Author response: Self-blinding citizen science to explore psychedelic microdosing
OpenAlex – December 11, 2020
Source: OpenAlex
Summary
Microdosing psychedelics like psilocybin offers no unique psychological benefits beyond expectation, a large clinical trial suggests. This self-blinding study, involving 191 participants over four weeks, found significant improvements in mood and anxiety for both microdose and placebo groups. Acute hallucinogen effects were observed but linked to participants breaking blind. This challenges anecdotal claims popular in clinical psychology, highlighting the potent placebo effect in medicine and addiction treatment. Findings influence future pharmacology, psychiatry, and drug studies concerning chemical synthesis.
Abstract
Article Figures and data Abstract eLife digest Introduction Materials and methods Results Discussion Appendix 1 Data availability References Decision letter Author response Article and author information Metrics 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. 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. Introduction There is renewed interest in the medical application of psychedelic drugs, such as lysergic acid diethylamide (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 conditions such as depression, end-of-life-anxiety, addiction, and obsessive-compulsive behaviors (Carhart-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 μg 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 Stevenson, 2019). This positivity bias, combined with the low dose and the subjective evaluation of effects, pave the way for a strong placebo response. 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 subjects (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 microdosing (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 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 psychedelics 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 Request a detailed protocol This study had a naturalistic design involving elements of experimental control (self-blinding), prospective 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. Figure 1 Download asset Open asset 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. Outcomes Request a detailed protocol 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 outcomes 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 personality 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 planning, 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 placebo 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. 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. TestDomainAcronymBaselineAcutePost-acuteAccumulativeDemographics--✔Previous drug experiences and expectations--✔Short suggestibility scaleSuggestibilitySSS✔Cognitive performance scoreCognitionCPS✔✔✔Daily effects of microdosing VASs--✔Positive and negative affection scaleEmotional statePANAS✔Warwick–Edinburgh mental well-being scaleWell-beingWEMWB✔Quick inventory of depressive symptomatologyDepressionQIDS✔Social connectedness scaleConnectednessSCS✔Spielberger’s state-trait anxiety inventoryAnxietySTAIT✔Ryff’s psychological well-being scalesWell-beingRPWB✔✔Cognitive and affective mindfulness scaleMindfulnessCAMS✔✔Green paranoid thought scalesParanoiaGPTS✔✔Big five personality inventoryPersonalityB5✔✔Satisfaction with lifeLife satisfactionSWL✔✔ Self-blinding setup procedure Request a detailed protocol 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: placebo (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. Figure 2 Download asset Open asset 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 D shows 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. 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 capsule 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 opaque 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 the experimenter to recover knowledge of capsule types after randomization without revealing that information to participants. Microdose preparation Request a detailed protocol 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 preferred 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 Request a detailed protocol Psychedelics users were recruited through advertisement on relevant online and offline forums. Individuals 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 participant 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 Request a detailed protocol All the questionnaires were implemented online using the SurveyGizmo platform (https://www.surveygizmo.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 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 Request a detailed protocol 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 that the participant the capsule for the day or week No guess was about group at the end of study, because information about group was not shared with participants. Request a detailed protocol differences in recreational drug and baseline scores of the accumulative outcomes were assessed with and for and Accumulative outcomes were with using the with were with change from baseline as the time and as and individuals as experimental were for significant baseline (the were tested as potential age, baseline dose, total dose, suggestibility scale number of number of current number of and number of To dose as a potential psilocybin was to an equivalent LSD dose g of dried et al., et al., The planned were of change over time from baseline to the primary endpoint at week 5 and from baseline to the final follow-up at week 9. Additionally, were vs. HH and vs. at week 5 and week 9. To acute and post-acute mixed were score as ID as a and as where was a binary For acute was PL/MD when the score was the of a placebo/microdose capsule, while for post-acute outcomes was PL/MD when the score was at the end of placebo/microdose were between scores and MD participant four scores to these corresponding to the four acute/post-acute assessment timepoints during the dose period. All acute/post-acute were for significant baseline were tested for as in the for the accumulative baseline score and total dose To better how guess a set of were with the addition of guess and Using these guess planned were between and MD the two binary and the data into 4 were between the vs. PL/MD vs. vs. PL/MD and vs. This was such that changes while guess in the first two and guess changes while in the last two Request a detailed protocol The study only who planned to microdose through their own initiative with their own psychedelic substance, but who to incorporate placebo control to make their with our study. not any use of psychedelics, and no was to participants. were the only data The email address was after study completion if was given by the participant to information future discarded The study was by and the at number Results and completion A total of participants started, and 191 participants completed the study. The optional follow-up at week was completed by individuals. No statistically significant differences were found between the groups in any recreational drug use or baseline measures, of the randomization (see 1 for on 2 for recreational drug and 3 for of baseline was similar across the three groups see Figure Figure 3 Download asset Open asset and completion through the study. The completion of the 4 weeks follow-up timepoint was For the most the sample of healthy from most participants had a positive psychedelic drugs, in particular medical and either agreed or agreed with the an active of psychedelic and an active of the use of See Appendix for on the about microdosing and The sample of healthy individuals for the most of participants to have had at one in the the most frequent were: anxiety and of the sample had current mental participants with LSD analogue by psilocybin containing and three individuals used other psychedelics The average dose for was while for psilocybin it was see Appendix 1—figure 3 for details. Accumulative outcomes Accumulative outcomes were first at baseline, then at week 5 (i.e. after the completion of the 4 weeks long dose and at the optional long-term follow-up timepoint at week 9. The two sets of were group of baseline vs. week 5, baseline vs. week over and at the week 5 and week timepoints. were at baseline, week 5 and week Data was also separately for and psilocybin microdoses, the results from matched the results of the combined For the group over of baseline vs. week 5, psychological outcomes improved significantly in the MD group: well-being (RPWB) increased with mindfulness (CAMS) increased with life satisfaction (SWL) increased with and (GPTS) with (B5) showed trait score and increased changes over the same period baseline to week were also observed in the and HH groups for mindfulness and but not for well-being or life satisfaction. also in the group in mindfulness and were at the week follow-up timepoint for groups, while only in the MD see 5 for details. CPS not change in the MD group baseline to week but significantly in the HH group cognitive over the same period, and odd one out increased significantly in the MD while spatial and paired in the HH group. The increased score in the MD group was at the follow-up but not the other no significant differences at either the week 5 or week follow-up including that in the HH group the paired scores HH treatment of the is in Figure See 4 for including and cognitive test over time and between group differences and Figure 4 Download asset Open asset shows the of the change from baseline and the for the accumulative outcomes. Top horizontal the over time for each group baseline to post-regime and from baseline to on of show the for the PL/HH/MD groups, (e.g. change from baseline to post-regime in well-being was significant