857204
research-article2019
JOP0010.1177/0269881119857204Journal of PsychopharmacologyKuypers et al.
Critique/Commentary
Microdosing psychedelics: More questions
than answers? An overview and suggestions
for future research Journal of Psychopharmacology
1–19
© The Author(s) 2019
Article reuse guidelines:
Kim PC Kuypers1 , Livia Ng2, David Erritzoe3, Gitte M Knudsen4, sagepub.com/journals-permissions
https://doi.org/10.1177/0269881119857204
DOI: 10.1177/0269881119857204
Charles D Nichols5, David E Nichols6, Anaïs Soula7 and David Nutt8 journals.sagepub.com/home/jop
Abstract
Background: 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.
Aim: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies.
Approach: 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.
Conclusion: 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.
Keywords
Psychedelics, microdosing, psychoactive substances
Background provoke lust to those who eat a number, or even a few, of them’.
However, by 1640, 94% of the Aztec population was wiped out
Psychedelics are a class of psychoactive substances that induce and alongside them, the traditions involving ‘teonanacatl’. Of
complex behavioural, psychological and physiological effects note, the mentioning of visions here suggests this ancient ‘low-
primarily through activation of serotonin 5-HT2A receptors. In dose’ use does not refer to what is currently seen as microdosing,
the past few years, the issue of ‘microdosing’ psychedelics has something that will be addressed below.
been openly discussed in the public arena with several books Psychedelic studies underwent a significant expansion fol-
(Cruz, 2017; Kumar, 2016; Waldman, 2017) claiming value to lowing the discovery of the mind-altering properties of LSD by
the authors who tried this concept. However, there are very few Albert Hofmann in 1943 (Hofmann, 1970). The subsequent
scientific studies that have specifically addressed this issue, and growth of psychedelic use allegedly had a profound effect on
there is no agreed scientific consensus on what microdosing
entails (Cameron et al., 2019; Horsley et al., 2018). This paper is
designed to address questions that need to be answered by future
1Department of Neuropsychology and Psychopharmacology, Faculty of
scientific studies and to offer guidelines for these studies.
Psychology and Neuroscience, Maastricht University, Maastricht, The
Although a number of classic psychedelics exist, two of them,
Netherlands
lysergic acid diethylamide (LSD) and psilocybin, are allegedly 2Department of Psychology, University College London, London, UK
most frequently used to microdose. The following review focuses 3Department of psychology, Neuropsychopharmacology Unit, Imperial
predominantly on psilocybin due to its proximity for a possible College London, London, UK
approval in clinical use and short-lasting pharmacokinetics 4Neurobiology Research Unit, Rigshospitalet and University of
(Passie et al., 2002) in comparison with LSD (Dolder et al., Copenhagen, Copenhagen, Denmark
2017). However, where relevant and available, data for other psy- 5Department of Pharmacology and Experimental Therapeutics, Louisiana
chedelic drugs are also mentioned. State University Health Sciences Center, New Orleans, LA, USA
6Purdue University College of Pharmacy, West Lafayette, LA, USA
As early as the 16th century, low doses of psilocybin, ‘teo-
7COMPASS Pathways, London, UK
nanacatl’ or sacred mushroom, were used medically (Schultes,
8Neuropsychopharmacology, Imperial College London, London, UK
1940). Bernardino de Sahagún, a Franciscan friar during the
period of the Spanish conquest of the Americas (1519–1521), Corresponding author:
reported that, ‘teonanacatl were … medicinal for fevers and for David Nutt, Neuropsychopharmacology, Imperial College London,
rheumatism. Only two or three need to be eaten. Those who eat London, UK.
them see visions and feel a faintness of the heart. And they Email: k.kuypers@maastrichtuniversity.nl
,2 Journal of Psychopharmacology 00(0)
innovation in science and technology. A popular example is that Drug Administration in 2006 (FDA, 2006) and the Ministery of
of Francis Crick, one of the co-discoverers of the double-helix Health, Labour and Welfare in Japan in 2008 (MHLW, 2008), and
structure of DNA, who used LSD, though this use was never con- the current definitive international guideline in 2009 (ICH, 2009)
firmed nor denied by him (Roberts, 2008). Furthermore, Kary as being a dose of drug that is 1% of the pharmacologically active
Mullis, who discovered a means to automate the polymerase dose, up to a maximum of 100 µg. Thus, psychedelic microdosing
chain reaction, claimed that the idea came to him after using LSD (‘5–10 µg of LSD’ (Fadiman, 2011)) would be 5–10% of a usual
(Doyle, 2002). These discoveries greatly advanced the field of psychoactive dose and lie between a full pharmacological dose
genetic research (Luke, 2006). In this atmosphere of innovation, (100%) and a ‘pharmacological microdose’.
Frederick Terman was appointed as Provost of Stanford, 1955– Microdosing psychedelics has been described in a similar
1965. During his tenure, Terman ‘set out to create a community manner by different individuals. Fadiman describes it as a
of technical scholars in Silicon Valley’ (Leslie and Kargon, practice ‘to use sub-threshold doses of psychedelic drugs in an
1996). This community developed alongside the psychedelic attempt to enhance cognitive tasks, to boost physical energy
capital of the world, San Francisco, and over time technology and levels, to promote emotional balance, and to treat anxiety,
psychedelics began to merge. By 2005, the founder of Apple and depression and addiction’ resulting in typically subtle though
one of the most influential figures in Silicon Valley, Steve Jobs, noticeable effects (Fadiman, 2011). Similarly, Aylet Waldman
highlighted that LSD had played a pivotal and transformative in her book (Waldman, 2017) states the same intention for
role in his life (Dormehl, 2012). microdosing but describes the process as ‘the act of integrating
Although there was accumulating evidence to suggest that the sub-perceptual doses of psychedelic drugs, in your weekly rou-
intake of psychedelics led not only to hallucinations but also to an tine’. In addition, Johnstad emphasizes that ‘to microdose with
improvement of cognition and creativity, scientific progress in the a psychedelic drug means to take a dose small enough to pro-
field was prohibited by government agencies on account of the vide no intoxication or significant alteration of consciousness’
growing political concern over the recreational use of psyche- (Johnstad, 2018).
delics (Belouin and Henningfield, 2018). Thus, the only study Thus, the term ‘microdosing’ appears to consist of three
investigating psychedelics in problem solving was ended by the components:
US Food and Drug administration (FDA) in 1966 (Harman et al.,
1966). However, James Fadiman, a young researcher in this study, 1. The use of a low dose below the perceptual threshold
continued his research after the UN Convention on Psychotropic that does not impair ‘normal’ functioning of an
Substances of 1971 banned psychoactive substances and bundled individual.
his knowledge into a book, which now acts as a guide for those 2. A procedure that includes multiple dosing sessions.
interested in microdosing. His book The Psychedelic Explorer’s 3. The intention to improve well-being and enhance cogni-
Guide: Safe, Therapeutic, and Sacred Journeys (Fadiman, 2011) tive and/or emotional processes.
published in 2011, is often referred to as a protocol for those
practising microdosing. Of note, no study to date has revealed sta- Existing dosing categories for psychedelics when used in research
tistically significant effects of microdosing on creativity under are very low dose, low dose, medium dose, and high dose (Table 1).
placebo-controlled circumstances (Passie, 2019). A microdose has been defined as approximately one-tenth to one-
Although microdosing became prominent due to the belief it twentieth of a recreational dose, varying within and between sub-
improved cognition, a growing number of individuals began to stances, so it can be seen as being somewhat below a very low dose.
microdose psychedelics to improve conditions of pain (Johnstad, Although microdosing of psychedelics does not have an agreed sci-
2018), cluster headache or migraine (Andersson et al., 2017). It entific definition, we have decided to continue to use the term
seems that the efficacy of microdosing may derive from its non- because of its prevalent societal use. Hopefully, this paper will help
psychedelic dose range, which provides treatment without affecting to facilitate research towards establishing it as a scientific construct.
cognition. Individuals also reported relief of pain with a long-term The most widely distributed species of psychedelic mush-
psychedelic microdosing regimen (Johnstad, 2018). Thus, psyche- rooms are Psilocybe cubensis and those of the genus Copelandia,
delic microdosing might constitute a different paradigm to single which consists of 12 species (Guzmán et al., 1998). The psilocin
psychedelic therapeutic sessions with macrodoses where the nature (the active metabolite of psilocybin) and psilocybin content in
and content of the experience plays a key role in predicting thera- the whole body of these mushrooms when dried was estimated to
peutic outcome (Roseman et al., 2018; Schenberg, 2018). However, be in the range of 0.14–0.42% (psilocin) and 0.37–1.30% (psilo-
many questions remain about the definition, safety, potential mech- cybin) for P. cubensis and 0.43–0.76% (psilocin) and 0.08–0.22%
anism and future research involving microdosing. (psilocybin) for Copelandia, respectively. Thus, the former is
more psilocybin-rich than the latter, and the latter contains more
Question 1: What does microdosing psilocin compared to the former (Tsujikawa et al., 2003). The
Psilocybe semilanceata is the most common British species. This
mean? mushroom only contains psilocybin, in the range from 0.17 to
The term microdosing is not a uniquely psychedelic term. In phar- 1.96%, as shown by one Norwegian analysis (Christiansen et al.,
macology, microdosing is a process used in drug development 1981; Rumack and Spoerke, 1994). These data show that the
(Lappin and Garner, 2008) and drug selection (Lappin et al., psilocybin concentration varies between and within species but is
2006) where a minute dose of a substance is used to assess the also dependent on the time of collection, the preservation of the
pharmacokinetics of a drug. A microdose, in this regulatory arena, material and growth conditions. User reported recreational doses
has been defined by a position paper from the European Medicines depend on the species and experience of the user (Rumack and
Agency 2004 (EMEA, 2003), guidelines from the U.S. Food and Spoerke, 1994).
, Kuypers et al. 3
Table 1. Varying doses of psychedelic compounds used in preclinical and clinical studies.
Substance Subjects/partici- Route of Microdose Very low Low dose Medium dose High dose
pants (animal/ administration dose
human)
Psilocin (Hasler et al., 2004; Human (both Oral <1 mg 3.15 mg 8 mg 15 mg 22 mg
Wackermann et al., 2008) studies)
LSD (Dandiya et al., 1969) Rats Intraperitoneally 10–25 μg 30– 40 μg 60–110 μg 150 μg 200+ μg
Ibogaine HCl (Glick et al., 2000; Rats Intraperitoneally 200 mg 300–400 mg 700 mg 1400 mga 2800 mg
Lotsof and Wachtel, 2002; Humansa Orala
Schechter and Gordon, 1993)a
DMT (Shulgin, 1976) Humans Intramuscular 6 mg 10 mg 20 mg 30 mg 50–70 mgb
injection
Per kilogram dose values have been converted to values for a 70-kg person. These doses are approximate values.
aStudy conducted in humans using a single oral dose of 1400 mg.
bWhen inhaled, 30 mg would be considered a high dose.
A hallucinogenic dose of dried P. cubensis, for example, is perception, mentation and concentration after administration of
between 3 and 5 g (Rumack and Spoerke, 1994). These values single doses of 5, 10, and 20 μg LSD. To our knowledge there has
equate to a recreational dosing range of 8.6 to 14.7 mg of psilocin been only one published study designed specifically to measure the
per dose. Thus, a microdose would range from 0.43 to 0.73 mg of effects of psilocybin microdosing per se (Prochazkova et al., 2018)
psilocin per dose because a microdose of psilocybin is generally where the effects of psychedelic mushrooms were explored in a
one-tenth of a full dose (Fadiman, 2011). That positions a recrea- recreational setting. This study suffers from a number of methodo-
tional dose of psilocin between a low and medium dose and a logical issues, particularly the lack of a placebo control as well as
microdose below a very low dose. However, variations in psilocin uncertainty over dose taken. However, there have been several
content between doses of dried mushroom may be seen due to more controlled studies where a low dose of psilocybin has been
variations between individual fungi within a species. A micro- used as a control for a regular dose; these are presented below.
dose of LSD ranges between 10 and 20 μg with 20 μg being the For example, Hasler and colleagues (2004) compared four doses
upper limit that might already produce perceptual changes in of psilocybin in healthy humans in a placebo-controlled experimen-
some. A microdose of ibogaine hydrochloride is approximately tal design and found slight physiological and psychological differ-
25 mg (Kroupa and Wells, 2005), and when smoked, that of N,N- ences between single administration of placebo and a very low dose
dimethyltryptamine (DMT) is approximately 6 mg (May, 2018). (VLD) (Hasler et al., 2004). A VLD was defined as 45 μg/kg p.o.,
equating to approximately 2.3 mg of psilocin for an average 70-kg
human. VLD was compared with a low dose (LD), a medium dose
Question 2: What microdosing (MD) and a high dose (HD) defined as 115, 215 and 315 μg/kg p.o.,
schedules have been used? respectively. Although most physiological measures were similar
between the VLD dose and placebo, a significant decrease was seen
The data presented here were collected using a search of micro-
in maximum heart rate at the 6-hour point after VLD administra-
dosing protocols that included books, online fora and surveys.
tion. Acute self-rated/self-reported psychological responses of
The keywords of this search included microdosing, microdosing
VLD included slight drowsiness, increased sensitivity and intensifi-
protocols, microdosing approaches and psilocybin microdose. In
cation of pre-existing mood states; an increase in introversion com-
this search, it was found that users mainly followed three
pared to placebo was only shown for the MD and HD at peak drug
approaches. The most popular of these was the Fadiman
effect, 95 minutes post-administration.
approach, outlined in his book (Fadiman, 2011), which involves
Building on that, Griffiths and colleagues (2011) investigated
two consecutive dosing days followed by two non-dosing days.
the effects of psilocybin in varying doses where each participant
Another popular approach involves ‘weekday’ dosing, i.e. from
received five dosing sessions, spread across 1-month intervals
Monday to Friday and not dosing on Saturday and Sunday.
(Griffiths et al., 2011). The doses used were 0, 5, 10, 20 and 30
Additionally, some users indicated that they followed a balanced
mg/70 kg. Using a Monitor Rating Questionnaire with a 5-point
low/microdose approach, which involved dosing every other
scale, they found that a dose of 5 mg/70 kg increased stimulation,
day. Dosing periods ranged from 1 week to 2 years. This varia-
distance from ordinary reality and sense of peace. Intensity, som-
tion in microdosing schedules was confirmed by a recent survey
aesthesia, affect, perception, cognition and volition measured on
which demonstrated that half of the respondents who micro-
the Hallucinogen Rating Scale all increased after administration
dosed came up with their own schedule (Hutten et al., 2019).
of a 5 mg/70 kg dose. In other words, they did not find a dose
without psychological effects. Interestingly, when using an
Question 3: What controlled studies 11 mg/70 kg and 15 mg/70 kg dose of psilocybin, Lewis and col-
leagues (2017) found a significant decrease in global cerebral
have been done so far? blood flow in the frontal, parietal, temporal, limbic, cingulate and
The first placebo-controlled LSD microdosing study was occipital cortex, insula, caudate, putamen, pallidum, amygdala,
published recently (Yanakieva et al., 2018). Findings showed a hippocampus and thalamus (Lewis et al., 2017). This may relate
delay of time perception in the absence of self-rated effects on to the psychological effects seen with lower doses.
