Flow diagram showing participation and completion rates through the study. The completion of the 4 weeks follow-up timepoint was optional.

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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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 in...

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Context 1
... rate was highly similar across the three groups ( 2 (12, N = 240)=0.64, p=0.99), see Figure 3. ...
Context 2
... participants microdosed with LSD (n = 147; 61%)/LSD analogue (n = 33; 14%), followed by psilocybin 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. ...

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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 in...

Citations

... Restrictive drug policies make placebo-controlled studies on CBMPs difficult and expensive to conduct in laboratory settings due to the need for home office licences and intensive regulatory oversight. Citizenscience approaches may help to overcome these challenges (48). Citizen science involves individuals implementing their own placebo control at home, using their own acquired medical cannabis products, following online instructions to conduct self experimentation over a given time period with self-reported clinical scales to assess the value of the intervention. ...
... Citizen science involves individuals implementing their own placebo control at home, using their own acquired medical cannabis products, following online instructions to conduct self experimentation over a given time period with self-reported clinical scales to assess the value of the intervention. The advantages are the low cost and the ability to recruit participants globally (48). ...
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Randomised controlled trials (RCTs) have long been considered the gold standard of medical evidence. In relation to cannabis based medicinal products (CBMPs), this focus on RCTs has led to very restrictive guidelines in the UK, which are limiting patient access. There is general agreement that RCT evidence in relation to CBPMs is insufficient at present. As well as commercial reasons, a major problem is that RCTs do not lend themselves well to the study of whole plant medicines. One solution to this challenge is the use of real world evidence (RWE) with patient reported outcomes (PROs) to widen the evidence base. Such data increasingly highlights the positive impact medical cannabis can have on patients’ lives. This paper outlines the value of this approach which involves the study of interventions and patients longitudinally under medical care. In relation to CBMPs, RWE has a broad range of advantages. These include the study of larger groups of patients, the use of a broader range and ratio of components of CBMPs, and the inclusion of more and rarer medical conditions. Importantly, and in contrast to RCTs, patients with significant comorbidities–and from a wider demographic profile–can also be studied, so providing higher ecological validity and increasing patient numbers, whilst offering significant cost savings. We conclude by outlining 12 key recommendations of the value of RWE in relation to medical cannabis. We hope that this paper will help policymakers and prescribers understand the importance of RWE in relation to medical cannabis and help them develop approaches to overcome the current situation which is detrimental to patients.
... It may be that the "standard" microdose of about 10% of a recreational dose: up to 20 μg of LSD and up to 300 mg of psilocybin-containing mushrooms (Anderson et al. 2019b) is not merely sub-perceptual but also ineffective. Other research on microdosing failed to detect an effect, although again, the dose and dosing schedule were unknown (Szigeti et al. 2021). It is possible that as the current model predicts, a mystical experience is required for the putative effects caused by psychedelics use (Carhart-Harris and Friston 2019). ...
... Firstly, if set and setting are a perennially important concept, the meaning-enhancing, contextdependent inducing effects of psychedelics should enhance it even with small doses. While data on the importance of context in the case of is still limited and inconclusive (Kaertner et al. 2021;Szigeti et al. 2021), current research postulates that the putative long-term effects are substantial and sometimes even dramatic (see Ona and Bouso 2020;Petranker et al. 2022). In view of such results, the role of context in microdosing appears undiminished and arguably even augmented. ...
... Current research is still debating whether the effects of microdosing are pharmacologically driven or based on expectancy. While several studies have pointed to the measurable effects of microdosing on indices such as mood, creativity, and well-being (Andersonet al. 2019b; Hutten et al. 2019; Polito and Stevenson 2019), others have argued that the effects of microdosing can essentially be explained by placebo (Szigeti et al. 2021). Interestingly, and perhaps counterintuitively, accepting this conjecture would not subtract from the crucial role of set and setting in microdosing. ...
Article
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Rationale The use of psychedelics for medical and recreational purposes is rising. Contextual factors such as expectancy, intention, and sensory and social environment (set and setting) are widely recognized as moderating the effects of these substances. Nevertheless, clinical trials of microdosing — the ingestion of small, sub-hallucinogenic doses of psychedelics — rarely report their set and setting. This fact suggests that such factors are not considered important in the context of microdosing. Objective This paper challenges this assumption and makes the case for the crucial relevance of set and setting in microdosing practice. Building on set and setting theory and placebo theory, we explain why set and setting are of crucial importance in the case of microdosing. Results This reasoning helps elucidate the role of set and setting in determining the outcomes of microdosing and helps explain some of the contradictory results that have emerged in microdosing research in recent years. Conclusion Set and setting are important constructs to be considered especially in the context of microdosing psychedelics. By reporting set and setting, the results of microdosing research can be made more reliable and consistent.
... These studies are diverse and broad in their scope of interest: they range from fundamental pharmacokinetical ones through general neurological and psychiatric and psychological ones-including those not conducted in the 'classical era', viz. placebocontrolled trials on healthy participants to explore general psychological effects-to quite 'exotic ones' [6], only to mention two of this latter kind: The first is the much media attention generating microdosing study of Szigeti and his colleagues in which they applied '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' [31]. The second is the study of Nour and colleagues on the possible association of political orientation-more precisely, a liberal, antiauthoritarian one-and psychedelic usage [32]. ...
Chapter
The inventor of LSD, Albert Hoffmann, himself referred to his most famous discovery as his ‘problem child’. In the first part of this chapter, we outline the past regulatory, ethical and political issues that surrounded this much researched and debated agent until it ended up as a Schedule I substance, falling under the strictest regulations worldwide. We believe that the ethical, legal and political aspects are equally important to understand what had led to decade-long loss of interest in experimentation on human subjects with LSD. Having explored these issues, we turn our attention to the present research landscape and the future challenges and prospects of trials with this substance. We focus mainly on the research and bioethics aspects; besides we make some explanatory remarks on the past and present political and cultural/socio-critical perspectives that shaped and still affect public and professional discourse on the subject matter.KeywordsLSDPsychedelicsResearch ethicsMKUltraLaingFDA
... Studies in rats report that chronic, intermittent, low doses of DMT produce antidepressant-like effects and enhanced fear extinction, without affecting working memory or social interaction (254). Also, recent studies in humans using two to four microdoses of LSD or psilocybin (255,256) report an increase in positive mood, a decrease in depression, augmented energy, and improved work effectiveness. However, more research using double-blind placebocontrolled trials is needed to really confirm the efficacy of this dosing approach. ...
Article
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The utility of classical drugs used to treat psychiatric disorders (e.g., antidepressants, anxiolytics) is often limited by issues of lack of efficacy, delayed onset of action or side effects. Psychoactive substances have a long history of being used as tools to alter consciousness and as a gateway to approach the unknown and the divinities. These substances were initially obtained from plants and animals and more recently by chemical synthesis, and its consumption evolved toward a more recreational use, leading to drug abuse-related disorders, trafficking, and subsequent banning by the authorities. However, these substances, by modulation of certain neurochemical pathways, have been proven to have a beneficial effect on some psychiatric disorders. This evidence obtained under medically controlled conditions and often associated with psychotherapy, makes these substances an alternative to conventional medicines, to which in many cases the patient does not respond properly. Such disorders include post-traumatic stress disease and treatment-resistant depression, for which classical drugs such as MDMA, ketamine, psilocybin and LSD, among others, have already been clinically tested, reporting successful outcomes. The irruption of new psychoactive substances (NPS), especially during the last decade and despite their recreational and illicit uses, has enlarged the library of substances with potential utility on these disorders. In fact, many of them were synthetized with therapeutic purposes and were withdrawn for concrete reasons (e.g., adverse effects, improper pharmacological profile). In this review we focus on the basis, existing evidence and possible use of synthetic cathinones and psychedelics (specially tryptamines) for the treatment of mental illnesses and the properties that should be found in NPS to obtain new therapeutic compounds.
... Klinička, kontrolisana, terapijski optimalna doza može da ponudi realne benefite (klasični psihodelici, empatogeni, disocijativi). Anegdotalni benefiti mikrodoziranja klasičnim psihodelicima su placebo efekat (Szigeti et al., 2021). otporniji. ...
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Personality and environment interact to influence attitudes formation. Group processes, reasoning, traits, and brain activity have been used to explain political attitudes and behavior. Social phenomena have been associated with clinical indicators, albeit with inconclusive results. Psychobiological model of personality measures temperament dispositions in interaction with character, i.e., with mental health and success of social adaptation. They overcome a need for separate measurements of adaptive and maladaptive trait correlates. Such an efficient approach integrates traits measurement along the dimension of normalcy-pathology. We set out to investigate associations between the model and Right-Wing Authoritarianism, Conspiracy Mentality, and Manichean Worldview in a non-representative community sample. The model accounted for 24% of variance in RWA and negligible percentages in the rest. The strongest predictor was found to be Self-Transcendence, followed by Impulsiveness and Persistence, with Exploratory Excitability and Reward Dependence as negative predictors. There were no correlations between mental health and socio-political constructs. Implications are discussed.
... While beyond the scope of the present discussion, it may be the case that such dosing has distinctive effects with unique benefits in both clinical and recreational contexts (Safron, 2020). Current evidence suggests that such benefits may often heavily involve placebo effects (Szigeti et al., 2021)-as is the case for many (if not most) interventions-but that does not mean that there may also be substantial clinically significant non-expectancy mediated treatment effects for some use cases (e.g. treating cognitive decline). ...
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Here we consider psychedelics with respect to their mechanisms of action, use, and implications for our understandings of brain and mind. This review is somewhat nontraditional in its scope, with discussions of both basic facts as well as theoretical speculations. We chose this approach given the unique historical context we find ourselves in at present. While we have decades of investigations to draw upon with respect to the clinical science and neuropsychopharmacology of psychedelics, we are also witnessing a renaissance (or perhaps a revolution) in which scientific and public interest in these compounds seems to be exploding. We have decided to split this review between the fundamental and theoretical, with hopes that we can give readers familiarity with well-established knowledge, as well as questions to hold in mind in attempting to make sense of a rapidly shifting epistemic landscape. Below we focus on serotonin 2A receptor (5-HT2aR) agonists, or “classic psychedelics,” and discuss research suggesting their potential roles in clinical and non-clinical contexts. Particular emphasis is placed on studies suggesting potentially surprising degrees of efficacy for conditions such as depression and addictive disorders. We also evaluate potential mediators and moderators of therapeutic outcomes, including factors such as mystical experiences and psychological flexibility. Finally, we consider likely future directions for psychedelics in science and society.
... Accordingly, this practice involves interspersing resting days with dosing days (two to four times per week) (Kuypers et al 2019). Microdosing has been gaining popularity over recent years, with lysergic acid diethylamide (LSD) and psilocybin (in the form of psychoactive mushrooms) being the compounds most frequently consumed for this purpose (Hutten et al. 2019a;Lea et al. 2020a, b, c;Polito and Stevenson 2019;Szigeti et al. 2021). Despite the illegal status of psychedelics in most countries, several websites contain discussions and suggestions related to microdosing and its effects, with users claiming that this practice can improve mood, stimulate productivity, and improve cognitive functions as well as mental concentration (Anderson et al. 2019a, b;Lea et al. 2020a, b, c). ...
... However, these generally involve self-selected samples and lack adequate control conditions; thus, given the subtle effects of microdosing, expectations and pre-existing traits may play a fundamental role in the perceived effects (Kaertner et al. 2021;Olson et al. 2020). In contrast, studies following double-blind and placebo-controlled experimental designs have found less support for positive outcomes of microdosing (Bershad et al. 2019;Family et al. 2020;Hutten et al. 2020;Szigeti et al. 2021;van Elk et al. 2021;Yanakieva et al. 2019). Yet, these studies generally include tasks and questionnaires validated in the context of high doses of psychedelics, which might lack the specificity and sensitivity necessary to capture the subtler effects induced by microdosing. ...
... We analyzed the effects of microdoses of Psilocybe cubensis mushrooms (0.5 g dried material, a typical microdose) (Polito and Stevenson 2019;Szigeti et al. 2021;van Elk et al. 2021) on verbal reports. Data was obtained following a double-blind placebo-controlled experimental design with two different measurement weeks per participant (Cavanna et al. 2022). ...
Article
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Rationale: Serotonergic psychedelics are being studied as novel treatments for mental health disorders and as facilitators of improved well-being, mental function, and creativity. Recent studies have found mixed results concerning the effects of low doses of psychedelics ("microdosing") on these domains. However, microdosing is generally investigated using instruments designed to assess larger doses of psychedelics, which might lack sensitivity and specificity for this purpose. Objectives: Determine whether unconstrained speech contains signatures capable of identifying the acute effects of psilocybin microdoses. Methods: Natural speech under psilocybin microdoses (0.5 g of psilocybin mushrooms) was acquired from thirty-four healthy adult volunteers (11 females: 32.09 ± 3.53 years; 23 males: 30.87 ± 4.64 years) following a double-blind and placebo-controlled experimental design with two measurement weeks per participant. On Wednesdays and Fridays of each week, participants consumed either the active dose (psilocybin) or the placebo (edible mushrooms). Features of interest were defined based on variables known to be affected by higher doses: verbosity, semantic variability, and sentiment scores. Machine learning models were used to discriminate between conditions. Classifiers were trained and tested using stratified cross-validation to compute the AUC and p-values. Results: Except for semantic variability, these metrics presented significant differences between a typical active microdose and the inactive placebo condition. Machine learning classifiers were capable of distinguishing between conditions with high accuracy (AUC [Formula: see text] 0.8). Conclusions: These results constitute first evidence that low doses of serotonergic psychedelics can be identified from unconstrained natural speech, with potential for widely applicable, affordable, and ecologically valid monitoring of microdosing schedules.
... A study of psilocybin microdose vs placebo for well-being and cognition in volunteers (N = 191) demonstrated improvement from baseline in both study arms, suggesting that improvement could be attributed to the placebo effect. 88 Human studies are summarized in Table 3 and the mechanism of action of psilocybin is described in Figure 1. ...
Article
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Psilocybin is a tryptamine alkaloid found in some mushrooms, especially those of the genus Psilocybe. Psilocybin has four metabolites including the pharmacologically active primary metabolite psilocin which readily enters the systemic circulation. The psychoactive effects of psilocin are believed to arise due to the partial agonist effects at the 5HT2A receptor. Psilocin also binds to various other receptor subtypes although the actions of psilocin at other receptors is not fully explored. Psilocybin administered at doses sufficient to cause hallucinogenic experiences has been trialled for addictive disorders, anxiety and depression. This review investigates studies of psilocybin and psilocin and assesses the potential for use of psilocybin and a treatment agent in neuropsychiatry. The potential for harm is also assessed, which may limit the use of psilocybin as a pharmacotherapy. Careful evaluation of the number needed to harm versus the number needed to treat will ultimately justify the potential clinical use of psilocybin. This field needs a responsible pathway forward.
... Surveys of microdosing psilocybin have identified diverse practices but generally converge on the self-administration, 3-5 times per week, of 0.1 to 0.3 g of dried mushrooms [7][8][9][10][11][12] . Improvements in mood, emotional well-being and cognition have been reported among the top motivations for microdosing 13 , and several cross-sectional studies have identified associations between microdosing and perceived improvements in mood [13][14][15][16][17] and cognitive functioning 10,11,16 , reductions in stress 7 , depression 7,9,16 and anxiety 7,9,14,18 . www.nature.com/scientificreports/ ...
... The effective use of placebo has presented a challenge in the few published studies that have attempted such a design in the context of psychedelic microdosing 17,19,20 . Specifically, a prospective study of microdosing that used a self-blinding intervention to approximate placebo control among 191 participants over 4 weeks identified improvements in emotional well-being among microdosers, but noted that correct identification of condition was reported by 72% of participants complicating the ability to conclusively estimate the influence of placebo effects on observed changes. ...
... The findings of this study contribute to the growing literature on microdosing in several ways. First, although our study design differs substantially from the designs of the relatively few prior longitudinal studies of microdosing psychedelics-particularly with regard to attempts to account for the potential influence of expectancies-our findings of improved mood and reduced symptoms of depression, anxiety and stress are nonetheless generally similar in direction and size to the unadjusted small to medium positive effects reported in those investigations 7,17,18 . To our knowledge, this is the largest longitudinal study to date of microdosing psilocybin and one of the few studies to engage a control group [17][18][19][20] . ...
Article
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Psilocybin microdosing involves repeated self-administration of mushrooms containing psilocybin at doses small enough to not impact regular functioning. Microdose practices are diverse and include combining psilocybin with substances such as lion's mane mushrooms (Hericium erinaceus; HE) and niacin (vitamin-B3). Public uptake of microdosing has outpaced evidence, mandating further prospective research. Using a naturalistic, observational design, we followed psilocybin microdosers (n = 953) and non-microdosing comparators (n = 180) for approximately 30 days and identified small-to medium-sized improvements in mood and mental health that were generally consistent across gender, age and presence of mental health concerns, as we all as improvements in psychomotor performance that were specific to older adults. Supplementary analyses indicated that combining psilocybin with HE and B3 did not impact changes in mood and mental health. However, among older microdosers combining psilocybin, HE and B3 was associated with psychomotor improvements relative to psilocybin alone and psilocybin and HE. Our findings of mood and mental health improvements associated with psilocybin microdosing add to previous studies of psychedelic microdosing by using a comparator group and by examining the consistency of effects across age, gender, and mental health. Findings regarding the combination of psilocybin, HE and B3 are novel and highlight the need for further research to confirm and elucidate these apparent effects.
... Microdosing has been growing as another modality of psychedelics consumption among individuals dealing with mental health issues, and researchers are starting to investigate more about it. The placebo effect might also influence the results, as shown by Szigeti et al. [308] in a 'self-blind' trial in which participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The results showed significant improvement for both the microdosing and the placebo groups, but no significant between-groups differences. ...
Article
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Substance use disorder (SUD) is a global public health concern that affects millions of people worldwide. Considering current research, addiction has been noted as the last stage of a chronic disease that may impair brain reward circuit responses and affects personal and social life. Treatments for SUD face challenges including availability and limited pharmacological response, often resulting in low retention of patients. A growing number of studies from the 'psychedelic renaissance' have highlighted the therapeutic potential of psychedelics for several psychiatric disorders, including SUD. In this non-systematic review we discuss past and current clinical and observational studies with classic (LSD, DMT, psilocybin and mescaline) and non-classic (ibogaine, ketamine, MDMA, salvinorin A and THC) psychedelics for the treatment of SUD published until December 2021. Although results are still inconclusive for LSD, DMT, mescaline, MDMA and Salvinorin A, in general, the literature presents moderate evidence on the controlled use of psilocybin and ketamine for Alcohol Use Disorder, ketamine for management of opiate and alcohol withdrawal, and THC preparations for reducing withdrawal symptoms in Cannabis and possibly in Opioid Use Disorder. Importantly, studies suggest that psychedelics should be more effective when employed as an adjunct therapy. Extensive research is warranted to further elucidate the role of psychedelics in the treatment of SUD.