It is concluded that while most anecdotal reports focus on the positive experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clinical studies including biological (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential negative consequences microdosing could have.

Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned.

This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies.

In the past few years, the issue of ‘microdosing’ psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is.

Question 2: What microdosing schedules have been used? The data presented here were collected using a search of microdosing protocols that included books, online fora and surveys. The keywords of this search included microdosing, microdosing protocols, microdosing approaches and psilocybin microdose. In this search, it was found that users mainly followed three approaches. The most popular of these was the Fadiman approach, outlined in his book (Fadiman, 2011), which involves two consecutive dosing days followed by two non-dosing days. Another popular approach involves ‘weekday’ dosing, i.e. from Monday to Friday and not dosing on Saturday and Sunday. Additionally, some users indicated that they followed a balanced low/microdose approach, which involved dosing every other day. Dosing periods ranged from 1 week to 2 years. This variation in microdosing schedules was confirmed by a recent survey which demonstrated that half of the respondents who microdosed came up with their own schedule (Hutten et al., 2019).

Question 4: Are there any relevant preclinical studies? We found only two preclinical studies involving microdosing (Cameron et al., 2019; Horsley et al., 2018). Horsley and colleagues (2018) investigated the effect of microdosing on anxiety using an elevated plus-maze and observation of ecological behaviours. They defined a microdose of psilocin as 0.05 mg/kg, which equates to 3.5 mg for an average 70-kg human. Rats received three dosing sessions over 6 days with the last dosing session on the 6th day. Anxiety profiles were measured in Wistar rats 2 days after the final dosing session. Ethological behaviours including rears, head dips and stretch-attend were also measured during this period. Psilocin at 0.05 mg/kg significantly reduced entries into open arms, suggesting that microdosing may have an anxiogenic effect. This effect was not replicated in the ethological measures. Although the authors conclude that these results might have implications for future therapeutic applications, as they produce counter-productive behaviour, one obvious limitation is the interspecies scaling issue (Sharma and McNeill, 2009). It is questionable whether doses administered to animals translate to humans and the authors also acknowledged that the translational value of their results needs to be determined in a therapeutic context. Cameron and colleagues (2019) tested the effect of repeated low doses of DMT in rats. They gave a dose for 2 months every third day and assessed behaviour with a broad range of tests. In a cued fear extinction learning test, they showed that animals froze significantly less than a control group, suggesting that DMT facilitates fear extinction memory. In the forced swim test, an antidepressant-like effect was observed. No change was observed in dendritic spine density in the layer V pyramidal neurons, and no changes were observed in gene expression (EGR1, EGR2, ARC, FOS, BDNF and 5HT2A). However, an impact on metabolism was observed in male rats; the weight increased by 182%, compared to 165% with vehicle (Cameron et al., 2019). Comparable to the Horsley et al. (2018) study, the interspecies scaling is a point of discussion together with the question of whether a short-acting substance such as DMT would show beneficial effects in humans without administration of a monoamine oxidase (MAO) inhibitor. Lastly, it should be emphasized that there is a need to conduct more research on long-term effects in order to assess the long-term safety of repeat doses.

Question 9: What is the legal position of microdosing? The answer to this question is complex due to differences in national regulations. In general, under the UN Conventions, LSD and related compounds, psilocybin and DMT are controlled as Schedule 1 drugs – i.e. are defined as being the most harmful and as having no medicinal value. In other words, they are subject to the most extreme restrictions and penalties for unapproved possession. These constraints apply to any dose of the drug, even a sub-psychoactive or microdose level. Research can be carried out with the right ethical regulatory and institutional approvals, but dosing would have to be conducted in a secure environment like a hospital or research ward. For repeated microdosing, this adds significant costs and complexity to any study, which is likely why none have yet been reported. However, this situation is easing for psilocybin as a result of several successful clinical trials in recent years, and both the European and US regulators have given approval for studies (NIH, 2018) with psychedelic doses of synthetic psilocybin made to GMP standards. That means that microdosing trials of similarly sourced product for clinical therapy are likely also to be approved, though as yet we do not believe any have been submitted.

Question 10: What are the regulatory issues? Unfortunately, due to their long history of anecdotal use in recreational settings, none of the psychedelics has ever followed the conventional drug research and development path expected by contemporary standards. Thus, at best, doses have been selected based on published data in a variety of indications but mostly to provide an indication for an upper safety limit. In a pooled analysis of psilocybin Studerus et al. (2011) classified active oral doses within a vast range of about one order of magnitude difference, between 0.045 and 0.315 mg/kg, which translates into 3.15 to 22.05 mg for a 70-kg human (Studerus et al., 2011). Such a range is quite surprising for active principles with the pharmacological potency of psychedelics. Given such underdetermination, regulatory standards will most likely require dedicated dose-finding studies (more than one) to provide a rationale explaining the known individual differences that have been reported in the clinical response to treatment and most importantly, the dose chosen for late development. In this context, the information provided from oral dosing, resulting plasma psilocin levels and corresponding brain 5-HT 2A receptor occupancy will turn out to be informative. Parallel fixed dose designs are usually recommended (ICH, 1994). In some cases, four arm range studies could be necessary; under these circumstances microdoses could be used to test pseudo-placebo properties or alternatively a peculiar pharmacological activity. Another issue pertains to the limited pharmacokinetic data available in order to evaluate a dose-concentration–response relationship for psychedelics. Updated ADME studies are not available for psychedelics, although the characterization of their metabolites and their role in the active principle efficacy or safety profile might prove relevant to interpret and predict their clinical effect. Once pharmacokinetics of the parent compound and its metabolite(s) are established, variation of clearance if any, its prediction by body weight and the concentration–response relationship for the claimed clinical effect must be presented. If possible, biomarker(s) (e.g. single-nucleotide polymorphisms (SNPs)) at the 5-HT receptor subtypes where they have affinity should be linked to the risk/benefit profile and thus to the therapeutic effect, and they could be used to enrich/stratify the population of interest. Because psychedelics have been reported by some to possess a large inter-individual sensitivity, the definition of a precise concentration–response relationship may be difficult to demonstrate, especially once a microdose range is reached.

Question 11: What are the future research needs? Microdosing is generally accepted as the use of a functionally low dose of a psychedelic compound over multiple dosing sessions with the intention of improving mental and physical well-being, cognition or creativity (Fadiman, 2011; Johnstad, 2018). A systematic study of microdosing psychedelics investigated by means of observation changes in psychological variables of microdosers. Small changes in a sub-set of variables were found, i.e. decreased depression and stress, decreased mind wandering, increased absorption and increased neuroticism. Interestingly, these variables were not those that participants most expected to change, suggesting that long-term changes may be due to biological changes and not only expectations (Polito and Stevenson, 2019). Nonetheless, the possible effects and implications of microdosing remain largely unknown. Although there is a large database of reported effects of ‘microdosing’ on online fora, the true amount of active substance in these is unknown as are the peak plasma psilocin concentrations achieved during ‘intoxication’. Further, while in these anecdotal reports the user deliberately ingests a substance for a reason, expecting positive effects, it is difficult to distinguish between expectation ‘placebo’ effects and the effect of a microdose. These non-pharmacological effects, described as set and setting, are also known to be of influence when taking a full dose of a psychedelic (Hartogsohn, 2017). Another unknown is whether effects are noticeable after only one microdose or that a certain ‘build-up’ is needed, supported by underlying neurobiological changes, before effects occur. Therefore, rigorous placebo-controlled clinical studies need to be conducted with different low doses of the drug to determine whether there is any evidence for the claims being made by microdosers. The types of cognitive testing performed should include several different validated psychological instruments and preferably cover the concepts mentioned in the Research Domain Criteria (Cuthbert and Kozak, 2013), and not simply rely on anecdotal accounts or simple tests. Generated knowledge in healthy volunteers will provide clear information on which cognitive aspects can be enhanced with microdosing. This knowledge will provide a first hint as to whether microdosing can be of value in the treatment of specific symptoms in psychiatric populations. Anecdotal reports suggest, for example, that microdosing might help in combatting attention deficit hyperactivity disorder (ADHD) symptoms; studies including measures related to symptom domains like executive functioning, attention and temporal processing will help to decode the potential of microdosing as a therapeutic agent. In terms of biological mechanism of action, more (pre)clinical work needs to be performed to understand fully the complex interaction of different cell types, and their responses to psychedelics at the molecular level such as elucidating peripheral or central signalling pathways involved, if any, in the process of microdosing (Kuypers, 2019). Resulting findings can provide theoretical grounds for why microdosing could work in alleviating cluster headache in patients suffering from it (Anderson et al., 2018; Johnstad, 2018). Whereas most anecdotal reports focus on the positive experiences with microdosing, future research should investigate the molecular mechanisms behind low-dose psilocybin behavioural effects as well as address potential risks of (multiple) administrations of a psychedelic in low doses. Although extensive toxicology has been conducted on a single active dose of psilocybin and has been proven to be safe (Brown et al., 2017; Johnson et al., 2018), further research is required to understand better the possible health risks incurred by microdosing, especially in relation to cardiac and lung tissue. These studies would involve (pre)clinical safety and tolerability tests of multiple low/microdoses of psilocybin over an extended period of time. To that end, continuous monitoring of physiological parameters including heart functioning in addition to assessment of receptor turnover at low/microdoses as well as receptor occupancy will shed light on the potential negative consequences microdosing could have.

Acknowledgements Livia Ng was a paid intern and Anaïs Soula an employee for COMPASS Pathways.

Declaration of conflicting interest

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: David Nutt is a scientific adviser and Luca Pani is a consultant for COMPASSPathways. The other authors declare that there is no conflict of interest. Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article. ORCID iD

Kim PC Kuypers https://orcid.org/0000-0001-7634-3809