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Self-blinding citizen science to explore psychedelic microdosing

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Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.
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balazs.szigeti07@imperial.ac.uk
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Received: 07 September 2020
Accepted: 20 January 2021
Published: 02 March 2021
Reviewing editor: Alexander
Shackman, University of
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Self-blinding citizen science to explore
psychedelic microdosing
Bala
´zs Szigeti
1
*, Laura Kartner
1
, Allan Blemings
1
, Fernando Rosas
1,2,3
,
Amanda Feilding
4
, David J Nutt
1,5
, Robin L Carhart-Harris
1
, David Erritzoe
1,5
1
Centre for Psychedelic Research, Imperial College London, London, United
Kingdom;
2
Data Science Institute, Imperial College London, London, United
Kingdom;
3
Center for Complexity Science, Imperial College London, London,
United Kingdom;
4
Beckley Foundation, Oxford, United Kingdom;
5
Centre for
Psychiatry, Imperial College London, London, United Kingdom
Abstract Microdosing is the practice of regularly using low doses of psychedelic drugs.
Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such
accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen
science initiative, where participants were given online instructions on how to incorporate placebo
control into their microdosing routine without clinical supervision. The study was completed by 191
participants, making it the largest placebo-controlled trial on psychedelics to-date. All
psychological outcomes improved significantly from baseline to after the 4 weeks long dose period
for the microdose group; however, the placebo group also improved and no significant between-
groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and
creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo
differences; however, these results can be explained by participants breaking blind. The findings
suggest that anecdotal benefits of microdosing can be explained by the placebo effect.
Introduction
There is renewed interest in the medical application of psychedelic drugs, such as lysergic acid dieth-
ylamide (LSD) and psilocybin. Contemporary research is predominantly focusing on ‘psychedelics
assisted psychotherapy’, where a few (one to three) large doses of psychedelics are used as adjunct
to psychotherapy. Using this paradigm, psychedelics have shown promise in the treatment of condi-
tions such as depression, end-of-life-anxiety, addiction, and obsessive-compulsive behaviors (Car-
hart-Harris and Goodwin, 2017;Nutt et al., 2020).
Recently, ‘microdosing’ has emerged as an alternative paradigm of psychedelic use. Due to its
underground origin, microdosing does not have a universally agreed upon definition,
and inconsistencies exist in substance, dose, frequency, and duration of use (Kuypers et al., 2019).
However, microdosing can be broadly defined as the frequent use (one to three times per week) of
low doses of psychedelics (10–20% of a typical ‘full’ dose, e.g. 10–15 mg LSD or 0.1–0.3 g of dried
psilocybin containing mushrooms).
Anecdotal evidence suggests that microdosing may improve well-being, creativity, and cognition
(Fadiman and Krob, 2017), and recent uncontrolled, observational studies have provided some
empirical support for these claims (Anderson et al., 2019;Polito and Stevenson, 2019;
Prochazkova et al., 2018). While encouraging, these studies are vulnerable to experimental biases,
including confirmation-bias and placebo effects, in particular, because microdosers are a self-
selected sample with optimistic expectations about psychedelics and microdosing (Polito and Ste-
venson, 2019). This positivity bias, combined with the low dose and the subjective evaluation of
effects, pave the way for a strong placebo response.
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RESEARCH ARTICLE
A few recent double-blind, controlled studies have been conducted on microdosing. All studies
used LSD and focused on the acute effects of a single microdose in a small number of healthy sub-
jects (Yanakieva et al., 2019;Bershad et al., 2019a;Bershad et al., 2019b;Family et al., 2020;
Hutten et al., 2020b). Studies have found large variability in LSD blood concentration after micro-
dosing (Family et al., 2020), along with increased BDNF blood levels (Hutten et al., 2020a). No
robust evidence was found to support the positive anecdotal claims about microdosing, but some
dose-related self-rated subjective effects were detected (e.g. self-ratings of ‘feel drug’, ‘feel high’,
and ‘like drug’) (Yanakieva et al., 2019;Bershad et al., 2019b;Hutten et al., 2020b), along with
concomitant changes in brain function (Bershad et al., 2019b).
Two key issues need to be considered when assessing the scientific credibility of microdosing:
the lack of placebo control in uncontrolled studies and the small sample size in controlled studies.
Uncontrolled, observational studies affirm the anecdotal reports, but by design, these studies cannot
provide evidence for beyond placebo benefits. Lab-based, controlled studies have small samples
(Yanakieva et al., 2019;Bershad et al., 2019a;Bershad et al., 2019b;Family et al., 2020) due to
restrictive drug policies that render randomized controlled trials prohibitively expensive, and hence
may be statistically underpowered.
In the present study we conceived of a novel citizen-science (Silvertown, 2009) initiative as a
solution to this problem, exploiting modern technology and the popularity of microdosing. The key
component is a self-blinding setup procedure that enabled self-experimenters, who microdose on
eLife digest Psychedelic psychotherapy, therapy enhanced with psychedelic drugs such as LSD
or psilocybin (the active ingredient of ‘magic mushrooms’), has been suggested to improve
psychological well-being. For this reason, trials on psychedelic therapy for the treatment of
depression, addiction and other conditions are ongoing. Recently, ‘microdosing’ – a way of
administering psychedelics that involves taking about 10% of a recreational dose two or three times
per week – has gained popularity. Unlike taking large doses of psychedelics, microdosing does not
induce hallucinations, but anecdotal reports suggest that it yields similar benefits as psychedelic
therapy.
A key feature of modern medicine are ‘placebo control’ studies that compare two groups of
patients: one that takes a drug and another that takes inactive pills, known as placebos. Crucially,
neither group knows whether they are taking drug or placebo. This control ensures that observed
effects are due to the drug itself and not to unrelated psychological causes. For example, in trials of
mood medicines, participants often expect to feel happier, which in itself improves their mood even
when taking a placebo. This is known as the placebo effect.
Restrictive drug policies make placebo-controlled studies on psychedelics difficult and expensive,
in particular for microdosing, which involves taking psychedelics over a longer time period. To
overcome this problem, Szigeti et al. developed a new citizen-science approach, where microdosers
implemented their own placebo control based on online instructions. The advantages are the low
cost and the ability to recruit participants globally. The experiment was completed by 191
microdosers, making it the largest placebo-controlled study on psychedelics to-date, for a fraction
of the cost of an equivalent clinical study.
The trial examined whether psychedelic microdosing can improve cognitive function and
psychological well-being. The team found that microdosing significantly increased a number of
psychological measures, such as well-being and life satisfaction. However, participants taking
placebo also improved: there were no significant differences between the two groups. The findings
confirmed positive anecdotes about microdosing improving people’s moods, but at the same time
show that taking empty capsules, knowing they might be microdoses, have the same benefits. This
result suggests that the observed benefits are not caused by the microdose, but rather by
psychological expectations.
The study’s innovative ‘do-it-yourself’ approach to placebo control may serve as a template for
future citizen science studies on other popular phenomena where positive expectations and social
factors could play a role, such as cannabidiol (CBD) oils, nootropics and nutrition.
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their own initiative using their own psychedelic, to implement placebo control and randomization
without clinical supervision. To investigate potential changes over the study period, participants
were directed to online self-report surveys and cognitive tasks at various timepoints. The strength of
this design is that it allowed us to obtain a large sample size while implementing placebo control at
minimal logistic and economic costs. The primary objective of the study was to test whether psyche-
delics microdosing produces superior outcomes compared to placebo on psychological state and
cognitive function. We hypothesized that improvements from baseline will be positively correlated
with the number of microdoses taken during the dose period and that acute/post-acute outcomes
will be better under/after taking a microdose.
Materials and methods
Design
This study had a naturalistic design involving elements of experimental control (self-blinding), pro-
spective data collection and online citizen-science. From baseline to the final endpoint, the study
was 10 weeks long (weeks 0–9), including a core 4-week microdosing period. Primary endpoint was
at week 5 and there was an optional follow-up at week 9. The self-blinding procedure randomly
assigned individuals to three groups, where the groups are defined by the number of weeks taking
placebos/microdoses during the dose period. The three groups were:
.Placebo (PL) group: 4 weeks of placebo,
.Half-Half (HH) group: 2 weeks of placebo and 2 weeks microdosing, and
.Microdosing (MD) group: 4 weeks of microdosing.
Individuals took two microdoses during each microdose week, resulting in 0/4/8 total microdoses
for the PL/HH/MD groups. Participants had equal probability (1/3) of being assigned to each group;
Figure 1 illustrates the experimental timeline and the groups’ dose schedule.
Outcomes
Outcomes can be organized into three categories capturing the effects of microdosing on different
timescales.
.Accumulative: assessed monthly, first at baseline, then after the completion of the dosing
regime at week 5, and finally at the optional long-term follow-up at week 9. Accumulative out-
comes were: Ryff’s psychological well-being (RPWB) (Ryff and Keyes, 1995), cognitive and
affective mindfulness scale (CAMS) (Feldman et al., 2007), satisfaction with life scale (SWL)
(Diener et al., 1985), green paranoid thought scales (GPTS) (Green et al., 2008), big five per-
sonality traits (B5) (McCrae and John, 1992) with the addition of intellect trait
(DeYoung, 2015) and cognitive performance. To quantify cognitive performance, participants
were tested in six tasks: spatial span, paired associates, rotations, odd one out, spatial plan-
ning, and feature match, see Hampshire et al., 2012 for details. Task scores were combined
as the cognitive performance score (CPS) to quantify overall cognitive performance as a single
outcome. Briefly, CPS is the average z-score across the six tasks after removing learning
effects, see Appendix 1 for details.
.Post-acute: assessed weekly during the dose period on Sundays, when no capsule was taken.
Measures were taken 48–72 hr after the last placebo/microdose capsule. Post-acute outcomes
were: Warwick–Edinburgh mental well-being scale (WEMWB) (Tennant et al., 2007), Quick
inventory of depressive symptomatology (QIDS) (Rush et al., 2003), Spielberger’s state-trait
anxiety inventory (STAIT) (Spielberger, 1983), and Social connectedness scale (SCS) (Lee and
Robbins, 1995).
.Acute: assessed weekly during the dose period on Thursdays, when either a microdose or pla-
cebo capsule was taken. The testing was carried out 2–6 hr after the ingestion of the capsule,
while the potential microdose was active. Acute outcomes were positive and negative affect
schedule (PANAS) (Watson et al., 1988), visual analogue scale items (drug intensity, mood,
energy, creativity, focus, and temper) and cognitive performance (see Accumulative above for
details).
An overview of the outcomes can be found in Table 1 and a description of each measure is in
Appendix 1. See Figure 1 for the experimental timeline and assessment timepoints.
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Self-blinding setup procedure
A high-level overview of self-blinding is provided here; for a detailed illustration see Figure 2. First,
two sets of capsules had to be prepared using non-transparent capsules: one set with microdoses
inside and another set without anything inside (placebos). Next, these capsules were packaged into
weekly sets, which were then placed inside envelopes together with a QR code (Figure 2A). The
envelopes were grouped and shuffled. Then, using a semi-random drawing process, four of them
were selected (Figure 2B) corresponding to the 4 weeks of the dose period (i.e. each envelope held
capsules for 1 week of the dose period). The drawing process was constrained such that only
three combinations of the envelopes were possible to draw, matching the three study groups: pla-
cebo (four placebo weeks), half-half (2–2 placebo and microdose weeks), and microdose group (four
microdose weeks; Figure 2C). At this stage, participants were ready to start the experiment.
When the dose period started, one envelope was opened per week and the capsules inside were
used as scheduled (Figure 2D). Additionally, the QR code from the envelope had to be scanned,
which shared a numeric code with our informatics infrastructure. The decryption key (i.e. how cap-
sule types are encoded by the numbers) was not shared with participants, so the numeric code
allowed only us to deduce which type of capsule was taken when.
In summary, the two key elements of self-blinding are to hide the active components inside opa-
que capsules while preparing identical looking placebos (1) and to position non human-readable QR
codes along the capsules prior to randomization (2). With the QR codes in place, it is possible for
Figure 1. Timeline and outcomes. Top horizontal arrow shows the experimental timeline and the three timepoints associated with accumulative
outcomes (blue frame). 1/3 of the participants were randomly assigned to one of the three groups, where the groups differ in the number of placebo/
microdose weeks during the dose-regime: 4/0 for PL, 2/2 for HH, and 0/4 for the MD group. Note that even for microdose weeks, placebo capsules are
mixed into the schedule, for example, weeks 1 and 3 for the HH group are microdose weeks. Acute measures (green frames) were taken on Thursdays,
while the potential microdose was still active. Post-acute measures (purple frame) were administered on Sundays, when no capsule was taken, these
outcomes test the weekly effects of microdosing. For a list of measures administered at each timepoint, see Table 1.
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the experimenter to recover knowledge of capsule types after randomization without revealing that
information to participants.
Microdose preparation
Participants were allowed to use any psychedelic substance to microdose with. The microdose dose,
which is the amount of substance to use as a microdose, was not defined for participants, rather
they were instructed to use a microdose dose that they would use outside the study. The rationale
for this direction was threefold. First, given that participants typically would source their substance
from the black market, the precise microdose dose could not have been known even if instructions
requested it. Second, based on community feedback, most experienced microdosers have a pre-
ferred dose that they would not have liked to change to participate in the study. Lastly, this study
was not a clinical trial and therefore from a regulatory perspective not allowing for control over and/
or directing about drug doses.
Recruitment and inclusion criteria
Psychedelics users were recruited through advertisement on relevant online and offline forums. Indi-
viduals could sign up through the study’s website, https://selfblinding-microdose.org/, where they
could find information about the study, including the study manual and explainer videos, the partici-
pant information’s sheet, and procedure for declaring informed consent. Once informed consent
was given, individuals were able to sign up by providing their email address and planned start date.
The inclusion criteria were: >18 years of age, good understanding of English, intention to microdose
with psychedelics, previous experience with psychedelics (either micro- or macrodosing), no use of
psychedelic drugs from a week before the start until the completion of the post-regime timepoint
(other than the study’s microdoses), and willingness to follow the study protocol.
Data collection
All the questionnaires were implemented online using the SurveyGizmo platform (https://www.sur-
veygizmo.com/). For the online assessment of cognitive performance, the Cambridge Brain Sciences
(https://www.cambridgebrainsciences.com/) service was used. At each timepoint, links to each test
Table 1. List of outcomes.
Outcomes have three types, depending on what is the timescale of the effect they aim to capture: accumulative are monthly, post-
acute are the weekly and acute are the daily effects. A scale is administered at every timepoint of the associated outcome type if the
checkmark is shown, for example, PANAS was administered at every acute timepoint, that is every Thursday during the dose period,
see Figure 1 for a visual overview of the timepoints and see Appendix 1 for a description of each scale.
Test Domain Acronym Baseline Acute Post-acute Accumulative
Demographics - - [
Previous drug experiences and expectations - - [
Short suggestibility scale Suggestibility SSS [
Cognitive performance score Cognition CPS [ [ [
Daily effects of microdosing VASs - - [
Positive and negative affection scale Emotional state PANAS [
Warwick–Edinburgh mental well-being scale Well-being WEMWB [
Quick inventory of depressive symptomatology Depression QIDS [
Social connectedness scale Connectedness SCS [
Spielberger’s state-trait anxiety inventory Anxiety STAIT [
Ryff’s psychological well-being scales Well-being RPWB [ [
Cognitive and affective mindfulness scale Mindfulness CAMS [ [
Green paranoid thought scales Paranoia GPTS [ [
Big five personality inventory Personality B5 [ [
Satisfaction with life Life satisfaction SWL [ [
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were sent in a dedicated email via the Psychedelics Survey (https://www.psychedelicsurvey.com/)
service. These links had a personal ID embedded, so each test completion could be matched to
individuals.
Blind breaking and collection of guess data
Participants were asked to guess which type of capsule they had taken that day during the dose
period (for days when capsule was taken). This guess was a forced binary choice between microdose
and placebo options. At the end of the post-acute test sessions, participants were asked separately
to guess whether the current week was a microdose or a placebo week (Figure 1A). In the discussion
of our results, the term ‘break blind’ indicates that the participant guessed the capsule correctly for
the day (acute outcomes) or week (post-acute outcomes). No guess was collected about perceived
group allocation at the end of study, because information about group structure was not shared
with participants.
Statistical analysis
Group differences in demographics, recreational drug use, and baseline scores of the accumulative
outcomes were assessed with ANOVA and chi-square tests for continuous and categorical variables.
Accumulative outcomes were analyzed with mixed-effect repeated measurement models, using
the SAS PROC MIXED method with compound symmetry covariance structure. Models were con-
structed with change from baseline as the dependent variable, group,time and group*time interac-
tion as factors, and individuals as experimental unit. Models were adjusted for all significant baseline
covariates (the following variables were tested as potential covariates: age, sex, education, baseline
score, dose, total dose, short suggestibility scale score, expectation score, number of past
Figure 2. Overview of the self-blinding setup. First, capsules are prepared: microdoses are put into opaque gel capsules, while empty capsules are
used as placebos. Next, weekly sets of capsules are assembled according to the dose schedule (A; no capsules taken on Wed., Sat., and Sun.). Then,
capsules are placed inside zip bags with a printed day label (Monday, Tuesday, etc.; zip bags and day labels not shown on figure). Next, each weekly
set and a unique QR code are placed inside envelopes. Eight such weekly envelopes are prepared, four of which correspond to microdose weeks (MD)
and four that corresponds to placebo weeks (PL). The eight envelopes are used in a semi-random drawing process (orange arrow, B), which involves
another set of QR codes and random number generation, see Appendix 1—figure 1 for details. The drawing selects four envelopes, corresponding to
the 4 weeks of the dose period, while the remaining four are discarded (green arrow). The drawing is constrained such that only the three combinations
of PL/MD weeks are possible, as shown in C, each with a probability of 1/3. Panel Dshows the content of each envelope. Participants open the
corresponding envelope each week and take the matching capsule every day. Scanning the QR links to the study’s IT system and enables to decode
which capsule was taken when.
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psychiatric diagnosis, number of current psychiatric medications, number of lifetime macrodose
experiences, and number of lifetime months microdosing). To accommodate dose as a potential
covariate, psilocybin mushroom mass was converted to an estimated equivalent LSD dose (0.1 g of
dried mushroom ~4.6 mg LSD; Kaplan et al., 1994;Carbonaro et al., 2016). The following planned
comparisons were made: within-group comparisons of change over time from baseline to the pri-
mary endpoint at week 5 and from baseline to the final follow-up at week 9. Additionally, between-
group comparisons were made (PL vs. HH and PL vs. MD) at week 5 and week 9.
To analyze acute and post-acute outcomes, mixed linear models were constructed. Models
included score as dependent variable, subject ID as a random-effect, and condition as fixed-effect,
where condition was a binary categorical variable (PL/MD). For acute outcomes, condition was PL/
MD when the score was obtained under the influence of a placebo/microdose capsule, while for
post-acute outcomes condition was PL/MD when the score was obtained at the end of placebo/
microdose week. Planned comparisons were made between scores obtained under PL and MD con-
ditions. Each participant contributed four scores to these models, corresponding to the four acute/
post-acute assessment timepoints during the dose period. All acute/post-acute models were
adjusted for all significant baseline covariates (same variables were tested for significance as in the
case for the accumulative outcomes, except baseline score and total dose consumed).
To better understand how guess influenced scores, a second set of models were constructed with
the addition of guess (binary categorical variable, PL/MD) and guess*condition factors. Using these
guess adjusted models, planned comparisons were made between PL and MD conditions. Finally,
the two binary variables (condition and guess) divided the data into 2*2 = 4 strata, post-hoc compar-
isons were made between the following strata (condition/guess): PL/PL vs. MD/PL, PL/MD vs. MD/
MD, PL/PL vs. PL/MD and MD/PL vs. MD/MD. This selection was made such that condition changes
while guess remains fixed in the first two comparisons, and guess changes while condition remains
fixed in the last two comparisons.
Ethical considerations
The study only engaged people who planned to microdose through their own initiative with their
own psychedelic substance, but who consented to incorporate placebo control to make their self-
experimentation compatible with our study. Investigators did not endorse any use of psychedelics,
and no financial compensation was offered to participants. Email addresses were the only personally
identifiable data collected. The email address was retained after study completion if permission was
given (checkbox) by the participant to receive information regarding future studies, discarded other-
wise. The study was approved by Imperial College Research Ethics Committee and the Joint
Research Compliance Office at Imperial College London (ICREC reference number 18IC4518).
Results
Demographics, randomization, and completion rate
A total of 1630 participants signed-up, 240 started, and 191 participants completed the study. The
optional follow-up at week 9 was completed by 159 individuals. No statistically significant differen-
ces were found between the groups in any demographic, recreational drug use or baseline meas-
ures, confirming efficiency of the randomization (see Supplementary file 1 for details on
demographics, Supplementary file 2 for recreational drug use, and Supplementary file 3 for statis-
tical analysis of baseline variables). Completion rate was highly similar across the three groups
(
2
(12, N= 240)=0.64, p=0.99), see Figure 3.
For the most part, the sample consisted of educated, middle-age (33.5 ±9.4), healthy males (70%
male, 19% female, 1% other) from western countries. As expected, most participants had a positive
attitude toward psychedelic drugs, in particular toward medical use: 74% and 90% either agreed or
strongly agreed with the statements ’I am an active advocate of psychedelic drug-use’ and ’I am an
active advocate of the therapeutic use of psychedelics’, respectively. See Appendix for details on
the sample’s expectations/attitude about microdosing and psychedelics. The sample consisted of
healthy individuals for the most part: 33% of participants reported to have had at least one psychiat-
ric diagnosis in the past, the most frequent past diagnoses were: anxiety disorder (13%), depression
(13%), and PTSD (7%). Only 7% of the sample had current mental diagnosis.
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Microdoses
Most participants microdosed with LSD (n = 147; 61%)/LSD analogue (n = 33; 14%), followed by psi-
locybin containing mushrooms (n = 57; 24%) and three individuals used other psychedelics (LSA:
n = 1; DOB: n = 2). The average reported dose for LSD/LSD analogues was 13 ±5.5 mg, while for
psilocybin mushroom it was 0.2 ±0.12 g, see Appendix 1—figure 3 for further details.
Accumulative outcomes
Accumulative outcomes were first collected at baseline, then at week 5 (i.e. after the completion of
the 4 weeks long dose period) and at the optional long-term follow-up timepoint at week 9. The fol-
lowing two sets of pre-planned comparisons were made: within group comparisons of baseline vs.
week 5, baseline vs. week 9 (changes over time) and between-group comparisons at the week 5 and
week 9 timepoints. Sample sizes were n = 240/191/159 at baseline, week 5 and week 9, respectively.
Data was also analyzed separately for LSD/LSD-analogues and psilocybin microdoses, the results
from both subgroups matched the results of the combined analysis presented here.
For the within group (change over time) comparison of baseline vs. week 5, all self-reported psy-
chological outcomes improved significantly in the MD group: well-being (RPWB) increased with
4.2 ±3.9 (adjusted mean estimate ±95% CI; p=0.04*), mindfulness (CAMS) increased with 2.4 ±1.1
(p<0.001***), life satisfaction (SWL) increased with 1.2 ±1.2 (p=0.04*), and paranoia (GPTS)
decreased with 5.0 ±1.7 (p<0.001***). Personality structure (B5) showed reduced neuroticism trait
score (1.3 ±0.9, p<0.01**) and increased openness (0.9 ±0.8, p=0.03*). Significant changes over
the same period (from baseline to week 5) were also observed in the PL and HH groups for mindful-
ness (PL: 1.6 ±1.1, p<0.01**; HH: 1.3 ±1.2, p=0.02*) and paranoia (PL: 3.4 ±1.7 p<0.001***; HH:
4.9 ±1.9 p<0.001***), but not for well-being or life satisfaction. Neuroticism also decreased in the
PL group (1.0 ±1.0, p=0.04*). Changes in mindfulness and paranoia were sustained at the week 9
Figure 3. Flow diagram showing participation and completion rates through the study. The completion of the
4 weeks follow-up timepoint was optional.
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follow-up timepoint for all groups, while decreased neuroticism only prolonged in the MD group,
see Supplementary file 5 for details. CPS did not change in the MD group (from baseline to week
5), but significantly decreased in the HH group (0.16 ±0.14, p=0.03*). Among individual cognitive
tests over the same period, rotations (0.34 ±0.28, p=0.02*) and odd one out (0.52 ±0.31,
p=0.001**) increased significantly in the MD group, while spatial span (0.49 ±0.30, p=0.02*) and
paired associates (0.51 ±0.30, p=0.02*) decreased in the HH group. The increased rotations score
in the MD group was sustained at the follow-up (0.45 ±0.46, p<0.01**), but not the other task
scores.
Planned comparisons revealed no significant between-group differences at either the week 5 or
week 9 follow-up timepoints, including all subscales, except that in the HH group the paired associ-
ates scores decreased (PL vs HH adjusted treatment difference: 0.55 ±0.43, p<0.01**). Time
course of the adjusted mean estimates is summarized in Figure 4. See Supplementary file 4 for
descriptive statistics, including subscale and individual cognitive test scores, adjusted over time and
between group differences (Supplementary file 5), and model parameters (Supplementary file 6).
Accumulative outcomes adjusted for number of microdose guesses
As secondary analysis to further examine the role of placebo-like expectation effects in the accumu-
lative outcomes, we performed a post-hoc adjustment by adding the ‘number of times microdose
capsule was guessed’ variable as a covariate to the models (irrespective whether the guess was cor-
rect or not). This variable was significant for some models (RPWB: p<0.01**; CAMS: p=0.02*; B5
agreeableness: p=0.02*; B5 openness: p=0.03*) and further decreased the already small between-
Figure 4. Each panel shows the adjusted mean estimate of the change from baseline and the 95% CI for the accumulative outcomes. Top horizontal
bars represent the over time comparisons for each group (from baseline to post-regime [week 5] and from baseline to follow-up). Symbols on top of
bars show the significance for the PL/HH/MD groups, respectively (e.g. change from baseline to post-regime in well-being was significant for the MD
group, but not significant for the other two groups, see legend). There was no significant between-groups difference at any timepoint for any scale.
Sample size was 240/191/159 at the pre-, post-regime and 4 weeks follow-up timepoints, respectively. See Supplementary files 4,5, and 6for the
unadjusted descriptive statistics, adjusted mean differences (and their significance) associated with both over time and between group comparisons
and model parameters, respectively.
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group differences on self-reported scales, while it did not affect cognitive outcomes. Specifically, the
adjusted treatment difference (±95% CI) at the week 5 timepoint between PL and MD groups with-
out/with the number of MD guesses covariate was: well-being (RPWB) 2.5 ±5.6 (p=0.37)/0.9 ±5.7
(p=0.76), mindfulness (CAMS): 0.8 ±1.5 (p=0.32)/0.4 ±1.5 (p=0.65), paranoia (GPTS): 1.6 ±2.5
(p=0.21)/1.2 ±2.5 (p=0.36), life satisfaction (SWL) 0.4 ±1.7 (p=0.67)/0.2 ±1.8 (p=0.83), B5 intel-
lect: 0.2 ±1.2 (p=0.80)/0.2 ±1.2 (p=0.71), B5 openness: 0.3 ±1.2 (p=0.57)/0.0 ±1.2 (p=0.97), B5
neuroticism: 0.3 ±1.4 (p=0.70)/0.1 ±1.4 (p=0.87), B5 extraversion: 0.2 ±1.2 (p=0.81)/
0.4 ±1.3 (p=0.52), B5 agreeableness: 0.5 ±1.1 (p=0.37)/0.2 ±1.1 (p=0.75), and B5 consciousness:
0.8 ±1.3 (p=0.24)/0.5 ±1.3 (p=0.44).
Acute and post-acute outcomes
First, outcomes are described without considering the guess component, which is discussed in the
next section. Acute outcomes were measured during the dose period while the potential microdose
was still active, while post-acute outcomes were measured every Sunday, when no capsule was
taken, 48–72 hr after the last placebo/microdose capsule. For psychological measures the average
sample size was 857 (between 849 and 884 due to partial completions; participants contributed four
scores corresponding to the four acute timepoints, see Materials and methods for details), while for
cognitive performance it was 684 (between 678 and 689). Data was also analyzed separately for
LSD/LSD-analogues and psilocybin microdoses, and the results from both subgroups matched the
results of the combined analysis presented here.
Among acute measures, condition (PL vs. MD) was significant for acute emotional state (PANAS)
(adjusted mean estimate ±95% CI: 2.2 ±1.4, p<0.01**) and the acute drug intensity (12.5 ±3.0,
p<0.001***), mood (4.6 ±2.9, p<0.001***), energy (5.3 ±2.7, p<0.001***), and creativity (4.7 ±2.6,
p<0.001***) VASs, meaning that scores collected on days when a microdose was taken were signifi-
cantly higher compared to scores collected on placebo days. Effect sizes, as quantified by Cohen’s
d, remained small (d< 0.3) on all scales, with the exception of the drug intensity VAS (d= 0.58).
Among post-acute measures, condition was significant only on the anxiety measure (STAIT;
1.4 ±1.3, p=0.03*), meaning that anxiety was reduced at the end of microdose weeks compared
with placebo weeks, see Table 2 for details on both acute and post-acute outcomes.
Association between guess and acute/post-acute outcomes
Next, the acute and post-acute results were re-analyzed with the addition of guess into the models.
Condition (PL vs. MD) was no longer significant for any scale, except for acute drug intensity VAS
(adjusted mean difference ±95% CI: 3.4 ±2.0; p<0.001***), which increased under MD (Table 2).
The guess*condition interaction term was non-significant for all scales, except for drug intensity
(p<0.01**).
To better understand the role of guess, the data was further analyzed by comparing the 2*2 = 4
strata formed by the two binary variables, condition (PL/MD), and guess (PL/MD), in the models. For
self-reported outcomes, no significant differences were found between microdose and placebo con-
ditions with fixed guess (condition/guess: PL/PL vs. MD/PL and PL/MD vs. MD/MD comparisons),
except for acute drug intensity visual analogue scale, which was higher when microdose was taken
(adj. mean difference ±95% CI; 7.3 ±3.1, p<0.001***). Conversely, when drug condition was fixed
(condition/guess: PL/PL vs. PL/MD and MD/PL vs. MD/MD comparisons), significant differences were
found in 21 of the 22 comparisons (=2*conditions*(4*post-acute+7*acute scales)), all favoring MD
guess. These findings suggest that scores are significantly better when the participant believed they
had taken a microdose irrespective of what was actually taken. Taking an actual microdose was only
associated with a significant difference in the drug intensity scale. Figure 5 shows the stratified dis-
tribution of selected outcomes, see Supplementary file 8 for all comparisons.
Blinding integrity
Break blind rate, defined as the proportion of correct capsule guesses (see section Blind breaking
and collection of guess data for details), was 0.72 ±0.18 (M ±SD). Specificity (true negative rate:
ratio of true placebo guesses to all placebo guesses) was 0.82 ±0.16, noticeably higher than sensitiv-
ity (true positive rate: ratio of true microdose guesses to all microdose guesses) 0.45 ±0.30, mean-
ing that placebo capsules were guessed correctly at a higher rate than microdoses. Based on
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knowledge of the ratio of PL/MD capsules (3/1) in the envelopes, which is evident to participants
when they prepare the capsules, a ‘random guesser’ would have a break blind rate of 0.62 with 0.75
specificity and 0.25 sensitivity. The high sensitivity exhibited by participants (0.46 vs. the random
guesser’s 0.25) suggests that the higher than random break blind rate is mostly due to superior abil-
ity to identify microdoses, see Appendix 1—table 1 for details.
Break blind rate was positively associated with reported microdose dose (F(1, 237)=7.4,
p<0.01**), meaning that the higher the dose was, the more likely participants guessed their daily
condition correctly. For this analysis psilocybin mushroom doses were converted to estimated LSD
dose equivalent, see Statistical analysis in Materials and methods for details. The estimated ‘detec-
tion threshold’, that is, the dose above which participants guess significantly better than random,
was 12 mg.
Table 2. Summary of acute and post-acute outcomes.
Acute outcomes were measured on dosing days (Thursdays), while the potential microdose was still active, comparison is made
between scores obtained under the influence of microdose vs placebo capsules. Post-acute outcomes were measured at the end of
the weeks (Sundays), when no capsule was taken, and comparison is made between scores obtained at the end of placebo weeks vs
microdose weeks. For the psychological measures (all except CPS) the sample size was 857 (participants contributed four scores corre-
sponding to the four acute/post-acute assessment timepoints during the dose period), while for cognitive performance it was 684. The
first three columns show the unadjusted, observed scores and Cohen’s dbetween the two conditions (PL/MD). In the next column,
results from the models without the guess component are shown, and last column shows model results with the guess component,
each cell shows the adjusted mean difference ±95% CI of condition (PL vs. MD, where PL is used as baseline), see
Materials and methods for details. Individual subscales/sub-tasks are shown when they exist (in the Test column, ‘X – y’ denotes that y
is a subscale or sub-test of X).
Observed scores Model wo. guess Model with guess
Test PL (M ±95% CI) MD (M ±95% CI) Cohen’s dM±95% CI M ±95% CI
Acute outcomes
Acute mood (PANAS) 14.2 ±0.9 16.2 ±1.1 0.19 2.2 ±1.4** 0.9 ±1.4
PANAS – positive 29.9 ±0.7 31.6 ±0.8 0.22 2.0 ±1.0*** 0.8 ±1.0
PANAS – negative 15.7 ±0.5 15.4 ±0.5 0.06 0.4 ±0.7 0.3 ±0.8
Daily effects VAS – intensity 8.5 ±1.6 21.4 ±2.7 0.58 12.5 ±3.0*** 3.4 ±2.0***
Daily effects VAS – energy 55.3 ±1.8 60.7 ±2.1 0.27 5.3 ±2.7*** 2.4 ±2.8
Daily effects VAS – mood 60.5 ±1.8 64.7 ±2.2 0.20 4.6 ±2.9*** 1.5 ±2.8
Daily effects VAS – creativity 53.5 ±1.6 58.3 ±2.0 0.25 4.7 ±2.6*** 1.8 ±2.6
Daily effects VAS – focus 57.3 ±1.7 58.7 ±2.1 0.07 1.3 ±2.8 0.6 ±2.8
Daily effects VAS – temper 36.5 ±2.0 36.0 ±2.5 0.02 1.3 ±3.2 0.1 ±3.2
Cognition (CPS) 0.08 ±0.05 0.06 ±0.07 0.05 0.05 ±0.08 0.04 ±0.07
CPS – rotations 0.09 ±0.09 0.06 ±0.11 0.03 0.11 ±0.14 0.12 ±0.14
CPS – odd one out 0.02 ±0.11 0.14 ±0.1 0.12 0.09 ±0.16 0.08 ±0.16
CPS – spatial planning 0.11 ±0.1 0.1 ±0.11 0.00 0.04 ±0.14 0.03 ±0.14
CPS – spatial span 0.18 ±0.09 0.18 ±0.11 0.00 0.01 ±0.14 0.02 ±0.14
CPS – feature match 0.06 ±0.09 0.05 ±0.13 0.00 0.05 ±0.15 0.07 ±0.16
CPS – paired associates 0.1 ±0.09 0.11 ±0.12 0.02 0.05 ±0.15 0.05 ±0.15
Post-acute outcomes
Mental well-being (WEMWB) 49.7 ±0.8 49.8 ±0.7 0.02 0.9 ±1.0 0.1 ±1.0
Depression (QIDS) 5.6 ±0.5 5.5 ±0.4 0.03 0.3 ±0.6 0.1 ±0.6
Anxiety trait (STAI-T) 38.5 ±1.2 38.1 ±1.0 0.04 1.5 ±1.3* 0.1 ±0.6
Social conn. (SCS) 32.1 ±0.7 32.1 ±0.6 0.00 0.1 ±0.8 0.3 ±0.8
*=p<0.05; **=p<0.01; ***=p<0.001.
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Discussion
We employed a novel self-blinding methodology to investigate the acute, post-acute, and long-
term, accumulative effects of psychedelic microdosing. To the best of our knowledge, this study is
the first one to use a self-blinding methodology, the first placebo-controlled investigation of the
accumulative effects of repeated microdosing, and the largest placebo-controlled psychedelic study
to-date.
When looking at changes over time from baseline to week 5 (accumulative outcomes) in the
microdose group alone, results confirmed the psychological benefits reported by anecdotes
(Fadiman and Krob, 2017) and observational, uncontrolled studies (Anderson et al., 2019;
Polito and Stevenson, 2019;Prochazkova et al., 2018): significant improvements were observed in
the domains of well-being, mindfulness, life satisfaction, and paranoia. However, when looking at
the between-group comparisons of the same outcomes, no significant differences were found
between the placebo and microdose groups. On the cognitive tests, which are less subjective than
the self-reported psychological outcomes, the microdose group did not even improve from baseline
to week 5 and the between-groups comparisons were not significant either. Thus, our study vali-
dates the positive anecdotal reports about the psychological benefits of microdosing (significant
improvements from baseline in a broad range of psychological measures); however, our results also
suggest that these improvements are not due to the pharmacological action of microdosing, but are
rather explained by the placebo effect (lack of significant between-groups differences).
Figure 5. Acute and post-acute outcomes stratified by guess and condition. On each panel, the four bars represent the adjusted mean estimates and
the associated 95% CI of the four strata corresponding to the four combinations of guess (PL/MD) and condition (PL/MD). For the psychological
measures (all, but CPS) the sample size was 857 (participants contributed four scores corresponding to the four acute/post-acute assessment timepoints
during the dose period), while for cognitive performance it was 684, see bottom of each panel for the condition, guess, and the proportion of scores in
the given strata. Top horizontal lines represent comparisons between strata derived from the models. The two short lines on top are the comparisons
between PL and MD conditions with fixed guess, while the two longer lines below are the comparisons between PL and MD guesses with fixed drug
condition, see Supplementary file 8 for numerical results. Note that for all self-reported outcomes, change in guess is almost always significant, while a
change in condition is never significant. In the case of cognitive performance, neither change in guess nor change in condition is significant.
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Similar conclusions can be drawn from the examination of the acute and post-acute outcomes as
well. In our initial analysis without incorporation of the guess component, we detected significant
effects on post-acute anxiety (STAIT), acute emotional state (PANAS), and mood,energy,creativity,
and drug intensity (visual analogue scale items). Effect sizes were small on all scales (Cohen’s d < 0.3
except drug intensity); thus, the clinical and practical value of these effects is debatable. Further-
more, when the guess component was added to the models, the already small differences disap-
peared on all scales, except for acute drug intensity. It can be argued that the addition of the guess
variable to the models may undermine the statistical significance of the condition effect due to col-
linearity between condition and guess. To overcome this potential issue, we conducted the stratifica-
tion analysis where only one of these variables is changing, while the other remains fixed. No
significant differences were observed between placebo and microdose conditions when the guess
was fixed (condition/guess; PL/PL vs. MD/PL and PL/MD vs. MD/MD comparisons), except for drug
intensity (MD>PL). Conversely, when condition was fixed (PL/PL vs. PL/MD and MD/PL vs. MD/MD
comparisons), scores obtained under placebo and microdose guesses were significantly different in
21 out of the 22 comparisons, always favoring the microdose guess, see Figure 5 and
Supplementary file 8. Importantly, neither CPS nor any cognitive subtask, the non-self-rated out-
comes where beliefs and subjective feelings are likely to be less influential, were significantly differ-
ent under either guess or drug conditions. In summary, these results strongly suggest that the actual
content of capsules did not determine differences between the conditions, but beliefs about their
content did.
An important observation was that participants guessed their capsules correctly in 72% of the
cases. This break blind rate was higher than random (random: 63% vs. participants: 72%), but not as
high as reported in antidepressant studies (around 80%) (Chen et al., 2011;Kirsch, 2019;
Rabkin et al., 1986). It is known from a variety of clinical studies that higher break blind rate is asso-
ciated with larger between-conditions effect-sizes (where placebo is the control condition)
(Baethge et al., 2013;Berna et al., 2017;Laferton et al., 2018). This relationship is explained by
non-specific treatment factors such as expectation of a benefit (Bausell, 2009) and investigator alli-
ance (Chatoor and Kurpnick, 2001). The influence of such factors is likely to be large for the present
study, because of highly positive expectations and favorable attitudes toward psychedelics, see atti-
tude analysis in the Appendix. These factors together suggest that the observed ‘significant’ acute
and post-acute effects may be an artifact of the combination of break blinds and expected benefits.
The acute and post-acute results observed could be understood as the difference between the
expected benefits when a microdose is perceived (i.e. guessed by participants) versus the absence
of expected benefits when placebo is perceived. This difference in expectations could be mistaken
for a ‘real’ drug effect in any study where blinding integrity is not considered during analysis. If this
explanation is correct, one prediction for future microdose studies with a similarly pro-psychedelics
sample is that they may observe larger effects when break blind rate is higher, or conversely, smaller
effects when break blind rate is lower.
What factors account for the blind breaking? Drug intensity was the only outcome that remained
significant even after adjusting for guess (3.4 ±2.0; p<0.001***). This observation suggests that drug
intensity is a small, but true drug effect. This increased drug intensity mostly manifested as body and
perceptual sensations, see Blind breaking cues in Appendix 1 for details. This finding suggests that
in most cases blind breaking induced clinically irrelevant side effects, rather than deduced from
improvements of outcome variables. We note that according to our data the threshold LSD dose
where participants guess better than random is 12 mg, see Figure 4, which is in line with the 13 mg
threshold dose estimated by a recent dose controlled study (Bershad et al., 2019a).
It is worth noting that the current study was designed to protect blinding integrity by including
placebos for the microdose group as well, administering the microdose capsules on different days of
the week and by including the half-half group. The 3-arm design can be seen as a strength in this
regard, adding ambiguity and thus strengthening blinding. Illustrative of the integrity of the blind,
we received several emails from participants in the PL group who were in disbelief after opening
their unused envelopes containing unused capsules after the conclusion of the study:
.“I counted the number of cut blotters I had in the left overs: they are 8...so you must be right...
Which is incredible [. . .] Some days during the test were really, really focused and colours more
vivid. This sensation was really new to me".
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."I have just checked the remaining envelopes and it appears that I was indeed taking placebos
throughout the trial. I’m quite astonished [...] It seems I was able to generate a powerful
’altered consciousness’ experience based only the expectation around the possibility of a
microdose".
."An empty pill with strong belief/intentions makes nearly everything. You put spirituality into
an empty pill here...wow!"
Limitations
It is our view that the present part-controlled, part-observational design yields data superior to con-
ventional observational data (inclusion of placebo control), but inferior to controlled clinical trial data
(incomplete control over recruitment, screening, assessment, drug administration, etc.). This study
does, however, have greater ecological validity than would a fully controlled lab study.
A key limitation of the present study is the lack of verification of the nature, purity, and dosage of
the psychedelic substance used for microdosing. Psilocybin-containing mushrooms were used by
23% of the sample, 14% used legal LSD analogues (such as 1P-LSD), whereas 62% sourced their sub-
stance from the black market, mostly LSD (61%). According to the Energy Control’s drug checking
service (Barcelona), LSD blotter adulteration rates were low during the period when our study was
running: in both 2018 and 2019 blotters sold as LSD contained LSD only in 90% (n = 735) of tested
samples [personal communication with M. Ventrua from EC, June 2020]. The exact quantity of active
ingredient within a given microdose cannot be known with certainty; however, the positive relation-
ship between dose and blind breaking (Figure 4) and that the threshold dose for psychoactivity was
consistent with a recent controlled study (12 mg vs 13 mg; Bershad et al., 2019a) provide some reas-
surance. Nonetheless, our results should be not understood as clinical evidence, rather they are rep-
resentative of ‘real life microdosing’.
We could not confirm whether participants followed accurately the self-blinding procedure. Three
individuals reported following an invalid sequence of weeks, but these individuals did their setups
together, all committing the same mistake (1.3% error rate). Furthermore, we had no way of confirm-
ing whether the capsules were taken as instructed during the dose period. Instructions emphasized
not to complete assessments planned on dosing days in case the dose schedule could not be fol-
lowed for any reason, but we could not confirm whether participants adhered to this rule.
Our stratification analysis does not allow for a strict determination of a causal relationship
between guess and outcome, because guess was recorded after completion of assessments, guess
was last question during test sessions. After closing the study, a survey was conducted among partic-
ipants, where 86% (n = 166) responded that "I was thinking about whether I took a microdose or
placebo even before I was asked to guess" (opposed to "I was not thinking about whether I took a
microdose or placebo, except when I was asked to guess"), making a causal interpretation more
likely. We note that the order we chose is consistent with previous work in psychiatric studies
(Baethge et al., 2013;Chen et al., 2011;Rabkin et al., 1986); had the guesses been requested
prior to the assessments, it could have primed responses. Also, we cannot rule out that performance
during the assessments influenced the guess. However, the lack of any feedback from the assess-
ments mitigates this risk. Most participants reported to break blind due to body and perceptual sen-
sations, rather than improved outcomes, see Blind breaking cues in the Appendix for details.
We cannot rule out the possibility that a study in a clinical population would yield more promising
results. In the present healthy sample, where well-being scores are high at baseline, there is less
scope for potential improvements, which could have prevented the observation of placebo-micro-
dose differences. Most study participants reported not to have any history of mental health prob-
lems; only 7% reported having a current psychiatric diagnosis, and 33% reported to have had a
psychiatric diagnosis in the past (Supplementary file 1). We conducted two post-hoc analysis for
two selective pseudo-depression subsamples: participants with the lowest 25% baseline well-being
scores and those with the highest 25% baseline neuroticism scores (Ryff and Keyes, 1995;
Wood and Joseph, 2010). Results in these subsamples were entirely consistent with those from the
complete sample: there were no significant differences between conditions for any of the accumula-
tive outcomes (adjusted treatment difference ±95% CI of PL vs MD at week 5 for the lowest 25%
baseline well-being subsample: well-being (RPWB) 1.6 ±13.6 (p=0.81), mindfulness (CAMS)
0.3 ±3.3 (p=0.85), paranoia (GPTS) 5.1 ±6.8 (p=0.14), life satisfaction (SWL) 0.3 ±4.5 (p=0.87),
cognition (CPS) 0.1 ±0.55 (p=0.71); same measures for the highest 25% baseline neuroticism
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subsample: well-being (RPWB) 4.8 ±14.3 (p=0.50), mindfulness (CAMS) 1.3 ±3.7 (p=0.49), paranoia
(GPTS) 3.1 ±8 (p=0.43), life satisfaction (SWL) 1.4 ±4.6 (p=0.53), cognition (CPS) 0.04 ±0.67
(p=0.90)). Thus, although not designed as a clinical study, data from this opportunistic naturalistic
study do not provide support for clinical effects of microdosing.
Although this was the largest placebo-controlled psychedelic research study published to-date,
we note that one could argue that the study was still underpowered to detect a true effect based on
the fact that the MD group did improve more than the PL group on all scales (from baseline to week
5), but just not to a statistically significant extent (Figure 4). On the well-being scale (RPWB), the
adjusted PL vs. MD group difference was 2.5 ±5.6 points. To illustrate this difference in practice,
this scale consists of 42 statements that participants rate on a 6-point Likert scale (Strongly disagree
- Strongly agree), thus, the full range of scores is thus 0–252, so the 2.5 point mean difference is 1%
of the total scale. This difference is equivalent to scoring one item, for example ‘I like most aspects
of my personality’,Strongly agree instead of Slightly agree or Slightly disagree, while responding
the same to the remaining 41 items. Based on our data, we calculated that the sample size (90%
power and alpha of 0.05) required to observe a true between-group difference would be: 1508 for
well-being (RPWB), 1638 for mindfulness (CAMS), 4918 for life satisfaction (SWL), 1392 for paranoia
(GPTS), and 366 for cognitive performance (CPS). These differences therefore are not clinically
meaningful or sufficient to justify the cost of intervention.
Future directions
The successful execution of this initiative here may inspire similar initiatives throughout the world in
a broad range of scientific and medical contexts. Controlling for placebo effects is important for
trending phenomena, such as cannabidiol (CBD) oils, nootropics, and nutrition, where social-pres-
sure, expectancy, positive-test strategies, and confirmation bias can lead to false-positive findings.
Self-blinding citizen-science initiatives could be employed in these areas as a cost-efficient screening
tool prior to conducting expensive clinical studies.
An important feature of the self-blinding methodology is the low cost; we estimate that the cur-
rent study’s costs were about 0.5–1% of an equivalent clinical study. Since the research team is not
providing the study drug/placebo and on-site staffing is not required, expenses are similar to a con-
ventional observational study, yet still with incorporation of randomization and placebo control.
Important lessons can be taken from the current study for the design of future microdosing trials.
The combination of the lack of detected efficacy in this study and an association between self-
reported doses and ability to break blind (see Figure 4) suggest that selecting dosage is fraught
with difficulties: if a low microdose is chosen, efficacy is unlikely if we extrapolate current results,
whereas a high microdose could jeopardize the blinding. Randomization to microdose versus an
active placebo conditions (e.g. niacin, which has been employed in macrodosing studies Ross et al.,
2016) and careful assessment of blinding could, in principle, alleviate some of these concerns.
The present study also has implications for full/‘macrodose’ psychedelic studies, where blinding is
impossible due to the intense nature of the experience. It can be hypothesized that the intense hallu-
cinations are essential for therapeutic outcome (Griffiths et al., 2011;Roseman et al., 2017), ques-
tioning the suitability of placebo-controlled trials in this context. The fact that one may be unable to
fully extricate belief, or ‘context’ more broadly, from the direct (e.g. pharmacological) action of a
given intervention, raises interesting philosophical and ethical question with implications for drug
development and regulation. One might also hypothesize that the action of microdosing and psy-
chedelics relies on prior and continuously updating belief combining (perhaps synergistically) with a
direct drug effect (Carhart-Harris et al., 2015;Carhart-Harris and Friston, 2019). Such a positive
interaction could, in theory, be tested (Carhart-Harris et al., 2018), and if endorsed, this could be
interpreted as implying that belief is an active component of the psychedelic treatment model,
rather than a problematic confound.
In summary, here we created a novel, cost-effective, self-blinding, citizen-science methodology
that enabled us to conduct the largest placebo-controlled study on psychedelics to-date and the first
placebo-controlled examination of repeated psychedelic microdosing. Our findings confirm the
anecdotal benefits of microdosing (improvements in a broad range of psychological measures); how-
ever, the results also suggest that the improvements are not due to the pharmacological action of
microdosing, but are rather explained by the placebo effect (lack of significant between-groups
effect).
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Acknowledgements
We are grateful for the Beckley foundation for providing funds for the study. This project could have
not happened without the contributions of many individuals; we are grateful to (no particular order):
Kenneth Jønck, Nicolai Lassen, Matt Wilson, Ahnjili Zhuparris, Gergely Kovacs, Haribacsi, Peter Sos,
Ga´ bor Menko´ , Kitti Borissza, Alvegi Lo´ ci, Juci Kele, Mike Doneghan, Zsuzsanna Nyitray, Valerie Bon-
nelle, Hein Pijnnaken, and Peter Sarosi. Last, but not the least, we would like to express our grati-
tude for all study participants, thank you all for making it happen!
Additional information
Funding
No external funding was received for this work.
Author contributions
Bala´ zs Szigeti, Conceptualization, Data curation, Software, Formal analysis, Investigation, Visualiza-
tion, Methodology, Writing - original draft, Project administration, Writing - review and editing;
Laura Kartner, Investigation, Writing - original draft, Writing - review and editing; Allan Blemings,
Data curation, Formal analysis, Validation, Investigation; Fernando Rosas, Investigation, Writing -
review and editing; Amanda Feilding, Funding acquisition, Writing - review and editing; David J
Nutt, Robin L Carhart-Harris, Supervision, Writing - review and editing; David Erritzoe, Supervision,
Investigation, Methodology, Writing - original draft, Writing - review and editing
Author ORCIDs
Bala´ zs Szigeti https://orcid.org/0000-0003-3809-6442
Fernando Rosas https://orcid.org/0000-0001-7790-6183
David J Nutt https://orcid.org/0000-0002-1286-1401
Ethics
Human subjects: Informed consent was obtained from all participants. The study was approved by
Imperial College Research Ethics Committee and the Joint Research Compliance Office at Imperial
College London (ICREC reference number 18IC4518).
Decision letter and Author response
Decision letter https://doi.org/10.7554/eLife.62878.sa1
Author response https://doi.org/10.7554/eLife.62878.sa2
Additional files
Supplementary files
.Supplementary file 1. Sample demographics.
.Supplementary file 2. Recreational drug use of sample.
.Supplementary file 3. Baseline comparison of groups.
.Supplementary file 4. Unadjusted accumulative scores.
.Supplementary file 5. Adjusted accumulative differences.
.Supplementary file 6. Accumulative model parameters.
.Supplementary file 7. Acute model parameters.
.Supplementary file 8. Adjusted strata differences.
.Transparent reporting form
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Research article Medicine Neuroscience
Data availability
All data is shared in CSV format at https://github.com/balazs1987/mcrds_public/tree/master/data
(copy archived at https://archive.softwareheritage.org/swh:1:rev:43bb44cc8b6b79536e4b2afd0a7-
c724e90f137f7/) together with appropriate documentation.
References
Anderson T, Petranker R, Rosenbaum D, Weissman CR, Dinh-Williams LA, Hui K, Hapke E, Farb NAS. 2019.
Microdosing psychedelics: personality, mental health, and creativity differences in microdosers.
Psychopharmacology 236:731–740. DOI: https://doi.org/10.1007/s00213-018-5106-2,PMID: 30604183
Baethge C, Assall OP, Baldessarini RJ. 2013. Systematic review of blinding assessment in randomized controlled
trials in schizophrenia and affective disorders 2000-2010. Psychotherapy and Psychosomatics 82:152–160.
DOI: https://doi.org/10.1159/000346144,PMID: 23548796
Bausell RB. 2009. Snake Oil Science: The Truth About Complementary and Alternative Medicine. Oxford
University Press.
Berna C, Kirsch I, Zion SR, Lee YC, Jensen KB, Sadler P, Kaptchuk TJ, Edwards RR. 2017. Side effects can
enhance treatment response through expectancy effects: an experimental analgesic randomized controlled
trial. Pain 158:1014–1020. DOI: https://doi.org/10.1097/j.pain.0000000000000870,PMID: 28178072
Bershad AK, Schepers ST, Bremmer MP, Lee R, de Wit H. 2019a. Acute subjective and behavioral effects
of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers. Biological Psychiatry 86:792–800.
DOI: https://doi.org/10.1016/j.biopsych.2019.05.019,PMID: 31331617
Bershad AK, Preller KH, Lee R, Keedy S, Wren-Jarvis J, Bremmer MP, de Wit H. 2019b. Preliminary report on the
effects of a low dose of LSD on resting state amygdalar functional connectivity. Biological Psychiatry: Cognitive
Neuroscience and Neuroimaging 5:461–467. DOI: https://doi.org/10.1016/j.bpsc.2019.12.007
Carbonaro TM, Bradstreet MP, Barrett FS, MacLean KA, Jesse R, Johnson MW, Griffiths RR. 2016. Survey study
of challenging experiences after ingesting psilocybin mushrooms: acute and enduring positive and negative
consequences. Journal of Psychopharmacology 30:1268–1278. DOI: https://doi.org/10.1177/
0269881116662634,PMID: 27578767
Carhart-Harris RL, Kaelen M, Whalley MG, Bolstridge M, Feilding A, Nutt DJ. 2015. LSD enhances suggestibility
in healthy volunteers. Psychopharmacology 232:785–794. DOI: https://doi.org/10.1007/s00213-014-3714-z,
PMID: 25242255
Carhart-Harris RL, Roseman L, Haijen E, Erritzoe D, Watts R, Branchi I, Kaelen M. 2018. Psychedelics and the
essential importance of context. Journal of Psychopharmacology 32:725–731. DOI: https://doi.org/10.1177/
0269881118754710,PMID: 29446697
Carhart-Harris RL, Friston KJ. 2019. REBUS and the anarchic brain: toward a unified model of the brain action of
psychedelics. Pharmacological Reviews 71:316–344. DOI: https://doi.org/10.1124/pr.118.017160,PMID: 31221
820
Carhart-Harris RL, Goodwin GM. 2017. The therapeutic potential of psychedelic drugs: past, present, and future.
Neuropsychopharmacology 42:2105–2113. DOI: https://doi.org/10.1038/npp.2017.84,PMID: 28443617
Chatoor I, Kurpnick J. 2001. The role of non-specific factors in treatment outcome of psychotherapy studies.
European Child & Adolescent Psychiatry 10:S19–S25. DOI: https://doi.org/10.1007/s007870170004
Chen JA, Papakostas GI, Youn SJ, Baer L, Clain AJ, Fava M, Mischoulon D. 2011. Association between patient
beliefs regarding assigned treatment and clinical response: reanalysis of data from the Hypericum depression
trial study group. The Journal of Clinical Psychiatry 72:1669–1676. DOI: https://doi.org/10.4088/JCP.
10m06453,PMID: 22053942
Costa PT, McCrae RR. 1992. Four ways five factors are basic. Personality and Individual Differences 13:653–665.
DOI: https://doi.org/10.1016/0191-8869(92)90236-I
Devilly GJ, Borkovec TD. 2000. Psychometric properties of the credibility/expectancy questionnaire. Journal of
Behavior Therapy and Experimental Psychiatry 31:73–86. DOI: https://doi.org/10.1016/S0005-7916(00)00012-4,
PMID: 11132119
DeYoung CG. 2015. Openness/intellect: A dimension of personality reflecting cognitive exploration. In:
Mikulincer M, Shaver P. R, Cooper M. L, Larsen R. J (Eds). APA Handbook of Personality and Social Psychology.
American Psychological Association. p. 369–399. DOI: https://doi.org/10.1037/14343-017
Diener E, Emmons RA, Larsen RJ, Griffin S. 1985. The satisfaction with life scale. Journal of Personality
Assessment 49:71–75. DOI: https://doi.org/10.1207/s15327752jpa4901_13,PMID: 16367493
Fadiman J, Krob S. 2017. Microdosing: the phenomenon, research results, and startling surprises. Lecture
Presented at the Psychedelic Science 2017 Conference.
Family N, Maillet EL, Williams LTJ, Krediet E, Carhart-Harris RL, Williams TM, Nichols CD, Goble DJ, Raz S. 2020.
Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in
healthy older volunteers. Psychopharmacology 237:841–853. DOI: https://doi.org/10.1007/s00213-019-05417-
7,PMID: 31853557
Feldman G, Hayes A, Kumar S, Greeson J, Laurenceau J-P. 2007. Mindfulness and emotion regulation: the
development and initial validation of the cognitive and affective mindfulness Scale-Revised (CAMS-R). Journal
of Psychopathology and Behavioral Assessment 29:177–190. DOI: https://doi.org/10.1007/s10862-006-9035-8
Szigeti et al. eLife 2021;10:e62878. DOI: https://doi.org/10.7554/eLife.62878 17 of 26
Research article Medicine Neuroscience
Green CE, Freeman D, Kuipers E, Bebbington P, Fowler D, Dunn G, Garety PA. 2008. Measuring ideas of
persecution and social reference: the green et al. paranoid thought scales (GPTS). Psychological Medicine 38:
101–111. DOI: https://doi.org/10.1017/S0033291707001638,PMID: 17903336
Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R. 2011. Psilocybin occasioned mystical-
type experiences: immediate and persisting dose-related effects. Psychopharmacology 218:649–665.
DOI: https://doi.org/10.1007/s00213-011-2358-5,PMID: 21674151
Haijen E, Kaelen M, Roseman L, Timmermann C, Kettner H, Russ S, Nutt D, Daws RE, Hampshire ADG, Lorenz R,
Carhart-Harris RL. 2018. Predicting responses to psychedelics: a prospective study. Frontiers in Pharmacology
9:897. DOI: https://doi.org/10.3389/fphar.2018.00897,PMID: 30450045
Hampshire A, Highfield RR, Parkin BL, Owen AM. 2012. Fractionating human intelligence. Neuron 76:1225–
1237. DOI: https://doi.org/10.1016/j.neuron.2012.06.022,PMID: 23259956
Hutten N, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, Varghese N, Eckert A, Feilding A,
Ramaekers JG, Kuypers KPC. 2020a. Low doses of LSD acutely increase BDNF blood plasma levels in healthy
volunteers. ACS Pharmacology & Translational Science 31:99. DOI: https://doi.org/10.1021/acsptsci.0c00099
Hutten N, Mason NL, Dolder PC, Theunissen EL, Holze F, Liechti ME, Feilding A, Ramaekers JG, Kuypers KPC.
2020b. Mood and cognition after administration of low LSD doses in healthy volunteers: a placebo controlled
dose-effect finding study. European Neuropsychopharmacology 41:81–91. DOI: https://doi.org/10.1016/j.
euroneuro.2020.10.002,PMID: 33082016
Kaplan H, Sadock BJ, Grebb JA. 1994. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences, Clinical
Psychiatry. Williams and Wilkins Co.
Kirsch I. 2019. Placebo effect in the treatment of depression and anxiety. Frontiers in Psychiatry 10:407.
DOI: https://doi.org/10.3389/fpsyt.2019.00407,PMID: 31249537
Kotov RI, Bellman SB, Watson DB. 2004. Short Suggestibility Scale: DSpace Repository. https://ir.stonybrook.
edu/xmlui/handle/11401/66801?show=full.
Kuypers KP, Ng L, Erritzoe D, Knudsen GM, Nichols CD, Nichols DE, Pani L, Soula A, Nutt D. 2019. Microdosing
psychedelics: more questions than answers? an overview and suggestions for future research. Journal of
Psychopharmacology 33:1039–1057. DOI: https://doi.org/10.1177/0269881119857204,PMID: 31303095
Laferton JAC, Vijapura S, Baer L, Clain AJ, Cooper A, Papakostas G, Price LH, Carpenter LL, Tyrka AR, Fava M,
Mischoulon D. 2018. Mechanisms of perceived treatment assignment and subsequent expectancy effects in a
double blind placebo controlled RCT of major depression. Frontiers in Psychiatry 9:424. DOI: https://doi.org/
10.3389/fpsyt.2018.00424,PMID: 30245644
Lee RM, Robbins SB. 1995. Measuring belongingness: the social connectedness and the social assurance scales.
Journal of Counseling Psychology 42:232–241. DOI: https://doi.org/10.1037/0022-0167.42.2.232
McCrae RR, John OP. 1992. An introduction to the five-factor model and its applications. Journal of Personality
60:175–215. DOI: https://doi.org/10.1111/j.1467-6494.1992.tb00970.x,PMID: 1635039
Nutt D, Erritzoe D, Carhart-Harris R. 2020. Psychedelic psychiatry’s Brave New World. Cell 181:24–28.
DOI: https://doi.org/10.1016/j.cell.2020.03.020,PMID: 32243793
Polito V, Stevenson RJ. 2019. A systematic study of microdosing psychedelics. PLOS ONE 14:e0211023.
DOI: https://doi.org/10.1371/journal.pone.0211023,PMID: 30726251
Prochazkova L, Lippelt DP, Colzato LS, Kuchar M, Sjoerds Z, Hommel B. 2018. Exploring the effect of
microdosing psychedelics on creativity in an open-label natural setting. Psychopharmacology 235:3401–3413.
DOI: https://doi.org/10.1007/s00213-018-5049-7,PMID: 30357434
Rabkin JG, Markowitz JS, Stewart J, McGrath P, Harrison W, Quitkin FM, Klein DF. 1986. How blind is blind?
assessment of patient and doctor medication guesses in a placebo-controlled trial of imipramine and
phenelzine. Psychiatry Research 19:75–86. DOI: https://doi.org/10.1016/0165-1781(86)90094-6,PMID: 3538107
Roseman L, Nutt DJ, Carhart-Harris RL. 2017. Quality of acute psychedelic experience predicts therapeutic
efficacy of psilocybin for Treatment-Resistant depression. Frontiers in Pharmacology 8:974. DOI: https://doi.
org/10.3389/fphar.2017.00974,PMID: 29387009
Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, Mennenga SE, Belser A, Kalliontzi K, Babb J, Su Z,
Corby P, Schmidt BL. 2016. Rapid and sustained symptom reduction following psilocybin treatment for anxiety
and depression in patients with life-threatening Cancer: a randomized controlled trial. Journal of
Psychopharmacology 30:1165–1180. DOI: https://doi.org/10.1177/0269881116675512,PMID: 27909164
Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan PT, Kornstein S,
Manber R, Thase ME, Kocsis JH, Keller MB. 2003. The 16-Item quick inventory of depressive symptomatology
(QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic
major depression. Biological Psychiatry 54:573–583. DOI: https://doi.org/10.1016/S0006-3223(02)01866-8,
PMID: 12946886
Ryff CD, Keyes CL. 1995. The structure of psychological well-being revisited. Journal of Personality and Social
Psychology 69:719–727. DOI: https://doi.org/10.1037/0022-3514.69.4.719,PMID: 7473027
Silvertown J. 2009. A new dawn for citizen science. Trends in Ecology & Evolution 24:467–471. DOI: https://doi.
org/10.1016/j.tree.2009.03.017,PMID: 19586682
Spielberger CD. 1983. State-Trait Anxiety Inventory for Adults: Mind Garden, Inc. https://www.sciencedirect.
com/topics/psychology/state-trait-anxiety-inventory.
Tennant R, Hiller L, Fishwick R, Platt S, Joseph S, Weich S, Parkinson J, Secker J, Stewart-Brown S. 2007. The
Warwick-Edinburgh mental Well-being scale (WEMWBS): development and UK validation. Health and Quality
of Life Outcomes 5:63. DOI: https://doi.org/10.1186/1477-7525-5-63,PMID: 18042300
Szigeti et al. eLife 2021;10:e62878. DOI: https://doi.org/10.7554/eLife.62878 18 of 26
Research article Medicine Neuroscience
Watson D, Clark LA, Tellegen A. 1988. Development and validation of brief measures of positive and negative
affect: the PANAS scales. Journal of Personality and Social Psychology 54:1063–1070. DOI: https://doi.org/10.
1037/0022-3514.54.6.1063,PMID: 3397865
Wood AM, Joseph S. 2010. The absence of positive psychological (eudemonic) well-being as a risk factor for
depression: a ten year cohort study. Journal of Affective Disorders 122:213–217. DOI: https://doi.org/10.1016/
j.jad.2009.06.032,PMID: 19706357
Yanakieva S, Polychroni N, Family N, Williams LTJ, Luke DP, Terhune DB. 2019. The effects of microdose LSD on
time perception: a randomised, double-blind, placebo-controlled trial. Psychopharmacology 236:1159–1170.
DOI: https://doi.org/10.1007/s00213-018-5119-x,PMID: 30478716
Szigeti et al. eLife 2021;10:e62878. DOI: https://doi.org/10.7554/eLife.62878 19 of 26
Research article Medicine Neuroscience
Appendix 1
Description of measures (in alphabetical order)
Big five personality inventory (B5)
64-item scale that captures each domain of the 5-factor model of personality (Extraversion, Agree-
ableness, Conscientiousness, Neuroticism, and Opennes), see [Costa and McCrae, 1992] for details.
Our implementation included an additional Intellect dimension (DeYoung, 2015). Participants rated
their agreement with items (e.g. ‘I make friends easily’) on a 5-point Likert scale and the score in the
given dimension was the sum of the relevant item ratings. Personality dimensions are not additive;
thus, each subscale was analyzed independently.
Cognitive and affective mindfulness scale (CAMS, revised version)
The revised CAMS is a 12-item scale measure of mindfulness. Items were rated on a 4-point scale
(Rarely/Not at all, Sometimes, Often, and Almost always), see Feldman et al., 2007 for details. Total
mindfulness score was used during analysis, which is a sum of the item scores.
Cognitive performance score (CPS)
Cognitive performance was measured both as an accumulative and as an acute outcome, because it
was not clear from the microdosing anecdotes whether the reported cognitive benefits are present
while under influence or after a period of microdosing. The Cambridge Bran Sciences (https://www.
cambridgebrainsciences.com/) platform was used to collect cognitive performance data. To quantify
cognitive performance, participants were tested in six tasks: spatial span, paired associates, rota-
tions, odd one out, spatial planning, and feature match (see Hampshire et al., 2012 for details).
Task scores were combined into a single CPS to quantify overall cognitive performance.
To calculate the CPS, first the raw scores of each task were converted to a z-score. Then, to
remove learning effects, the average score of the placebo group at the corresponding timepoint
was subtracted:
Zadj
ind;tp;t¼Zind;tp;tinds in
PL group
XZind;tp;t
nPL;tp
0
B
@
1
C
A;
where Zind;tp;tis the z-score of individual ind at timepoint tp on task tand nPL;tp is the number of indi-
viduals in the placebo group at timepoint tp. Finally, the CPS is calculated as the average adjusted
z-score across the six tasks:
CPSind;tp ¼
t
XZadj
ind;tp;t
6:
In summary, CPS score is the z-score difference from the average of the placebo group who had
the same number of previous opportunities to perform the tasks. Whenever the scores of the individ-
ual tasks are presented, the learning effects are always removed from the scores as described above
(all steps prior to taking the average across the six subtasks).
Daily effects of microdosing VASs (DEMS)
DEMS is a set of self-constructed visual analogue scales designed to measure the acute effects of
microdosing. Responses were collected on a scale of 0–100. The survey consisted of the following
items with the corresponding [low; mid; high] anchor points:
.Please rate the intensity of the drug experience [No drug effects (placebo); Neutral/Average;
Very intense drug effects]
.Please rate your mood for the day [Very negative; Neutral/Average; Very positive]
.Please rate your temper for the day (temper) [Very calm; Neutral/Average; Very tense]
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.Please rate the (physical) energy you had today [Very low energy; Neutral/Average; Very high
energy]
.Please rate your ability to keep focused today [Very easily distracted; Neutral/Average; Very
focused]
.Please rate your creativity for today [Very uncreative; Neutral/Average; Very creative]
For all VAS items, the slider’s default position was the midpoint, but for a valid response the
slider had to be moved.
Demographics
A self-constructed, general purpose 12-item questionnaire about sample demographics and mental
health status; for details see Haijen et al., 2018.
Green paranoid thought scales (GPTS)
The 16-item ‘social reference’ subscale was used, which focuses on social reference relevant to para-
noia. Each item was rated on a 5-point Likert scale, and the sum score was used in analysis, see
Green et al., 2008 for details. Note that higher scores indicate higher levels of paranoia, and thus,
lower scores indicate improvements on this scale.
Positive and negative affection scale (PANAS)
A 20-item scale that consists of a number of words that describe different feelings and emotions.
Each item is rated on a 5-point scale (Not at All, A Little, Moderately, Quite a Bit, and Extremely),
see Watson et al., 1988 for details. PANAS has two subscales (positive and negative), and the final
score used during analysis is the sum of the positive subscale minus the sum of the negative scale.
Previous drug experiences and expectations (PDEE)
A self-constructed 26-item questionnaire designed to measure the current and past recreational
drug use intensity and participants’ relationship to psychedelics drugs, see Attitude toward psyche-
delics and microdosing section and (Haijen et al., 2018) for details.
Quick inventory of depressive symptomatology (QIDS)
The 16-item self-report version of the scale was used. It is a unidimensional scale, where each item
has four response options that are assigned a numeric value, see Rush et al., 2003 for details. Sum
of the item values was used in analysis, and lower score indicates fewer depressive symptoms.
Ryff’s psychological well-being (RPWB)
A 42-item instrument that consists of six subscales (positive relations, personal growth, autonomy,
environmental mastery, purpose in life, and self-acceptance). To quantify well-being as a single out-
come, the sum of the six subscales was used during analysis. The original scale uses a six-step rating
(from Strongly disagree to Strongly agree), see Ryff and Keyes, 1995 for details. In our online
implementation a seven-step rating was used by accident (Neutral was added as an extra response
option). To make our scores comparable with other studies, all RPWB scores have been rescaled by
multiplying them with 6/7 and rounding it to the closest digit.
Satisfaction with life (SWL)
A 5-item unidimensional scale designed to measure judgment of one’s own life satisfaction, see
Diener et al., 1985 for details. The scale uses a 7-point rating that ranges from Strongly agree to
Strongly disagree; final score is the sum of item scores.
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Short suggestibility scale (SSS)
SSS is a 21-item, unidimensional scale that quantifies an individual tendency to accept messages.
Each item is rated on a 5-point scale (Not at all, A little, Somewhat, Quite a bit, and A lot), see
Kotov et al., 2004 for details. The sum of the items was used in analysis.
Social connectedness scale (SCS)
SCS is a 8-item unidimensional scale that captures social belongingness, see Lee and Robbins, 1995
for details. Each item was rated on a 5-point Likert scale; final score is the sum of item scores.
Spielberger’s state-trait anxiety inventory (STAIT)
A 20-item scale where each item corresponds to a feeling or mental state (e.g. ‘I have disturbing
thoughts’), participants rate how often they felt that way on a 4-point scale (Almost never, Some-
times, Often, and Almost always), see Spielberger, 1983 for details. The appropriate sum of item
scores (some items reverse scored) was used in analysis.
Warwick–Edinburgh mental well-being (WEMWB)
A 14-item unidimensional scale that covers both the feeling and functional aspects of mental well-
being. Each item is rated on a 5-point scale (None of the time, Rarely, Some of the time, Often,
and All of the time), see Tennant et al., 2007 for details. Sum of item scores was used in analysis.
Additional information on the self-blinding setup and data collection
For the MD group, all 4 weeks are microdose weeks, but the four variations of MD weeks (see Fig-
ure 1 for the variations) could be in any order. The order is determined by the random shuffling dur-
ing setup. Similarly, for the HH group, the MD weeks during dose regime could be any two of the
MD weeks (see Figure 1 for the four variations of the MD week). Furthermore, the sequence of MD
and PL weeks has two variations, either MD-PL-MD-PL or PL-MD-PL-MD. During analysis no distinc-
tion was made between these variants.
Variants of the setup were provided if psilocybin containing mushrooms or liquid was used. In the
case of mushrooms (grinded powder), placebo capsules had to be filled with equal weight of non-
psychoactive mushrooms, chaga (Inonotus obliquus) was recommended, otherwise the capsules
could be distinguished based on their weight. For liquids, plastic vials had to be used to hold the
substance and the placebo vials had to be filled with the same volume of liquid without the psyche-
delic component.
Participants received an automated report after the completion of the long-term follow-up time-
point if all timepoints were completed. The report indicated what they have taken when, together
with their CPSs (but not psychometric scores). As the report was sent after the completion of the
last timepoint, its content did not affect any outcome measures.
Participants were offered the option to construct their own dosing schedule with minimal restric-
tions, where the restrictions ensured the appropriate conditions for the acute and post-acute time-
points. Twelve participants choose this option. Seven of them maintained two microdoses/week (on
MD weeks) and only moved the days of microdoses. Data from these individuals was included in the
final analysis. The remaining five participants either had three (3) or a single (2) microdose during
microdose weeks. To simplify the analysis, data from these five individuals was excluded.
The time of completion was checked for every response and the data was discarded if the test
was not completed in the appropriate time window. For the accumulative outcomes, tests had to be
completed anytime during the week, while acute and post-acute tests had to be completed on the
corresponding day. If a participant did not complete either the post-regime or the 4 weeks follow-
up timepoints, an automated reminder was sent. If the test was completed within 48 hr, then the
data was still considered valid.
Participants were instructed not to complete tests if the dose schedule was not followed. Partici-
pants were allowed to withdraw from the study at any point. Their data was deleted if they explicitly
asked for it, otherwise, the data was still included in the analyses.
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After scanning the QR codes, three participants had an invalid dose schedule (3PL weeks and a
single MD week), likely due to errors during the setup. These three participants knew each other in
real life and prepared the setup together, committing all the same mistake. Data from these individ-
uals were discarded from the between-group analysis, as their dose regime does not conform to any
of the groups, but data for the acute and post-acute measures was used.
Attitude toward psychedelics and microdosing
Appendix 1—figure 1. Semi-random drawing process during the self-blinding setup, which corre-
sponds to panel B of Figure 2 in the main text. After the eight envelopes are prepared, pairs of
microdose and placebo envelopes are placed inside big envelopes together with the corresponding
‘big envelope QR’ (a set of four QRS in the red frame) and then sealed. Once each big envelope is
assembled, they are shuffled, and one is randomly selected. ‘1’ and ‘3’ are written on the two small
envelopes inside (that contain the capsules and the weekly QR code, see Figure 2 of the main text)
to designate that these will be used for weeks 1 and 3 (Panel A). Next, the other big envelope
needs to be selected with the help of the big envelope QRs. Each big envelope QR has four QR
codes: envelope id and 1,2,3. First, a random number is generated between 1 and 3 (dice roll) and
the corresponding QR is scanned (Panel B). Scanning displays a message ‘You need to find big
envelope with ID XXXX’. Then, a random big envelope is opened and the ‘Envelope ID’ field is
scanned from the big envelope QR inside. Scanning displays ‘This big envelope’s ID is YYYY’. This
process is continued until big envelope XXXX is found. ‘2’ and ‘4’ are written on the two small
envelopes inside to designate that these will be used for weeks 2 and 4.
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Appendix 1—figure 2 below shows the attitude toward psychedelic drugs in the sample. In gen-
eral, the sample had a positive attitude toward psychedelics and consisted of knowledgeable users.
Participants’ expectations about microdosing were measured at baseline using three visual analogue
scales (VAS; 0–100) items.
1. How confident are you that the upcoming microdosing experience will have a long-lasting pos-
itive effect? (0 = not at all confident, 50 = somewhat confident, 100 = very confident),
2. At this point, how logical does the microdosing experience seem to you? (0 = not at all logical,
50 = somewhat logical, 100 = very logical),
3. At this point, how successfully do you think this experience will be in improving your overall
well-being? (0 = not at all useful, 50 = somewhat useful, 100 = very useful).
These items were inspired by the credibility/expectancy questionnaire (Devilly and Borkovec,
2000), but were revised for the current study. An overall expectation score was calculated by calcu-
lating the mean of these scores. By this measure, the sample had highly positive expectations about
microdosing, 68 ±19.
Appendix 1—figure 2. Attitude toward psychedelics in the sample at baseline. At the top of each
panel is the item answered and below the bar graphs show the percentage of participant responses
(n = 240).
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Microdose characteristics
Appendix 1—figure 3. Characteristics of the microdoses used by participants. Top panel shows the
distribution of doses for both LSD/LSD analogues (n = 180, 12.8 ±5.5 mg) and psilocybin containing
mushrooms (n = 56, 0.19 ±0.12 g), bottom table provides additional information on the microdose
preparation.
Blind breaking cues
After the data collection was closed, a short survey was conducted among participants. It included
one question about clues that lead to the guess, specifically: ‘When you guessed that your daily cap-
sule was a microdose, what factors made you suspected that it was a microdose?’ (n = 166). The
results were:
.Body/perceptual sensations only (24%)
.Mostly body/perceptual sensations, but some mental/psychological effects as well (31%)
.Equally because of body/perceptual sensations and mental/psychological effects (22%)
.Mostly mental/psychological effects, but some body/perceptual sensations as well (19%)
.Mental/psychological effects only (4%)
Below the question, there was a non-mandatory text box, where participants could have elabo-
rated. Here, considerably fewer responses were received (n = 26). The consistent themes in the
responses were muscle tingling/tension (n = 15), increased color saturation/visual warping (n = 12),
and stomach stress/strain (n = 7). Only three text responses included effects related to the outcome
measures (better mood/‘giggliness’). We note that due to a technical error, some participants were
not invited to this survey, while a small fraction of participants were invited twice.
Comparison to random guesser
To compare participant’s performance to a random guesser, it was assumed that the random
guesser only knows the ratio of PL/MD capsules (3/1) in the envelopes, and further assumes that this
ratio remains constant through the experiment. Appendix 1—table 1 below shows the comparison
of guessing performance of study participants per group and the random guesser.
Appendix 1—table 1. Comparison of guessing performance to a random guesser.
X/Y (in the header columns) denotes condition X and guess Y. Sensitivity is the ratio of true positives
to all positives (i.e. MD guessed and taken/MD taken), specificity is the ratio of true negatives to all
negatives (i.e. PL guessed and taken/PL taken), while F1 is the harmonic mean of these metrics, used
Szigeti et al. eLife 2021;10:e62878. DOI: https://doi.org/10.7554/eLife.62878 25 of 26
Research article Medicine Neuroscience
as a single number summary of accuracy. Sensitivity is not defined for the PL group, as they never
take a microdose.
True positive
rate (MD/MD)
False negative
rate (MD/PL)
False positive
rate (PL/MD)
True negative
rate (PL/PL) Sensitivity Specificity
F1-
score
PL group
participants
0 0 0.21 0.79 - 0.79 0
HH group
participants
0.14 0.12 0.12 0.62 0.54 0.84 0.54
MD group
participants
0.21 0.3 0.08 0.41 0.41 0.84 0.53
All
participants
0.12 0.15 0.13 0.59 0.45 0.82 0.46
Random
guesser
0.06 0.19 0.19 0.56 0.25 0.75 0.25
To calculate the threshold dose, above which participants guess significantly better than the ran-
dom guesser defined above, numeric simulation of the setup and random guessing were conducted
200 times. Then, this distribution of random guess accuracies was tested with against the partici-
pant’s guess accuracy (with independent t-tests) who took equal or less than X mg. The dose was
increased until the test was significant. With this method, the threshold dose was found to be 12 mg
(t(317) = 1.92, p=0.05); above this dose participants tend to guess better than random. For this cal-
culation, psilocybin containing mushroom doses were converted to LSD equivalents as described in
the Additional information on statistical models section.
Szigeti et al. eLife 2021;10:e62878. DOI: https://doi.org/10.7554/eLife.62878 26 of 26
Research article Medicine Neuroscience
... As a recent practice with illegal substances, there have been great differences in substance, dose, frequency, and duration between users . However, microdosing was commonly conceptualized as the frequent use of psychedelic substances in low doses (e.g., 10-15 µgrams of LSD) (Szigeti et al., 2021). It has become a popular practice, with many thousands of individuals reporting benefits in creativity and productivity, and paving the road to "microdosing" becoming interchangeable with "nootropics" (Machek, 2019), "smart drugs" (d 'Angelo, Savulich, & Sahakian, 2017), or "mental tonics" (Pollan, 2019, p. 304). ...
... In a web-based prospective survey about microdosing, positive expectations seemed to index improvements in mental health (Kaertner et al., 2021). In a placebo-controlled study with a self-blinding protocol, there were no significant differences in psychological outcomes between microdosing and placebo groups (Szigeti et al., 2021). Whereas this online survey and self-blinding study, respectively, question whether microdosing differs from a placebo, most publications are sanguine about the beneficial effects of microdosing (cf. ...
... By the same token, psychedelics have been framed as meaning-response magnifiers, or as hyper-active placebo catalysts, perhaps by amplifying contextual factors and expectations (Hartogsohn, 2016(Hartogsohn, , 2020. Compared to regular doses with psychedelics, contextual factors (setting) may be less influential in lower doses, however psychological factors such as expectations and beliefs (set) would still play a big role in drug response as in microdosing (Kaertner et al., 2021;Szigeti et al., 2021). Positivity bias refers to an effect among individuals with extensive psychedelic experience who appear partial toward microdosing and praise its benefits (Anderson, Petranker, Rosenbaum, et al., 2019;Kaertner et al., 2021). ...
Article
To date, the clinical and scientific literature has best documented the effects of classical psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, and dimethyltryptamine (DMT), in typical quantities most often associated with macrodosing. More recently, however, microdosing with psychedelics has emerged as a social trend and nascent therapeutic intervention. This variation in psychedelic practice refers to repeat, intermittent ingestion of less-than-macrodose amounts that do not cause the effects associated with full-blown “trips”. Microdosing paves the road to incorporating psychedelic drugs into a daily routine while maintaining, or even improving, cognitive and mental function. Unlike macrodosing with psychedelics, the influence of microdosing remains mostly unexplored. And yet, despite the paucity of formal studies, many informal accounts propose that microdosing plays an important role as both a therapeutic intervention (e.g., in mental disorders) and enhancement tool (e.g., recreationally—to boost creativity, improve cognition, and drive personal growth). In response to this relatively new practice, we provide an integrative synthesis of the clinical, social, and cultural dimensions of microdosing. We describe some of the overarching context that explains why this practice is increasingly in vogue, unpack potential benefits and risks, and comment on sociocultural implications. In addition, this article considers the effects that macro- and microdoses have on behavior and psychopathology in light of their dosage characteristics and contexts of use.
... Different serotonergic psychedelics are used for this purpose, such as lysergic acid diethylamide (LSD), dimethyltryptamine (DMT) ingested with a monoamine oxidase inhibitor (MAOI)-as in the concoction known as "ayahuasca"and psilocybin, the active compound of several mushrooms in the Psilocybe genus. The most frequently used compounds are LSD and psilocybin, the latter in the form of dried psychoactive mushrooms [7][8][9]26]. There is considerable variability in dose and dosing schedules [25]. ...
... Dosing periods are also highly variable, ranging between 1 week to several years [25]. In the case of psilocybin mushrooms, microdoses are within the range of 0.1 g to 0.5 g of dried mushroom material [18], with 0.1 g considered roughly equivalent to ≈4.6 µg of LSD [26]. ...
... Indeed, low doses of LSD can have effects that are different (or even opposite) to those expected by individuals who microdose [33][34][35][36]. Nevertheless, other reports have documented positive and dosedependent enhancements in mood, emotional cognition and aesthetic perception, as well as significant improvements in emotional state, anxiety, energy and creativity, among other relevant variables [26,35,37,38]. Importantly, some of these results could be explained by unblinding of the experimental condition, i.e., by subjects correctly distinguishing the placebo from the active dose [26,38]. ...
Article
Full-text available
The use of low sub-perceptual doses of psychedelics (“microdosing”) has gained popularity in recent years. Although anecdotal reports claim multiple benefits associated with this practice, the lack of placebo-controlled studies severely limits our knowledge of microdosing and its effects. Moreover, research conducted in standard laboratory settings could fail to capture the motivation of individuals engaged or planning to engage in microdosing protocols, thus underestimating the likelihood of positive effects on creativity and cognitive function. We recruited 34 individuals starting to microdose with psilocybin mushrooms (Psilocybe cubensis), one of the materials most frequently used for this purpose. Following a double-blind placebo-controlled experimental design, we investigated the acute and short-term effects of 0.5 g of dried mushrooms on subjective experience, behavior, creativity (divergent and convergent thinking), perception, cognition, and brain activity. The reported acute effects were significantly more intense for the active dose compared to the placebo, but only for participants who correctly identified their experimental condition. These changes were accompanied by reduced EEG power in the theta band, together with preserved levels of Lempel-Ziv broadband signal complexity. For all other measurements there was no effect of microdosing except for few small changes towards cognitive impairment. According to our findings, low doses of psilocybin mushrooms can result in noticeable subjective effects and altered EEG rhythms, but without evidence to support enhanced well-being, creativity and cognitive function. We conclude that expectation underlies at least some of the anecdotal benefits attributed to microdosing with psilocybin mushrooms.
... Further support comes from the widely used practice of microdosing in which doses of psilocybin that are only a fraction (one tenth or less) of the psychedelic dose are taken by individuals in a nonmedicinal context. While results are not consistent and comprehensive studies are lacking, there is evidence that microdosing may have positive effects on mood, creative processes, and energy [168,169]. In a recent large internet-based study psilocybin was the most frequently microdosed psychedelic agent. ...
Article
Schizophrenia is a widespread psychiatric disorder that affects 0.5–1.0% of the world’s population and induces significant, long-term disability that exacts high personal and societal cost. Negative symptoms, which respond poorly to available antipsychotic drugs, are the primary cause of this disability. Association of negative symptoms with cortical atrophy and cell loss is widely reported. Psychedelic drugs are undergoing a significant renaissance in psychiatric disorders with efficacy reported in several conditions including depression, in individuals facing terminal cancer, posttraumatic stress disorder, and addiction. There is considerable evidence from preclinical studies and some support from human studies that psychedelics enhance neuroplasticity. In this Perspective, we consider the possibility that psychedelic drugs could have a role in treating cortical atrophy and cell loss in schizophrenia, and ameliorating the negative symptoms associated with these pathological manifestations. The foremost concern in treating schizophrenia patients with psychedelic drugs is induction or exacerbation of psychosis. We consider several strategies that could be implemented to mitigate the danger of psychotogenic effects and allow treatment of schizophrenia patients with psychedelics to be implemented. These include use of non-hallucinogenic derivatives, which are currently the focus of intense study, implementation of sub-psychedelic or microdosing, harnessing of entourage effects in extracts of psychedelic mushrooms, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies that employ appropriate animal models are a prerequisite and clinical studies will need to be carefully designed on the basis of preclinical and translational data. Careful research in this area could significantly impact the treatment of one of the most severe and socially debilitating psychiatric disorders and open an exciting new frontier in psychopharmacology.
... Moreover, while we believe that a naturalistic observational approach is important to explore mental health effects that are experienced by participants in a typical HBW practice, this does result in one important limitation: The study did not feature a control group to assess the influence of confounding parameters such as the impact of set and setting and expectancy on any of the outcome measures. Previous studies have demonstrated that personal expectations can drive alterations in mental health parameters and constitute a placebo effect (Heaton, 1975;Szigeti et al., 2021;M. Uthaug et al., 2021). ...
Article
Full-text available
Background Holotropic breathwork (Grof ® Breathwork), was developed by Stanislav Grof and Christina Grof as a ‘non-drug’ alternative technique to evoke altered states of consciousness (ASC). Interestingly, although HBW has been anecdotally reported to evoke experiences and mental health effects corresponding to those of psychedelic substances, the scientific literature on the matter is scarce. Aims The objective of this study was to assess the (sub)acute and long-term effects of HBW on satisfaction with life, and whether these depend on the depth of the experience evoked by the HBW session. Methods A naturalistic observational design was employed in the present study. Between January 2019 and July 2020, 58 Czech-speaking participants who had an experience with HBW were assessed using three separate anonymous online-surveys created and hosted on Qualtrics. Assessments of mindfulness, satisfaction with life, depression, anxiety, and stress were made once prior to (baseline), and two times following (sub-acutely and 4-weeks) the participants’ experience with HBW. The ego dissolution inventory and the 5-dimensional altered states of consciousness scale was used to quantify the HBW experience. Results Despite low ratings of the psychedelic experience (mean range of 0–34% out of 100%), ratings of non-judgement significantly increased sub-acutely following the HBW session and persisted for 4-weeks. Stress-related symptoms significantly decreased while satisfaction with life significantly increased at 4-weeks after HBW. Conclusion An experience with HBW may be associated with improvement in non-judgement, satisfaction with life, and reductions of stress-related symptoms.
... None of these studies identified used psilocybin without psychotherapy and none evaluated micro-dosing (i.e., repeated low doses of psilocybin); however, one observational study suggested benefits of micro-dosing were equivalent to placebo. 69 The first study was an open-label, single-armed, feasibility trial involving two sessions (first dose 10 mg, second dose 25 mg oral psilocybin) of psilocybin-assisted psychotherapy spaced 7 days apart in 12 participants with TRD. There was a significant reduction in depressive symptoms (as measured by the Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR]) after 7 days (hedges' g = 3.1; P = 0.002) and 3 months (g = 2.0; P = 0.003) after the second (high dose; 25 mg) session. ...
Article
Objective Serotonergic psychedelics are re-emerging as potential novel treatments for several psychiatric disorders including major depressive disorder. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence and provide a consensus recommendation for the clinical use of psychedelic treatments for major depressive disorder. Methods A systematic review was conducted to identify contemporary clinical trials of serotonergic psychedelics for the treatment of major depressive disorder and cancer-related depression. Studies published between January 1990 and July 2021 were identified using combinations of search terms, inspection of bibliographies and review of other psychedelic reviews and consensus statements. The levels of evidence for efficacy were graded according to the Canadian Network for Mood and Anxiety Treatments criteria. Results Only psilocybin and ayahuasca have contemporary clinical trials evaluating antidepressant effects. Two pilot studies showed preliminary positive effects of single-dose ayahuasca for treatment-resistant depression (Level 3 evidence). Small randomized controlled trials of psilocybin combined with psychotherapy showed superiority to waitlist controls and comparable efficacy and safety to an active comparator (escitalopram with supportive psychotherapy) in major depressive disorder, with additional randomized controlled trials showing efficacy specifically in cancer-related depression (Level 3 evidence). There was only one open-label trial of psilocybin in treatment-resistant unipolar depression (Level 4 evidence). Small sample sizes and functional unblinding were major limitations in all studies. Adverse events associated with psychedelics, including psychological (e.g., psychotomimetic effects) and physical (e.g., nausea, emesis and headaches) effects, were generally transient. Conclusions There is currently only low-level evidence to support the efficacy and safety of psychedelics for major depressive disorder. In Canada, as of 2022, psilocybin remains an experimental option that is only available through clinical trials or the special access program. As such, Canadian Network for Mood and Anxiety Treatments considers psilocybin an experimental treatment and recommends its use primarily within clinical trials, or, less commonly, through the special access program in rare, special circumstances.
... Another form of psilocybin use, called "microdosing", consists of regular intake of very low doses (< 1-3 mg) in the treatment of various psychiatric disorders as well as in the search for improved cognitive and creative performance. The results are so far mitigated [20], especially against placebo [21], and require further exploration. ...
Article
Full-text available
Purpose of the Review We aim to provide an overview of the current state of knowledge about the efficacy of psilocybin in the treatment of depression, as well as its mechanisms of action. Recent Findings Psilocybin has a large, rapid, and persistent clinical effect in the treatment of resistant or end-of-life depression. Tolerance is good, with mild side effects limited to a few hours after dosing. The studies conducted to date have had small sample sizes. One clinical trial has been conducted against a reference treatment (escitalopram) without showing a significant superiority of psilocybin in the main outcome. The neurobiological mechanisms, mostly unknown, differ from those of SSRI antidepressants. Summary Psilocybin represents a promising alternative in the treatment of depression. Further research with larger sample sizes, particularly against reference treatments, is needed to better understand the neurobiological factors of its effects and to investigate its potential for use in everyday practice.
... Medicinal motives are likely to be related to positive prior expectancy, a major component of the action of all effective treatments, including placebo (Olson et al., 2020) and SSRIs (Hjorth et al., 2021). Positive expectancy has recently come under the spotlight in psychedelic research where for example, belief about receipt of a psychedelic appears to be major driver of outcomes (Kaertner et al., 2021;Olson et al., 2020;Szigeti et al., 2021;Van Elk et al., 2021). Whether expectancy is a (justifiably or experimentally) extricable component of any treatment, not just psychedelic therapy, is a question worthy of some thought (Carhart-Harris et al., 2021b). ...
Article
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Background Over the last two decades, a number of studies have highlighted the potential of psychedelic therapy. However, questions remain to what extend these results translate to naturalistic samples, and how contextual factors and the acute psychedelic experience relate to improvements in affective symptoms following psychedelic experiences outside labs/clinics. The present study sought to address this knowledge gap. Aim Here, we aimed to investigate changes in anxiety and depression scores before versus after psychedelic experiences in naturalistic contexts, and how various pharmacological, extrapharmacological and experience factors related to outcomes. Method Individuals who planned to undergo a psychedelic experience were enrolled in this online survey study. Depressive symptoms were assessed at baseline and 2 and 4 weeks post-psychedelic experience, with self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR-16) as the primary outcome. To facilitate clinical translation, only participants with depressive symptoms at baseline were included. Sample sizes for the four time points were N = 302, N = 182, N = 155 and N = 109, respectively. Results Relative to baseline, reductions in depressive symptoms were observed at 2 and 4 weeks. A medicinal motive, previous psychedelic use, drug dose and the type of acute psychedelic experience (i.e. specifically, having an emotional breakthrough) were all significantly associated with changes in self-rated QIDS-SR-16. Conclusion These results lend support to therapeutic potential of psychedelics and highlight the influence of pharmacological and non-pharmacological factors in determining response. Mindful of a potential sample and attrition bias, further controlled and observational longitudinal studies are needed to test the replicability of these findings.
... 4 Recent studies reported on the effects of microdosing classic psychedelics, i.e., administration of less than 20% of the usual total dose in a semi-regular schedule. 5 Although there is a lack of robust research on ibogaine microdosing for psychiatric disorders, we report this practice in a patient with bipolar depression as a possibly innovative treatment alternative. ...
... [38][39][40] Not only have psychedelics been shown to enhance suggestibility, 41 their perceived benefits have also been associated with positive expectancies, particularly in the case of microdosing. 42,43 To evaluate the role played by expectancy in pain relief reports, we asked participants whether or not they had been using psychedelics with the specific intention of managing pain. In the group of respondents who did not use psychedelics for pain management, macrodoses of psychedelics were still perceived as exerting a significant analgesic effect, superior to that of conventional medication, while the analgesic effect of microdoses was reported as similar to that of conventional medication. ...
Article
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Although several studies and reports have shown the potential analgesic use of serotonergic psychedelics in cancer pain, phantom limb pain and cluster headache, evidence supporting their use for chronic pain is still limited. The past years have seen a considerable renewal of interest toward the therapeutic use of these compounds for mood disorders, resulting in a marked increase in the number of people turning to psychedelics in an attempt to self-medicate a health condition or improve their wellbeing. In western countries particularly, this population of users overlaps substantially with chronic pain sufferers, representing a unique opportunity to evaluate the effects these compounds have on pain and wellbeing. Here, we report results from an online survey conducted between August 2020 and July 2021 in a population of 250 chronic pain sufferers who had experience with psychedelics, either in microdoses (small sub-hallucinogenic doses), macrodoses (hallucinogenic doses), or both. Macrodoses, while less often used for analgesic purposes than microdoses, were reported to induce a higher level of pain relief than both microdoses and conventional pain medications (including opioids and cannabis). Although the effects were weaker and potentially more prone to expectation bias than with macrodoses, our results also suggested some benefits of psychedelics in microdoses for pain management. The reported analgesic effect appeared unrelated to mood improvements associated with psychedelic use, or the advocacy of psychedelic use. Taken together, our findings indicate interesting potential analgesic applications for psychedelics that warrant further clinical research.
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Concussion, sometimes called a mild traumatic brain injury (mTBI), is an acquired brain injury resulting in alterations to brain function underpinned by a sequence of neuropathological and neurometabolic events that can result in excitotoxicity, oxidative stress, oedema, neuroinflammation and cell death. To date, pharmaceutical therapies have had limited success in treating TBI, presenting considerable interest in nutritional therapies in the form of dietary supplementation to alleviate the deleterious pathological sequelae following neurotrauma. Many nutritional supplements have low toxicity, few drug interactions, and are already approved for human use making them attractive potential therapies following a concussion. In the setting of brain injury models, a considerable body of preclinical evidence has accumulated supporting the use of nutritional supplements including essential fatty acids, vitamins, minerals, amino acids, polyphenols, bioflavonoids and other bioactive compounds to facilitate aspects of functional recovery. Here, we review studies presenting diet supplements as therapeutic strategies as potential treatments for mTBI or to augment neurological resistance against mTBI in experimental models, as well as emerging therapeutic targets including the gut microbiome, and psychedelic and non-psychedelic compounds derived from fungi.
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There is a popular interest in microdosing with psychedelics such as LSD. This practice of using one-tenth of a full psychedelic dose according to a specific dosing schedule, anecdotally enhances mood and performance. Nonetheless, controlled research on the efficacy of microdosing is scarce. The main objective of the present dose-finding study was to determine the minimal dose of LSD needed to affect mood and cognition. A placebo-controlled within-subject study including 24 healthy participants, was conducted to assess the acute effects of three LSD doses (5, 10, and 20 mcg) on measures of cognition, mood, and subjective experience, up until 6 h after administration. Cognition and subjective experience were assessed using the Psychomotor Vigilance Task, Digit Symbol Substitution Test, Cognitive Control Task, Profile of Mood States, and 5-Dimensional Altered States of Consciousness rating scale. LSD showed positive effects in the majority of observations by increasing positive mood (20 mcg), friendliness (5, 20 mcg), arousal (5 mcg), and decreasing attentional lapses (5, 20 mcg). Negative effects manifested as an increase in confusion (20 mcg) and anxiety (5, 20 mcg). Psychedelic-induced changes in waking consciousness were also present (10, 20 mcg). Overall, the present study demonstrated selective, beneficial effects of low doses of LSD on mood and cognition in the majority of observations. The minimal LSD dose at which subjective and performance effects are notable is 5 mcg and the most apparent effects were visible after 20 mcg.
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After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. Outcomes of neuroscience and clinical research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.
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Background: The practice of "microdosing," or the use of repeated, very low doses of lysergic acid diethylamide (LSD) to improve mood or cognition, has received considerable public attention, but empirical studies are lacking. Controlled studies are needed to investigate both the therapeutic potential and the neurobiological underpinnings of this pharmacologic treatment. Methods: The present study was designed to examine the effects of a single low dose of LSD (13 μg) versus placebo on resting-state functional connectivity and cerebral blood flow in healthy young adults. Twenty men and women, 18 to 35 years old, participated in 2 functional magnetic resonance imaging scanning sessions in which they received placebo or LSD under double-blind conditions. During each session, the participants completed drug effect and mood questionnaires, and physiological measures were recorded. During expected peak drug effect, they underwent resting-state blood oxygen level-dependent and arterial spin labeling scans. Cerebral blood flow as well as amygdala and thalamic connectivity were analyzed. Results: LSD increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum, and decreased amygdala connectivity with the left and right postcentral gyrus and the superior temporal gyrus. This low dose of LSD had weak and variable effects on mood, but its effects on positive mood were positively correlated with the increase in amygdala-middle frontal gyrus connectivity strength. Conclusions: These preliminary findings show that a very low dose of LSD, which produces negligible subjective changes, alters brain connectivity in limbic circuits. Additional studies, especially with repeated dosing, will reveal whether these neural changes are related to the drug's purported antidepressant effect.
Article
Background: Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100-200 μg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0-26 μg) on mood and behavior in healthy volunteers under double-blind conditions. Methods: Healthy young adults (N = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in randomized order at 1-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed. Results: LSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 μg). At the highest dose, the drug also increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected. Conclusions: Single microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.