Psilocybin microdosers demonstrate greater observed improvements in mood and mental health at one month relative to non-microdosing controls

Abstract

Psilocybin microdosing involves repeated self-administration of mushrooms containing psilocybin at doses small enough to not impact regular functioning. Microdose practices are diverse and include combining psilocybin with substances such as lion’s mane mushrooms (Hericium erinaceus; HE) and niacin (vitamin-B3). Public uptake of microdosing has outpaced evidence, mandating further prospective research. Using a naturalistic, observational design, we followed psilocybin microdosers (n = 953) and non-microdosing comparators (n = 180) for approximately 30 days and identified small- to medium-sized improvements in mood and mental health that were generally consistent across gender, age and presence of mental health concerns, as we all as improvements in psychomotor performance that were specific to older adults. Supplementary analyses indicated that combining psilocybin with HE and B3 did not impact changes in mood and mental health. However, among older microdosers combining psilocybin, HE and B3 was associated with psychomotor improvements relative to psilocybin alone and psilocybin and HE. Our findings of mood and mental health improvements associated with psilocybin microdosing add to previous studies of psychedelic microdosing by using a comparator group and by examining the consistency of effects across age, gender, and mental health. Findings regarding the combination of psilocybin, HE and B3 are novel and highlight the need for further research to confirm and elucidate these apparent effects.

Introduction
The use of fungi containing psilocybin to enhance health and well-being has a long history across diverse cultures1. After centuries of aggressive colonial suppression most recently manifested in the US-led “war on drugs”, psilocybin has reemerged outside of its traditional indigenous contexts, as a therapeutic agent to treat mental illness and enhance well-being. Indeed, discussions of the medicinal properties of psilocybin mushrooms have proliferated in mainstream North American and European culture in recent years2,3. This interest has focused predominantly on doses sufficient to engender dramatic alterations in consciousness; however, the use of smaller “microdoses” has also become a topic of substantial public and scientific interest4,5.

Microdosing involves regular self-administration of psychedelic substances in doses small enough to not impair normal cognitive functioning6. The most widely reported substances used for microdosing are psilocybin mushrooms and LSD, and to a lesser degree other psychedelic substances such as mescaline and 2-CB7. Surveys of microdosing psilocybin have identified diverse practices but generally converge on the self-administration, 3–5 times per week, of 0.1 to 0.3 g of dried mushrooms7,8,9,10,11,12. Improvements in mood, emotional well-being and cognition have been reported among the top motivations for microdosing13, and several cross-sectional studies have identified associations between microdosing and perceived improvements in mood13,14,15,16,17 and cognitive functioning10,11,16, reductions in stress7, depression7,9,16 and anxiety7,9,14,18.

Relatively few prospective studies have evaluated microdosing. The first longitudinal study of microdosing analyzed daily assessments of 98 microdosers for 6 weeks, and found acute transient improvements across broad domains of psychological functioning on microdosing days, and reductions in stress, depression and distractibility from baseline to study conclusion. Further, although that study’s conclusions are limited by the lack of a non-microdosing control group, supplementary examinations concluded that the observed effects were not consistent with what might be anticipated based on common expectancies related to microdosing7. A subsequent prospective study that followed 81 microdosers for four weeks also reported improvements across several domains of psychological well-being, including enhanced emotional stability and decreased anxiety and depression. However, supplementary analyses suggested that these positive effects may be attributable to expectancies and highlighted the need for further research with non-microdosing control participants to better distinguish the effects of microdosing from placebo effects and other longitudinal confounds18.

The effective use of placebo has presented a challenge in the few published studies that have attempted such a design in the context of psychedelic microdosing17,19,20. Specifically, a prospective study of microdosing that used a self-blinding intervention to approximate placebo control among 191 participants over 4 weeks identified improvements in emotional well-being among microdosers, but noted that correct identification of condition was reported by 72% of participants complicating the ability to conclusively estimate the influence of placebo effects on observed changes. Similarly, a double-blind placebo-control crossover study of 30 respondents followed for eight weeks identified higher levels of self-reported awe in response to aesthetic experiences among microdosers relative to controls. Nonetheless, authors acknowledged the potential confounding effects of breaking blind, as two-thirds of participants accurately guessed their condition19. Further analysis of the same participant pool did not identify differences in symptoms of anxiety and depression among microdosers relative to placebo20. However, the study noted that participants’ prior experience with psychedelics in addition to low levels of depression and anxiety may have resulted in attenuated microdosing effects. Moreover, a significant proportion of participants correctly guessed their condition in half the trial blocks, however the apparent null effects in the study may render the potential influence of placebo less germane.

Breaking blind and the broader category of expectancy or placebo effects are identified challenges to the interpretation of studies of regular doses of psychedelics21, and may also complicate the interpretation of microdosing research. For example, the longitudinal study which attempted to adjust for expectancies by controlling for scores on a modified measure of microdosing expectancies18 noted that more than 80% of participants reported prior experience using psychedelics, which makes it likely that scores on the expectancies measure were influenced by past experiences of direct drug effects. Individual differences in drug response due to metabolism and numerous other factors make past pharmacological drug effects likely to be strongly correlated with subsequent direct pharmacological effects, and as such partialing out (i.e. controlling for) expectancies may underestimate direct pharamacological effects22,23. In sum, extant longitudinal studies have observed positive effects associated with microdosing but have not been able to confidently estimate the direct pharmacological contributions to such effects. More broadly, parsing direct effects of psychedelics from indirect factors such as set, setting, individual differences, and expectancies presents epistemological and practical challenges, and the study of psychedelics may be best served by going beyond a potentially Procrustean emphasis on blinding and other approaches to maximizing control24. For example, the naturalistic examination of large cohorts provides powerful opportunities to examine the consistency of effects across subgroups, and the use of a comparison group absent the premise of blinding, but with similar demographic characteristics and roughly equivalent levels of study-related activities allows for the assessment of the impact of microdosing as distinct from indirect effects such as study engagement, practice effects, regression to the mean, and other potential artefacts common to prospective research.

Concurrent with the increased interest in microdosing psilocybin-containing mushrooms is an acceleration of interest in other putatively therapeutic fungi. In particular, lion’s mane, (Hericium erinaceus; HE), has garnered substantial interest for its proposed treatment of depression25 and mild cognitive impairment26 and preclinical evidence of facilitation of neurogenesis with implications for treating neurodegenerative disorders27,28. Recent evidence suggests that some microdosers combine psilocybin with HE in a process referred to as stacking8. A cross-sectional survey of over 4000 microdosers, which used a sample that partially overlaps with that of the present study, found that over 50% of psilocybin microdosers combined psilocybin with diverse substances, and that HE was the most prevalent addition followed by a combination of niacin (vitamin-B3) and HE8. As this is the lone study to report on stacking, the generalizability of these results is unknown. The combination of HE, B3, and psilocybin has been popularized in informal microdosing information networks based on the conjecture that B3 may facilitate psilocybin and HE bioavailability via vasodilation29. The salutary effects of both psilocybin and HE have been proposed to operate via BDNF-related processes, raising the possibility of super-additive effects30,31. However, the potential effects of psilocybin and HE—with and without B3—have yet to be formally investigated, and the popularity of stacking likely derives from self-experimentation and anecdotal reports.

In sum, despite suggestive results and expanding public interest, the empirical literature remains equivocal on the consequences of microdosing. Further research with control groups and large samples that allow for the examination of potential moderators such as mental health status, age, and gender are required to better appreciate the health consequences of this emerging phenomenon. In the present study, we aim to extend this literature by examining prospective changes associated with microdosing psilocybin as compared to a non-microdosing control group on domains of mental health, mood, and cognitive and psychomotor functioning. To our knowledge, this is the largest prospective study to date of microdosing psilocybin, the first to distinguish between microdosing admixtures (i.e., stacking), and among the few prospective studies to systematically disaggregate analyses according to age and mental health concerns.