Abstract

Background

Psychedelics are a class of psychoactive substances that induce complex behavioural,psychological and physiological effects primarily through activation of serotonin5-HT_2A receptors. In the past few years, the issue of ‘microdosing’psychedelics has been openly discussed in the public arena with several books (Cruz, 2017;Kumar, 2016;Waldman, 2017) claimingvalue to the authors who tried this concept. However, there are very few scientificstudies that have specifically addressed this issue, and there is no agreedscientific consensus on what microdosing entails (Cameron et al., 2019;Horsley et al., 2018). This paper isdesigned to address questions that need to be answered by future scientific studiesand to offer guidelines for these studies. Although a number of classic psychedelicsexist, two of them, lysergic acid diethylamide (LSD) and psilocybin, are allegedlymost frequently used to microdose. The following review focuses predominantly onpsilocybin due to its proximity for a possible approval in clinical use andshort-lasting pharmacokinetics (Passie et al., 2002) in comparison with LSD (Dolder et al., 2017). However, whererelevant and available, data for other psychedelic drugs are also mentioned.

As early as the 16th century, low doses of psilocybin, ‘teonanacatl’or sacred mushroom, were used medically (Schultes, 1940). Bernardino de Sahagún, aFranciscan friar during the period of the Spanish conquest of the Americas(1519–1521), reported that, ‘teonanacatl were … medicinal for fevers and forrheumatism. Only two or three need to be eaten. Those who eat them see visions andfeel a faintness of the heart. And they provoke lust to those who eat a number, oreven a few, of them’. However, by 1640, 94% of the Aztec population was wiped outand alongside them, the traditions involving ‘teonanacatl’. Of note, the mentioningof visions here suggests this ancient ‘low-dose’ use does not refer to what iscurrently seen as microdosing, something that will be addressed below.

Psychedelic studies underwent a significant expansion following the discovery of themind-altering properties of LSD by Albert Hofmann in 1943 (Hofmann, 1970). The subsequent growth ofpsychedelic use allegedly had a profound effect on innovation in science andtechnology. A popular example is that of Francis Crick, one of the co-discoverers ofthe double-helix structure of DNA, who used LSD, though this use was never confirmednor denied by him (Roberts,2008). Furthermore, Kary Mullis, who discovered a means to automate thepolymerase chain reaction, claimed that the idea came to him after using LSD (Doyle, 2002). Thesediscoveries greatly advanced the field of genetic research (Luke, 2006). In this atmosphere ofinnovation, Frederick Terman was appointed as Provost of Stanford, 1955–1965. Duringhis tenure, Terman ‘set out to create a community of technical scholars in SiliconValley’ (Leslie and Kargon,1996). This community developed alongside the psychedelic capital of theworld, San Francisco, and over time technology and psychedelics began to merge. By2005, the founder of Apple and one of the most influential figures in SiliconValley, Steve Jobs, highlighted that LSD had played a pivotal and transformativerole in his life (Dormehl,2012).

Although there was accumulating evidence to suggest that the intake of psychedelicsled not only to hallucinations but also to an improvement of cognition andcreativity, scientific progress in the field was prohibited by government agencieson account of the growing political concern over the recreational use ofpsychedelics (Belouin andHenningfield, 2018). Thus, the only study investigating psychedelics inproblem solving was ended by the US Food and Drug administration (FDA) in 1966(Harman et al.,1966). However, James Fadiman, a young researcher in this study, continuedhis research after the UN Convention on Psychotropic Substances of 1971 bannedpsychoactive substances and bundled his knowledge into a book, which now acts as aguide for those interested in microdosing. His bookThe PsychedelicExplorer’s Guide: Safe, Therapeutic, and Sacred Journeys (Fadiman, 2011) published in2011, is often referred to as a protocol for those practising microdosing. Of note,no study to date has revealed statistically significant effects of microdosing oncreativity under placebo-controlled circumstances (Passie, 2019).

Although microdosing became prominent due to the belief it improved cognition, agrowing number of individuals began to microdose psychedelics to improve conditionsof pain (Johnstad, 2018),cluster headache or migraine (Andersson et al., 2017). It seems that the efficacy of microdosing mayderive from its non-psychedelic dose range, which provides treatment withoutaffecting cognition. Individuals also reported relief of pain with a long-termpsychedelic microdosing regimen (Johnstad, 2018). Thus, psychedelic microdosing might constitute adifferent paradigm to single psychedelic therapeutic sessions withmacrodoses where the nature and content of the experience playsa key role in predicting therapeutic outcome (Roseman et al., 2018;Schenberg, 2018). However, many questionsremain about the definition, safety, potential mechanism and future researchinvolving microdosing.

Question 1: What does microdosing mean?

The term microdosing is not a uniquely psychedelic term. In pharmacology, microdosingis a process used in drug development (Lappin and Garner, 2008) and drug selection(Lappin et al., 2006)where a minute dose of a substance is used to assess the pharmacokinetics of a drug.A microdose, in this regulatory arena, has been defined by a position paper from theEuropean Medicines Agency 2004 (EMEA, 2003), guidelines from the U.S. Food and Drug Administration in2006 (FDA, 2006) and theMinistery of Health, Labour and Welfare in Japan in 2008 (MHLW, 2008), and the current definitiveinternational guideline in 2009 (ICH, 2009) as being a dose of drug that is 1% of the pharmacologicallyactive dose, up to a maximum of 100 µg. Thus, psychedelic microdosing (‘5–10 µg ofLSD’ (Fadiman, 2011))would be 5–10% of a usual psychoactive dose and lie between a full pharmacologicaldose (100%) and a ‘pharmacological microdose’.

Microdosing psychedelics has been described in a similar manner by differentindividuals. Fadiman describes it as a practice ‘to use sub-threshold doses ofpsychedelic drugs in an attempt to enhance cognitive tasks, to boost physical energylevels, to promote emotional balance, and to treat anxiety, depression andaddiction’ resulting in typically subtle though noticeable effects (Fadiman, 2011). Similarly,Aylet Waldman in her book (Waldman, 2017) states the same intention for microdosing but describesthe process as ‘the act of integrating sub-perceptual doses of psychedelic drugs, inyour weekly routine’. In addition, Johnstad emphasizes that ‘to microdose with apsychedelic drug means to take a dose small enough to provide no intoxication orsignificant alteration of consciousness’ (Johnstad, 2018).

Thus, the term ‘microdosing’ appears to consist of three components:

1. The use of a low dose below the perceptual threshold that doesnotimpair ‘normal’ functioning of an individual.

2. A procedure that includes multiple dosing sessions.

3. The intention to improve well-being and enhance cognitive and/or emotionalprocesses.

Existing dosing categories for psychedelics when used in research areverylow dose, low dose, medium dose, andhigh dose (Table 1). A microdose hasbeen defined as approximately one-tenth to one-twentieth of a recreational dose,varying within and between substances, so it can be seen as being somewhat below avery low dose. Although microdosing of psychedelics does not have an agreedscientific definition, we have decided to continue to use the term because of itsprevalent societal use. Hopefully, this paper will help to facilitate researchtowards establishing it as a scientific construct.

The most widely distributed species of psychedelic mushrooms arePsilocybecubensis and those of the genusCopelandia, whichconsists of 12 species (Guzmánet al., 1998). The psilocin (the active metabolite of psilocybin) andpsilocybin content in the whole body of these mushrooms when dried was estimated tobe in the range of 0.14–0.42% (psilocin) and 0.37–1.30% (psilocybin) forP.cubensis and 0.43–0.76% (psilocin) and 0.08–0.22% (psilocybin) forCopelandia, respectively. Thus, the former is morepsilocybin-rich than the latter, and the latter contains more psilocin compared tothe former (Tsujikawa et al.,2003). ThePsilocybe semilanceata is the most commonBritish species. This mushroom only contains psilocybin, in the range from 0.17 to1.96%, as shown by one Norwegian analysis (Christiansen et al., 1981;Rumack and Spoerke, 1994).These data show that the psilocybin concentration varies between and within speciesbut is also dependent on the time of collection, the preservation of the materialand growth conditions. User reported recreational doses depend on the species andexperience of the user (Rumackand Spoerke, 1994).

A hallucinogenic dose of driedP. cubensis, for example, is between3 and 5 g (Rumack and Spoerke,1994). These values equate to a recreational dosing range of 8.6 to 14.7mg of psilocin per dose. Thus, a microdose would range from 0.43 to 0.73 mg ofpsilocin per dose because a microdose of psilocybin is generally one-tenth of a fulldose (Fadiman, 2011).That positions a recreational dose of psilocin between a low and medium dose and amicrodose below a very low dose. However, variations in psilocin content betweendoses of dried mushroom may be seen due to variations between individual fungiwithin a species. A microdose of LSD ranges between 10 and 20 μg with 20 μg beingthe upper limit that might already produce perceptual changes in some. A microdoseof ibogaine hydrochloride is approximately 25 mg (Kroupa and Wells, 2005), and when smoked,that ofN,N-dimethyltryptamine (DMT) is approximately 6 mg (May, 2018).

Question 2: What microdosing schedules have been used?

The data presented here were collected using a search of microdosing protocols thatincluded books, online fora and surveys. The keywords of this search includedmicrodosing, microdosing protocols, microdosing approaches and psilocybin microdose.In this search, it was found that users mainly followed three approaches. The mostpopular of these was the Fadiman approach, outlined in his book (Fadiman, 2011), whichinvolves two consecutive dosing days followed by two non-dosing days. Anotherpopular approach involves ‘weekday’ dosing, i.e. from Monday to Friday and notdosing on Saturday and Sunday. Additionally, some users indicated that they followeda balanced low/microdose approach, which involved dosing every other day. Dosingperiods ranged from 1 week to 2 years. This variation in microdosing schedules wasconfirmed by a recent survey which demonstrated that half of the respondents whomicrodosed came up with their own schedule (Hutten et al., 2019).

Question 3: What controlled studies have been done so far?

The first placebo-controlled LSD microdosing study was published recently (Yanakieva et al., 2018).Findings showed a delay of time perception in the absence of self-rated effects onperception, mentation and concentration after administration of single doses of 5,10, and 20 μg LSD. To our knowledge there has been only one published study designedspecifically to measure the effects of psilocybin microdosing per se (Prochazkova et al., 2018)where the effects of psychedelic mushrooms were explored in a recreational setting.This study suffers from a number of methodological issues, particularly the lack ofa placebo control as well as uncertainty over dose taken. However, there have beenseveral more controlled studies where a low dose of psilocybin has been used as acontrol for a regular dose; these are presented below.

For example,Hasler andcolleagues (2004) compared four doses of psilocybin in healthy humans ina placebo-controlled experimental design and found slight physiological andpsychological differences between single administration of placebo and a very lowdose (VLD) (Hasler et al.,2004). A VLD was defined as 45 μg/kg p.o., equating to approximately 2.3mg of psilocin for an average 70-kg human. VLD was compared with a low dose (LD), amedium dose (MD) and a high dose (HD) defined as 115, 215 and 315 μg/kg p.o.,respectively. Although most physiological measures were similar between the VLD doseand placebo, a significant decrease was seen in maximum heart rate at the 6-hourpoint after VLD administration. Acute self-rated/self-reported psychologicalresponses of VLD included slight drowsiness, increased sensitivity andintensification of pre-existing mood states; an increase in introversion compared toplacebo was only shown for the MD and HD at peak drug effect, 95 minutespost-administration.

Building on that,Griffiths andcolleagues (2011) investigated the effects of psilocybin in varying doseswhere each participant received five dosing sessions, spread across 1-monthintervals (Griffiths et al.,2011). The doses used were 0, 5, 10, 20 and 30 mg/70 kg. Using a MonitorRating Questionnaire with a 5-point scale, they found that a dose of 5 mg/70 kgincreased stimulation, distance from ordinary reality and sense of peace. Intensity,somaesthesia, affect, perception, cognition and volition measured on theHallucinogen Rating Scale all increased after administration of a 5 mg/70 kg dose.In other words, they did not find a dose without psychological effects.Interestingly, when using an 11 mg/70 kg and 15 mg/70 kg dose of psilocybin,Lewis and colleagues (2017)found a significant decrease in global cerebral blood flow in the frontal, parietal,temporal, limbic, cingulate and occipital cortex, insula, caudate, putamen,pallidum, amygdala, hippocampus and thalamus (Lewis et al., 2017). This may relate to thepsychological effects seen with lower doses.

Psychological effects of microdosing have been regularly reported by users aftermultiple administrations of psilocybin. Independent accounts from online fora andsurveys (Fadiman and Korb,2019;www.thethirdwave.co;www.dmt-nexus.me, 2018;www.reddit.com, 2018) reveal thatusers report improvements in energy, mood, cognition, concentration, management ofstress, creativity, spiritual awareness, productivity, language capabilities,relationships and visual capabilities. Further, users also reported reduced anxiety,depression and addiction and pain relief. In a recent survey byAnderson and colleagues(2018), users also noted drawbacks such as illegality, stigma, physicaldiscomfort, anxiety, overstimulation, cognitive interference, emotional difficultyand uncertainty of effect (Anderson et al., 2018). All of these reports are confounded by the lackof certainty relating to the actual dose used, or indeed the provenance of theactive ingredient, and the absence of placebo conditions. For a recent review ofpast research with psychedelic microdosing, please seePassie (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 anelevated plus-maze and observation of ecological behaviours. They defined amicrodose of psilocin as 0.05 mg/kg, which equates to 3.5 mg for an average 70-kghuman. Rats received three dosing sessions over 6 days with the last dosing sessionon the 6th day. Anxiety profiles were measured in Wistar rats 2 days after the finaldosing session. Ethological behaviours including rears, head dips and stretch-attendwere also measured during this period. Psilocin at 0.05 mg/kg significantly reducedentries into open arms, suggesting that microdosing may have an anxiogenic effect.This effect was not replicated in the ethological measures. Although the authorsconclude that these results might have implications for future therapeuticapplications, as they produce counter-productive behaviour, one obvious limitationis the interspecies scaling issue (Sharma and McNeill, 2009). It isquestionable whether doses administered to animals translate to humans and theauthors also acknowledged that the translational value of their results needs to bedetermined in a therapeutic context.

Cameron and colleagues(2019) tested the effect of repeated low doses of DMT in rats. They gavea dose for 2 months every third day and assessed behaviour with a broad range oftests. In a cued fear extinction learning test, they showed that animals frozesignificantly less than a control group, suggesting that DMT facilitates fearextinction memory. In the forced swim test, an antidepressant-like effect wasobserved. No change was observed in dendritic spine density in the layer V pyramidalneurons, and no changes were observed in gene expression (EGR1, EGR2, ARC, FOS, BDNFand 5HT2A). However, an impact on metabolism was observed in male rats; the weightincreased by 182%, compared to 165% with vehicle (Cameron et al., 2019). Comparable to theHorsley et al. (2018)study, the interspecies scaling is a point of discussion together with the questionof whether a short-acting substance such as DMT would show beneficial effects inhumans without administration of a monoamine oxidase (MAO) inhibitor. Lastly, itshould be emphasized that there is a need to conduct more research on long-termeffects in order to assess the long-term safety of repeat doses.

Question 5: What is the pharmacology of psychedelics when used inmicrodoses?

The pharmacology of psilocybin and psilocin is still unclear due to the rapid declinein psychedelic drug research following their being made Schedule 1 drugs in 1968(Rucker et al.,2018). This decline predated the growth of modern neuropharmacology. Thus,more research is required to build a more complete pharmacological profile ofpsilocybin and psilocin.

Psilocybin (3[2-(dimethylamino)ethyl]indol-4-ol dihydrogen phosphate ester;O-phosphoryl-4-hydroxy-N,N-dimethyltryptamine)belongs to the indolealkylamine class of psychoactive compounds (Table 2). It is an indoleprodrug characterised by a 4-substituent, a phosphate group (Repke et al., 1977), six hydrogen bondacceptors and low lipophilicity (Geiger et al., 2018). Low lipophilicity may contribute to the notionthat psilocybin does not cross the blood–brain barrier (Rautio et al., 2008).

In vivo, however, the majority of the prodrug psilocybin is rapidly converted topsilocin by alkaline phosphatases present in the blood and tissues. Psilocin hasfewer hydrogen bond acceptors in its structure, which increases lipophilicity. Inaddition, NMR spectral studies have implicated an intramolecular hydrogen bond inpsilocin that reduces the basicity of psilocin, increases its lipophilicity and alsomay render it stable to the action of MAO (Migliaccio et al., 1981). Followingsystemic circulation, psilocin is metabolized by either phase I or phase IImetabolism (Figure 1). Theformer involves an oxidation reaction to form 4-hydroxyindole-3-acetaldehydefollowed by either an oxidation to 4-hydroxyindole-3-acetic acid or a reduction to4-hydroxytryptophole. It is believed that none of these metabolites are biologicallyactive. The latter pathway involves the formation of a psilocinO-glucuronide conjugate through small intestine and liver enzymesUGT1A10 and UGT1A9, respectively. There is evidence that to some extent,glucuronidated psilocin can be converted back to psilocin (Brown et al., 2017). Although more than 80%of psilocin undergoes phase II metabolism, both phase I and II metabolites areultimately eliminated through renal excretion.

Depending on body weight, the minimum active oral dose of psilocybin is approximately4 to 10 mg in humans (vanAmsterdam et al., 2011). Onset of action as defined by the firstappearance of acute psychological symptoms begins 20 to 60 minutes following oralingestion and 10 to 40 minutes following buccal administration (Geiger et al., 2018) andalmost immediately following i.v. injection (Carhart-Harris et al., 2012).

Psilocin begins to appear in the plasma approximately 25 minutes after oral dosage,with peak levels reached after approximately 105 ± 37 minutes (Brown et al., 2017). A typical userresponds to a full active dose for approximately 4 to 7 hours. Even a VLD canproduce responses for up to 6 hours after dose administration (Hasler et al., 2004).

Question 6: Is microdosing safe?

Preclinical studies to assess the safety of repeated doses of psilocybin in rodentshave not been conducted. That may be due to several factors, including thehistorical background of psilocybin as an ingredient in magic mushrooms that hadbeen used in many cultures without apparent harm. Evidence from these accountsdemonstrates a lack of serious adverse events resulting from psilocybinadministration. There are, however, several non-clinical investigations ofpsilocybin’s safety profile. The risk of an adverse cardiovascular event due to hERG(human ether-a-go-go-related protein) potassium channel blockade is low, with hERGassay results demonstrating minimal effect of psilocybin at concentrations up to1000 μM (nominal) and completely without effect at 100 μM. That means that unwantedcardiac chronotropic effects with microdosing are very unlikely as the maximumplasma concentration of psilocybin produced by a 25-mg dose would not reach 160 nM(Brown et al.,2017).

Other potential and serious adverse events are cardiac valvulopathies due to repeatedactivation of serotonin 5-HT_2B receptors, which psilocin activates alongwith many other serotonin receptors. Several drugs have recently been pulled fromthe market due to this concern. The first example of this was the diet medicationPhen/Fen, which had an unacceptably high fatality rate due to its effects on5-HT_2B receptors in the heart (Connolly et al., 1997). Another example ismethysergide, an ergot-derived prescription drug that is still being used today as aprophylaxis in difficult to treat migraine and cluster headache (MacGregor and Evers, 2017).It has a known risk of increasing cardiac valve dysfunction (Joseph et al., 2003). In early reports itwas shown that although aortic insufficiencies disappeared in most cases afterarrest of the methysergide therapy, the mitral insufficiencies remained unchanged(Graham, 1967). Itremains to be seen whether repeated low-dose psilocybin administration inpreclinical studies might produce valvular hyperplasia, and whether or not thiswould translate to the human user population. This concern is discussed more in thenext section. So far psilocybin testing in preclinical studies has not revealed anysignals of valvulopathy.

A different psychedelic that is more often used for microdosing, LSD, has beenexamined in rodents after repeated dosing schedules similar to microdosing.Comparatively low doses of LSD administered every other day for several months wereshown to produce persistent negative behavioural changes that lasted for at leastseveral weeks to months after LSD administration was discontinued (Marona-Lewicka et al.,2011). These changes included increased aggression, scruffy appearance,anhedonia and hyper-reactivity. Analysis of gene expression in key cortical regionslike the medial prefrontal cortex indicated that LSD produced alterations in genesenriched for schizophrenia and bipolar depression that lasted long after the drugwas discontinued (Martin etal., 2014). Of note, here the interspecies scaling question arises, andit is disputable whether the (low) doses used in animals are comparable to thoseused by humans (Sharma andMcNeill, 2009). Related to these preclinical findings, another primarysafety concern for 5-HT_2A agonists is the potential for adversepsychological response in humans (Carhart-Harris et al., 2016;Johnston et al., 2010;Vollenweider et al.,1998).

The lethal dose of psilocybin in a single administration in 50% of animals tested(the LD50) ranges from 280 mg/kg in rats and mice to 12.5 mg/kg in rabbits (Usdin and Efron, 1972;Williams, 2013).Animals receiving a very HD of psilocybin (10 mg/kg) exhibit sympathetic systemeffects such as irregularities in heart and breathing rate as well as mydriasis,piloerection, hyperglycaemia and hypertonia (Cerletti, 1958). Similar central excitatoryeffects were seen after the administration of 2–4 mg/kg intraperitoneal psilocybinin rhesus monkeys (Horibe,1974).

Question 7: What receptors will be involved in the activity of microdosedpsilocybin?

Psilocin predominantly binds to serotonin receptors: 5-HT_1A,5-HT_1D, 5-HT_1E, 5-HT_2A, 5-HT_2B,5-HT_2C, 5-HT₅, 5-HT₆ and 5-HT₇(Table 3) (McKenna et al., 1990) andthe serotonin transporter and partially to the norepinephrine transporter, similarto MDMA (Rickli et al.,2016). Hill slope values demonstrate that psilocin binds independently atall 5-HT receptors except 5-HT_2B where cooperative binding is exhibited(McKenna et al.,1990).

Cerebral 5-HT receptors that can be stimulated by psilocin are highly distributedamong different regions (Table3). Many behavioural and neuropsychological effects claimed to beelicited by microdosing are known to be modulated by these receptors (Anderson et al., 2018).

Psilocin acts as a partial agonist at the 5-HT_2A receptor with 46%(+/−2.4) response compared with the response produced by serotonin for signallingthrough the phospholipase C (PLC) pathway (Kurrasch-Orbaugh et al., 2003). It has alower binding affinity to the 5-HT_2A receptor compared to LSD (Rickli et al., 2016).Currently there is only one study of the in vivo cerebral 5-HT_2A receptoroccupancy produced by the psilocybin metabolite psilocin in humans. That was done bythe Copenhagen group led by Knudsen who used the PET tracer[¹¹C]Cimbi-36. This tracer is an agonist of the 5-HT_2Areceptor and therefore particularly sensitive to displacement by another agonist,psilocin. Having performed a dose-finding study of psilocybin that ranged from 3 to30 mg p.o. per person, they found that the plasma concentration that produced a 50%occupancy of the 5-HT_2A receptor was 1.95 (range 1.16–3.15) μg psilocin/L(Madsen et al.,2019). They also found that plasma psilocin was positively correlated withsubjective intensity ratings and that doses producing less than 20% occupancy (i.e.probably less than 0.028 mg/kg body weight) were not detectable either bypsychological or physiological measurements (Madsen et al., 2019), suggesting that thisconcentration might represent the threshold for microdosing, based on brain5-HT_2A receptor occupancy.

At this dose level, several 5-HT receptors other than the 5-HT_2A receptormay also be affected. This could include antagonist activity at the 5-HT₆and 5-HT₇ receptors that may improve mood and cognition (Ballaz et al., 2007;Mnie-Filali et al., 2009).The 5-HT₇ receptor is also implicated in the regulation of circadianrhythms (Lovenberg et al.,1993). Upon assessing binding affinity of LSD and DMT at 5-HT₇receptors, similarly high K_i values of 9.5 nM (Ruat et al., 1993) were found.Additionally, it has been found that 5-HT₇ receptor activation reducessecondary hypersensitization in response to capsaicin in mice (Brenchat et al., 2009). Thus, psilocybinagonist activity at 5-HT₇ may relate to the ancient use of ‘teonanacatl’to ease rheumatism.

Further, psilocin also binds with relatively high affinities to 5-HT_1D(K_i = 36.4 nM) and 5-HT_2B (K_i = 4.6 nM)receptors. 5-HT_1D is predominantly expressed in the trigeminal system,which may account for the recent reports of self-medication using microdoses ofpsychedelics to produce migraine prophylaxis (May, 2018). With regard to the5-HT_2B there are concerns of the development of cardiac valvulopathyassociated with agonism at 5-HT_2B (Elangbam et al., 2005). It is mostly theuse of intermittent high-dose psilocybin intake that has been discredited. However,even with repeated microdosing there is a possibility that 5-HT_2Breceptors might be stimulated enough to lead to tissue overgrowth. A potentialmitigation against this risk is the suggestion that the efficacy of psilocin (EC50> 20 μM) (May, 2018)is lower than that of 5-HT. Nonetheless, because psilocin also has a higher affinityfor the 5-HT_2B receptor than 5-HT, further investigation is needed tounderstand better the risks associated with microdosing.

Some stimulation at 5-HT_1A receptors may also occur. Such activity hasbeen implicated in the mechanism of action of antidepressant medications includingSSRIs (Celeda et al., 2013). Activation of these receptors by psilocin couldconceivably be involved in reduction in anxiety and increased mood swings (Carhart-Harris and Nutt,2017) due to dense distribution of the receptor in the midbrain, limbicand cortical regions that regulate stress and emotion.

Question 8: Are the claims of the benefits of microdosing biologicallyplausible?

There have been only a few studies on the basic neurobiology of psychedelics at the5-HT_2A receptor. Recent work has shown that psychedelics like DOI andLSD directly produce transcriptional activation of Immediate Early Genes (IEGs) likecfos in only about 5% of neurons within key brain structures,and that these activated Trigger Population neurons express significantly higherlevels of receptor than the non-activated neurons (Martin and Nichols, 2016). Transcriptionalactivation of IEGs within neurons is generally accepted to be a reliable marker forneural activity (Joo et al., 2016). Further, psychedelics also act on subsets ofinhibitory neurons, and non-neuronal cells like glia and astrocytes (Martin and Nichols, 2016).Together, these data indicate that within specific brain regions, psychedelicstrigger complex patterns of excitatory and inhibitory neurons in small subsets ofcells, and that how these cells are activated differs between brain regions (Martin and Nichols,2016).

Genes acutely activated by LSD in the brain are predominantly involved in synapticplasticity (Nichols andSanders-Bush, 2002;Nichols and Sanders-Bush, 2004). Accordingly, activation of5-HT_2A receptors in brain slice culture modulates aspects oflong-term plasticity, and expression of brain-derived neurotrophic factor (BDNF)(Vollenweider and Kometer,2010). BDNF expression is also observed to increase in primary culturesof cortical neurons 24 hours following the application of psychedelics (DOI, DMT,LSD) (Ly et al., 2018).Blockade of the receptor for BDNF, Trk-B, prevents increased spinogenesis andsynaptogenesis in cortical neurons that have been treated with psychedelics.Interestingly, the mammalian target of the rapamycin (mTOR) pathway is activateddownstream of psychedelics in cortical neuron cultures similarly to ketamine, andlikely mechanistically underlies the synaptogenesis (Ly et al., 2018). None of these preclinicalstudies, however, utilized psilocybin, and it remains to be seen if it produces thesame effects, and if so, at what dose?

Psychedelics are known to induce behavioural tolerance, an absence of behaviouraleffects after repeated intake of a substance. Previously it was shown thatbehavioural effects were for example diminished after repeated doses of LSD (Abramson et al., 1956); inaddition, another study showed these effects to be associated with reduced cortical5-HT_2A receptor binding (Gresch et al., 2005). Serotoninsyndrome-related symptoms, skin jerks, shaking behaviour and hyperthermia, inducedby a single dose of the 5-HT_2A agonist DOI in rats were absent afterrepeated low dosing, suggesting behavioural tolerance (Pranzatelli and Pluchino, 1991). Althoughspeculative, this downregulation of the 5-HT_2A receptor might be amechanism of action underlying some of its putative therapeutic effects. An exampleis obsessive-compulsive disorder (OCD), a psychiatric condition that ischaracterized by increased 5-HT_2A binding (Adams et al., 2005). Preliminary data haveshown that administration of low to high doses of psilocybin lead to symptomreduction in patients with OCD (Moreno et al., 2006). It was previously suggested that a re-balancebetween 5-HT_1A and 5-HT_2A receptors might be responsible forobserved therapeutic actions (Buchborn et al., 2014), but this remains to be investigated.

In peripheral tissues, very low doses of psychedelics have profound anti-inflammatoryeffects (Yu et al.,2008). In general, psychedelics in the phenethylamine class such as DOI havemore potency than those in the ergoline class such as LSD. In a rodent model ofasthma, for example, levels of the R stereoisomer (R)-DOI that are30 times lower than the behavioural threshold can have profound effects to preventinflammation, T-Helper Cell Type 2 (Th2) cell recruitment, eosinophilia and mucusproduction in the lung, resulting in animals that can breathe normally afterexposure to an allergen (Nau etal., 2015). In another animal model of inflammatory bowel disease, levelsof the psychedelic (R)-DOI 30 times lower than the behaviouralthreshold nearly completely prevented intestinal inflammation (Nau et al., 2013). It remains to be seenwhether very low levels of psychedelics are also anti-inflammatory in humans, and ifthe anti-inflammatory activity also occurs in the brain, but if these findings dotranslate then levels typically used in microdosing regimes for some psychedeliccompounds would be predicted to have significant and beneficial anti-inflammatoryeffects. Interestingly, although LSD is one of the most powerful and potentmind-altering psychedelics, it is comparatively among the least potentanti-inflammatories tested (Yuet al., 2008).

Question 9: What is the legal position of microdosing?

The answer to this question is complex due to differences in national regulations. Ingeneral, under the UN Conventions, LSD and related compounds, psilocybin and DMT arecontrolled as Schedule 1 drugs – i.e. are defined as being the most harmful and ashaving no medicinal value. In other words, they are subject to the most extremerestrictions and penalties for unapproved possession. These constraints apply to anydose of the drug, even a sub-psychoactive or microdose level. Research can becarried out with the right ethical regulatory and institutional approvals, butdosing would have to be conducted in a secure environment like a hospital orresearch ward. For repeated microdosing, this adds significant costs and complexityto any study, which is likely why none have yet been reported.

However, this situation is easing for psilocybin as a result of several successfulclinical trials in recent years, and both the European and US regulators have givenapproval for studies (NIH,2018) with psychedelic doses of synthetic psilocybin made to GMPstandards. That means that microdosing trials of similarly sourced product forclinical therapy are likely also to be approved, though as yet we do not believe anyhave 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 anddevelopment path expected by contemporary standards. Thus, at best, doses have beenselected based on published data in a variety of indications but mostly to providean indication for an upper safety limit. In a pooled analysis of psilocybinStuderus et al. (2011)classified active oral doses within a vast range of about one order of magnitudedifference, between 0.045 and 0.315 mg/kg, which translates into 3.15 to 22.05 mgfor a 70-kg human (Studerus etal., 2011). Such a range is quite surprising for active principles withthe pharmacological potency of psychedelics. Given such underdetermination,regulatory standards will most likely require dedicated dose-finding studies (morethan one) to provide a rationale explaining the known individual differences thathave been reported in the clinical response to treatment and most importantly, thedose chosen for late development. In this context, the information provided fromoral dosing, resulting plasma psilocin levels and corresponding brain5-HT_2A receptor occupancy will turn out to be informative.

Parallel fixed dose designs are usually recommended (ICH, 1994). In some cases, four arm rangestudies could be necessary; under these circumstances microdoses could be used totest pseudo-placebo properties or alternatively a peculiar pharmacologicalactivity.

Another issue pertains to the limited pharmacokinetic data available in order toevaluate a dose-concentration–response relationship for psychedelics. Updated ADMEstudies are not available for psychedelics, although the characterization of theirmetabolites and their role in the active principle efficacy or safety profile mightprove relevant to interpret and predict their clinical effect. Once pharmacokineticsof the parent compound and its metabolite(s) are established, variation of clearanceif any, its prediction by body weight and the concentration–response relationshipfor the claimed clinical effect must be presented. If possible, biomarker(s) (e.g.single-nucleotide polymorphisms (SNPs)) at the 5-HT receptor subtypes where theyhave affinity should be linked to the risk/benefit profile and thus to thetherapeutic effect, and they could be used to enrich/stratify the population ofinterest. Because psychedelics have been reported by some to possess a largeinter-individual sensitivity, the definition of a precise concentration–responserelationship may be difficult to demonstrate, especially once a microdose range isreached.

Question 11: What are the future research needs?

Microdosing is generally accepted as the use of a functionally low dose of apsychedelic compound over multiple dosing sessions with the intention of improvingmental and physical well-being, cognition or creativity (Fadiman, 2011;Johnstad, 2018). A systematic study ofmicrodosing psychedelics investigated by means of observation changes inpsychological variables of microdosers. Small changes in a sub-set of variables werefound, i.e. decreased depression and stress, decreased mind wandering, increasedabsorption and increased neuroticism. Interestingly, these variables were not thosethat participants most expected to change, suggesting that long-term changes may bedue 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 onlinefora, the true amount of active substance in these is unknown as are the peak plasmapsilocin concentrations achieved during ‘intoxication’. Further, while in theseanecdotal reports the user deliberately ingests a substance for a reason, expectingpositive effects, it is difficult to distinguish between expectation ‘placebo’effects and the effect of a microdose. These non-pharmacological effects, describedas set and setting, are also known to be of influence when taking a full dose of apsychedelic (Hartogsohn,2017). Another unknown is whether effects are noticeable after only onemicrodose or that a certain ‘build-up’ is needed, supported by underlyingneurobiological changes, before effects occur.

Therefore, rigorous placebo-controlled clinical studies need to be conducted withdifferent low doses of the drug to determine whether there is any evidence for theclaims being made by microdosers. The types of cognitive testing performed shouldinclude several different validated psychological instruments and preferably coverthe concepts mentioned in the Research Domain Criteria (Cuthbert and Kozak, 2013), and not simplyrely on anecdotal accounts or simple tests. Generated knowledge in healthyvolunteers will provide clear information on which cognitive aspects can be enhancedwith microdosing. This knowledge will provide a first hint as to whether microdosingcan be of value in the treatment of specific symptoms in psychiatric populations.Anecdotal reports suggest, for example, that microdosing might help in combattingattention deficit hyperactivity disorder (ADHD) symptoms; studies including measuresrelated to symptom domains like executive functioning, attention and temporalprocessing 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 beperformed to understand fully the complex interaction of different cell types, andtheir responses to psychedelics at the molecular level such as elucidatingperipheral or central signalling pathways involved, if any, in the process ofmicrodosing (Kuypers,2019). Resulting findings can provide theoretical grounds for whymicrodosing 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-dosepsilocybin behavioural effects as well as address potential risks of (multiple)administrations of a psychedelic in low doses. Although extensive toxicology hasbeen 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 healthrisks incurred by microdosing, especially in relation to cardiac and lung tissue.These studies would involve (pre)clinical safety and tolerability tests of multiplelow/microdoses of psilocybin over an extended period of time. To that end,continuous monitoring of physiological parameters including heart functioning inaddition to assessment of receptor turnover at low/microdoses as well as receptoroccupancy will shed light on the potential negative consequences microdosing couldhave.

Acknowledgments

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

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Acknowledgments

I thank Daniel Trachsel, Felix Müller, Patrick Vizeli, Yasmin Schmid andFriederike Holze for comments on the manuscript and Michael Arends formanuscript editing.

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Psychedelics and creativity

I would recommend not mentioning just these very few anecdotal cases in respectto creativity and psychedelics. There are some good studies and reviews aboutthe subject (Hartmann,1969) on 40 prominent painters at the German Max Planck Institute ofPsychiatry in Munich and the review on the subject byKrippner (1985).

When it comes to the very few studies looking for low doses of psychedelics andcreativity (review inPassie, 2019), no study revealed any significant/relevant effectsunder controlled scientific conditions (e.g.McGlothlin et al., 1967). The study ofProchazkova et al.(2018) claimed (under weakly controlled conditions in respect todosing and environment) increased lateral thinking, which has been discussed asa marker of creativity. This study employed doses of psilocybin that were abovethe perceptible level (4–8 mg p.o.). However, increased lateral thinking doesnot mean that the drugged subjects have shown increased creativity in a validsense, e.g. creating more original painting.

Definitions: Microdosing and minidosing

I do not agree with the authors’ narrow definition, since it does not reflectfully what is used in the literature and the appropriate Internet entries. Ithas been proposed that the term ‘mini-dosing’ could be used to separate theapproach of taking small perceptible doses. It is also clear that many authorsand Internet entries suggest the practice of just taking one dose at a timerather than a few ones consecutively as, for example, seen with the Fadimanscheme. 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/definitionof what is considered a ‘full dose’. In the case of LSD, some authors reasonablyargue that 150 µg is a full dose (especially in females), whereas othersconsider 250 µg a full dose. This is a significant issue, because 15 µg isusually not perceptible by most subjects, but a dose of 25 µg is for mostsubjects (as shown in some scientific studies). Therefore, the definition has tobe sharpened before scientific consensus can be reached and the evidence fromso-called microdosers disseminated on the Internet as well as studies ofanecdotal evidence (e.g.Johnson, 2018), which suffers from such inaccuracies, can be takenseriously.

Dosing of dried mushrooms

Plant/fungal material is generally quite unreliable for calculating a dose. I donot agree with the author’s statement that 3.5 gP. cubensis is‘a usual recreational dose’. Most recreational users take 1 to 2.5 g as arecreational dose, which is also recommended in most books in the field. From myexperience, and the research studies ofAbramson and Rolo (1967), I wouldstate 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, moreconsistent 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 microdosesrecreationally for ‘bettering performance’ take doses that give them someperceptible effects. Even a microdosing proponent like Paul Austin recommendsdoses where you can feel/perceive some alterations to some extent. How would youbetter your performance if nothing can be felt from a dose?

Following my comprehensive research into this topic (Passie, 2019), I have never come acrossanything about a ‘workaholic approach’ (dosing during weekdays, but not onweekends) as suggested by the authors. This also does not make much sense form apharmacological point of view, because tolerance to LSD develops very quickly.Be reminded, that the US military has dosed soldiers with increasing daily dosesto 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 (whichI define as something below 20 µg LSD, e.g. 5–15 µg), makes a significantdifference in terms of recreational as well as scientific studies as itdefinitely alters psychological functioning and the cognitive system.

However, this alteration is not in any way equivalent to stimulants like Ritalinor amphetamine as is sometimes reported anecdotally. It is more a dissociationfrom the environment and the person itself. Cognitive abilities have been provento be compromised in many studies with LSD and psilocybin employing a very lowdose range (Passie,2019). It is also important to register these (potentially)distracting effects. There are also a few scientific reports of people who havebeen given very low doses of LSD for treating depressive mood. These hadnegative results with very few patients experiencing a small improvement.

What is plausible (and has been experienced by this author) is that a minimalsympathomimetic effect (for sure not compatible with any sort of usualstimulant!), which might be still there up to 20 hours after a 10- to 15-µg doseof 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. Onecould think of a train of effects induced in the organism, which is pushed onand may influence the organism even after virtually all of the substance hasleft the organism.

I definitely do not see the Fadiman protocol (5–15 µg LSD every third day) as themost 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 alsomakes it very questionable what effects can be/are felt or not, especially whenit comes to taking 10 µg just a few times per year (which is apparently whatmost users do). As Fadiman’s coworker on his more or less systematic Internetsurveys, Sophia Korb has mentioned in a lecture (conference ‘BeyondPsychedelics’, Prague 2018) that they know of just three persons who have dosedregularly (according to the Fadiman protocol) for more than 3 weeks. These threesubjects 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, withdaily fluctuations), as measured using the PANAS scale.

To my mind, the study published byHorsley et al. (2018) does not have anyseriously calculable implications for humans. Its limitations should bediscussed.

Possible alterations of gene expression and receptor proteins

There are serious doubts that the repeated doses of LSD, which have been used inrodents, are comparable to microdoses in humans. I am not an expert oninterspecies scaling, but, for example, (just by simplified arithmetic) thestudies byMartin et al.(2014) have used doses which are 12,000 times higher than a microdosein humans. According to a recent review (Sharma et al., 2009), it appears notto be congruent with scientific data to state that the dose used byMartin et al. (2014)is in any way comparable to a microdose in humans. Therefore, to date we knownothing about possible changes in gene expression induced by regular LSD intakein humans.

I doubt that the gene/BDNF changes which were found with very high daily doses inanimals can be scaled up to humans using microdoses every few days. Issues ofadaption and tolerance should be discussed in this respect.

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

On the possible induction of cardiovascular valvopathy

In respect to a possible induction of cardiovascular valvulopathy by chronic2-HT2R activation, it is worth mentioning that the studies ofBender and Sankar(1968) in the 1960s involved doses of 100 µg LSD for up to 35 monthson a daily basis without any observable damage. However, their methods ofinvestigation might not have been sensitive enough to detect damage. It is alsotrue that just a very small part of the patient population taking ergotcompounds (e.g. methysergide) do in fact develop valvulopathy. It is also worthmentioning that if a valvulopathy is detected in a patient, in all cases itdisappears within a short time after stopping the medication. There is just onecase documented in the literature where surgery was necessary (Graham, 1967).

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