furthermore, future controlled studies should incorporate active-placebo controls and always assess blinding veracity. One clear theme in the reviewed microdosing literature is bidirectional effects. Future studies should explore the key predictors of subgroup effects and explore changes in variance or absolute shift from baseline in addition to mean score differences. Future microdosing research should focus on assessing specific cognitive and other capacities. This may lead to stronger evidence of changes in specific cognitive functions such as time perception and pain perception. Most microdosing research to date has consisted of enthusiastic microdosing volunteers, and no clinical study has yet taken place. A representative sample of the general population is needed to investigate the clinical utility of low dose psychedelics.

Future research should look at long-term effects of microdosing, and should use large, demographically diverse samples. Moreover, controlled studies should test different doses once each on the same volunteers, which does not resemble naturalistic practice. Research into the safety of microdosing is needed, as the usage pattern associated with microdosing is quite different to the way that high dose psychedelics are typically consumed. Little is known about potential risks related to long term chronic use.

The field of microdosing research is at an inflection point, with the initial studies being exploratory in nature, with minimal experimental control. More rigorous studies are now emerging to investigate acute and long-term benefits and risks, mechanisms of change, response prediction, and differences across substances, doses and dosing regimens.