I would recommend not mentioning just these very few anecdotal cases in respect to creativity and psychedelics. There are some good studies and reviews about the subject (Hartmann, 1969) on 40 prominent painters at the German Max Planck Institute of Psychiatry in Munich and the review on the subject by Krippner (1985). 

When it comes to the very few studies looking for low doses of psychedelics and creativity (review in Passie, 2019), no study revealed any significant/relevant effects under con- trolled scientific conditions (e.g. McGlothlin et al., 1967). The study of Prochazkova et al. (2018) claimed (under weakly con- trolled conditions in respect to dosing and environment) increased lateral thinking, which has been discussed as a marker of creativity. This study employed doses of psilocybin that were above the perceptible level (4–8 mg p.o.). However, increased lateral thinking does not mean that the drugged sub- jects have shown increased creativity in a valid sense, e.g. cre- ating more original painting. 

Definitions: Microdosing and minidosing 

I do not agree with the authors’ narrow definition, since it does not reflect fully what is used in the literature and the appropri- ate Internet entries. It has been proposed that the term ‘mini- dosing’ could be used to separate the approach of taking small perceptible doses. It is also clear that many authors and Internet entries suggest the practice of just taking one dose at a time rather than a few ones consecutively as, for example, seen with the Fadiman scheme. This is also valid for taking a tenth or a twentieth of a usual dose. However, the issues related to definitions point towards the question/definition of what is considered a ‘full dose’. In the case of LSD, some authors reasonably argue that 150 μg is a full dose (especially in females), whereas others consider 250 μg a full dose. This is a significant issue, because 15 μg is usually not perceptible by most subjects, but a dose of 25 μg is for most subjects (as shown in some scientific studies). Therefore, the definition has to be sharpened before scientific consensus can be reached and the evidence from so-called microdosers disseminated on the Internet as well as studies of anecdotal evidence (e.g. Johnson, 2018), which suffers from such inaccuracies, can be taken seriously. 

Dosing of dried mushrooms 

Plant/fungal material is generally quite unreliable for calculating a dose. I do not agree with the author’s statement that 3.5 g P. cubensis is ‘a usual recreational dose’. Most recreational users take 1 to 2.5 g as a recreational dose, which is also recommended in most books in the field. From my experience, and the research studies of Abramson and Rolo (1967), I would state that a dose of psilocybin below 3 mg is below the perceptible range. Usually, doses above this level can become apparent. For example, Prochazkova et al. (2018) used 4–8 mg psilocybin, i.e. more than a microdose, thus, more consistent with the definition of what might be considered a minidose. 

The most used dosing regime and effects of micro- and minidosing 

It can be easily seen in Internet entries that most subjects who take microdoses recreationally for ‘bettering performance’ take doses that give them some perceptible effects. Even a microdos- ing proponent like Paul Austin recommends doses where you can feel/perceive some alterations to some extent. How would you better your performance if nothing can be felt from a dose? 

Following my comprehensive research into this topic (Passie, 2019), I have never come across anything about a ‘workaholic approach’ (dosing during weekdays, but not on weekends) as suggested by the authors. This also does not make much sense form a pharmacological point of view, because tol- erance to LSD develops very quickly. Be reminded, that the US military has dosed soldiers with increasing daily doses to try to make them ‘immune’ to LSD’s effects (Ketchum, 2006). 

I think that a minidose (e.g. 20 to 50 μg LSD), in contrast to a microdose (which I define as something below 20 μg LSD, e.g. 5–15 μg), makes a significant difference in terms of recreational as well as scientific studies as it definitely alters psychological functioning and the cognitive system. 

However, this alteration is not in any way equivalent to stimu- lants like Ritalin or amphetamine as is sometimes reported anecdo- tally. It is more a dissociation from the environment and the person itself. Cognitive abilities have been proven to be compromised in many studies with LSD and psilocybin employing a very low dose range (Passie, 2019). It is also important to register these (poten- tially) distracting effects. There are also a few scientific reports of people who have been given very low doses of LSD for treating depressive mood. These had negative results with very few patients experiencing a small improvement. 

What is plausible (and has been experienced by this author) is that a minimal sympathomimetic effect (for sure not compatible with any sort of usual stimulant!), which might be still there up to 20 hours after a 10- to 15-μg dose of LSD, can cause problems with falling asleep, especially in sensitive persons. It is of interest how long it takes following intake for effects to occur. One could think of a train of effects induced in the organism, which is pushed on and may influence the organism even after virtually all of the substance has left the organism. 

I definitely do not see the Fadiman protocol (5–15 μg LSD every third day) as the most used approach. It might be viewed as the most widely known, but by far (!) the most ‘microdosers’ use one occasional dose, not a regular intake. This also makes it very questionable what effects can be/are felt or not, especially when it comes to taking 10 μg just a few times per year (which is apparently what most users do). As Fadiman’s coworker on his more or less systematic Internet surveys, Sophia Korb has mentioned in a lecture (conference ‘Beyond Psychedelics’, Prague 2018) that they know of just three persons who have dosed regularly (according to the Fadiman protocol) for more than 3 weeks. These three subjects were terminal cancer patients and felt quite normal up to day 50. Between days 50 and 60 they all became much more psychologically labile, i.e. having larger mood changes (in the positive as well negative direction, with daily fluctuations), as measured using the PANAS scale. 

To my mind, the study published by Horsley et al. (2018) does not have any seriously calculable implications for humans. Its limitations should be discussed. 

Possible alterations of gene expression and receptor proteins 

There are serious doubts that the repeated doses of LSD, which have been used in rodents, are comparable to microdoses in humans. I am not an expert on interspecies scaling, but, for exam- ple, (just by simplified arithmetic) the studies by Martin et al. (2014) have used doses which are 12,000 times higher than a microdose in humans. According to a recent review (Sharma et al., 2009), it appears not to be congruent with scientific data to state that the dose used by Martin et al. (2014) is in any way comparable to a microdose in humans. Therefore, to date we know nothing about possible changes in gene expression induced by regular LSD intake in humans. 

I doubt that the gene/BDNF changes which were found with very high daily doses in animals can be scaled up to humans using microdoses every few days. Issues of adaption and toler- ance should be discussed in this respect. 

Receptors are proteins. These proteins and others might be altered by repeated intake of, e.g. LSD, even in very low doses (Buchborn et al., 2016). Even if this is somewhat speculative, it seems probable. 

On the possible induction of cardiovascular valvopathy 

In respect to a possible induction of cardiovascular valvulopathy by chronic 2-HT2R activation, it is worth mentioning that the studies of Bender and Sankar (1968) in the 1960s involved doses of 100 μg LSD for up to 35 months on a daily basis without any observable damage. However, their methods of investigation might not have been sensitive enough to detect damage. It is also true that just a very small part of the patient population taking ergot compounds (e.g. methysergide) do in fact develop valvu- lopathy. It is also worth mentioning that if a valvulopathy is detected in a patient, in all cases it disappears within a short time after stopping the medication. There is just one case documented in the literature where surgery was necessary (Graham, 1967). 

Declaration of conflicting interests 

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. 

Funding

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

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Commentary published in the Journal of Psychopharmacology 2019, Vol. 33(9) 1055–1056