Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review

This systematic review (2020) of (mostly) observational studies on microdosing psychedelics (LSD & psilocybin) finds that it is experienced both positively and negatively by participants (n=3,619).

Abstract

“Microdosing psychedelic drugs-that is, taking sub-behavioral doses of lysergic acid diethylamide (LSD) or psilocybin-is a growing practice in Western societies. Taken mainly for creative or mood-enhancing purposes, thousands of users are increasingly being exposed to (micro)doses of psychedelic drugs. In this systematic review, we searched the available evidence from human studies, focusing our results in terms of three main axes: efficacy, safety, and the influence of the placebo effect in microdosing practices. While the available evidence has some strengths (e.g. large sample sizes, robust methodologies) there are also remarkable limitations (e.g. gender bias, heterogeneity of dosing schedules and drugs used). Highly contradictory results have been found, showing both the benefits and detriments of microdosing in terms of mood, creative processes, and energy, among other regards. This review provides a general overview of the methods and approaches used, which could be useful for improving future studies.”

Authors: Genís Ona & José C. Bouso

Notes

This review included 17 studies, of which 10 were observational, three qualitative, and (only) 4 randomized, double-blind, placebo-controlled clinical trials. The latter are linked below:

• Bershad et al (2019) – effects at increased dosages, n=20, 6.5-26µg LSD
• Bershad et al (2020) – mostly fMRI measures, n=20, 13µg LSD
• Family et al (2020) – no negative effects on elderly population, n=48, 5-20µg LSD
• Yanakieva et al (2019) – same participants as one above

The review focused on 1) efficacy/benefits, 2) safety, and 3) placebo effects.

1. Survey studies and the qualitative interviews found positive effects on mood, focus, and creativity. Bershad et al (2019) found increases in experiences of unity and bliss.
2. The legality of drugs was the biggest safety worry (e.g. getting arrested, unknown purity), followed by physiological discomfort, impaired focus and anxiety. The clinical studies found small effects on anxiety (at 26 µg), an increase in blood pressure (at 13 µg), and more frequent headaches.
3. Placebo effects are described in the article with regards to the clinical studies, but it (fully?) misses the expectancy effect which is (probably) a big part of the effects in the observational studies.

Summary

Highlights

Journal Pre-proof

Microdosing psychedelic drugs is a growing practice in Western societies, but the available evidence is contradictory. This review provides a general overview of the methods and approaches used, which could be useful for improving future studies.

The “psychedelic renaissance” in the mid-1990s brought renewed academic interest in psychedelic drugs’ mechanisms of action and therapeutic potential, as well as increased usage by the general population. In pharmacological research, microdosing consists of low exposure or Phase 0 clinical trials with no greater than 100 g (for small molecules) or 1/100th of the No Observed Adverse Effect Level (NOAEL). However, microdosing psychedelics has noticeable effects, such as mood-enhancing effects, improved creative thinking, and the relief of various psychological disorders.

Using tiny amounts of psychedelic drugs to enhance creativity and efficiency was first proposed by Albert Hofmann, but it was not until the 2010s that this practice spread globally. As more people tried microdosing LSD, psilocybin, ayahuasca, and ibogaine, it seems that others started to take microdoses of these substances as well. More research is urgently needed in this field to assess the safety of this practice and the potential risks it might pose to public health.

We conducted a search using the electronic databases PubMed, Scopus, and Web of Science, and conducted manual searches using Google Scholar and Core (core.ac.uk) to identify other relevant studies. We summarized the current evidence on microdosing and discussed the limitations of the available evidence.

To find all relevant research published on the safety of microdosing, its reported benefits, and the possible influence of a placebo effect, researchers searched the literature using search terms and criteria. They identified 64 separate references that were reviewed by abstract screening.

The included studies include 10 observational studies, three qualitative studies, and 4 randomized, double-blind, placebo-controlled clinical trials. The most frequently used drugs in this research were LSD and psilocybin. Although much less common, other drugs, such as cannabis, 1P-LSD, and mescaline, have also been reported on in some of the included studies.

A study by Andersson and Kjellgren (2019) qualitatively analyzed videos posted on YouTube by individuals who microdosed LSD and psilocybin and explained their experiences. The study found that users reported benefits regarding depression, anxiety, post-traumatic stress disorder, bipolar disorder, addiction, attention deficit and hyperactivity disorder, autism spectrum disorder, and cluster headaches.

Anderson et al. (2019a) conducted a retrospective survey study on 278 microdosing users of LSD and psilocybin, and Cameron et al. (2020) designed an online-survey to collect data from microdosing practitioners. In an international survey, individuals who reported having microdosed reported improved mood and reduced anxiety, enhanced connectivity to people and the environment, and enhanced cognition. In a different study, individuals who had been diagnosed with physical and/or psychological disorders reported higher self-rated effectiveness of microdosing.

The only prospective, observational study with a sample of microdosing practitioners showed an increase in all scores on days when users microdosed. Long-term improvements were reported for depression and stress. Webb et al. (2019) and Johnstad (2018) performed individual interviews with microdosing users and reported that the main benefits were enhanced mood, increased productivity and creativity, and heightened sociability. Prochazkova et al. (2018) conducted a quasi-experimental study in which assessed creativity and intelligence among users under the effects of psilocybin truffles.

Anderson et al. (2019a) report that study participants reported several safety concerns, including illegality, physiological discomfort, impaired focus, increased anxiety, impaired energy, impaired mood, and social interference.

Some users experienced negative effects after microdosing, including cognitive interference, self-interference, increased symptoms, increased psychological dependence, substance tolerance, hangover, and adverse psychological events. Others reported experiencing insomnia, over-stimulation, and a “bad trip” when an LSD microdose was combined with cannabis.

Participants reported experiencing occasional unwanted effects, including difficulty concentrating, insomnia, symptoms of anxiety, feelings overwhelmed, and irritability. They also reported experiencing frequent unwanted effects, including insomnia, overstimulation, undesired thoughts, emotions, and memories, anxiety, and muscle/joint pain. Three placebo-controlled studies were found among the search results. They found that 13 and 26 g of LSD increased ratings for “feel drug” and “like drug”, as well as systolic blood pressure and diastolic blood pressure.

Participants correctly identified a placebo, seven identified a sedative, one identified a stimulant, one identified an opioid, one identified a cannabinoid, one was unsure, and only one identified a psychedelic drug. No significant differences were found regarding subjective effects in the LSD conditions. This systematic review collected the available evidence regarding microdosing, including observational studies, qualitative studies, and randomized, placebo-controlled clinical trials.

Although clinical trials are scarce, observational studies are very strong and provide data collected from a sample of over 3000 people who tried microdosing in a naturalistic setting. These studies have high external validity and are much larger than Phase-I and Phase-II clinical trials commonly use. Among the studies reviewed, mood enhancement was the most frequently reported benefit. Related concepts such as personal and thoughtful insights, improvements in self-confidence and self-acceptance, and deeper connections with other people and with nature were also reported.

Given the associations between amygdala hyperreactivity and various psychological disorders, microdosing of psychedelic drugs may partially explain reported mood enhancements and enhanced creativity. Contrary findings were found between observational studies and a clinical trial performed by Bershad et al. (2019) regarding both mood and creativity. Although regular doses of psychedelic drugs can increase some measures of creativity, the evidence regarding improvements to mood and creativity is weak.

Studies included in the review reported on microdosing in relation to various mental health conditions, including depression, anxiety, PTSD, ADHD, pain, and cluster headaches. These results are in line with the preliminary results of ongoing research on psychedelic drugs at regular doses. In a study, microdosing of 2,5-Dimethoxy-4-iodoamphetamine (DOI) was found to have potent anti-inflammatory effects. This suggests that microdosing could be used as a replacement for prescribed psychiatric medication.

The use of psychedelic drugs in both regular and microdoses should be further explored as a treatment for addictions, given the lack of efficacy and side effects associated with psychiatric medications. A remarkable proportion of study participants reported adverse events, including increased anxiety, sadness, irritability, and worsening of symptoms of depression. The most commonly reported issues were increased anxiety and insomnia, and a “bad trip” was also reported, involving a microdose of LSD that was combined with a regular dose of cannabis. Some adverse events might be explained by overdosing, where a small- to medium-sized dose was taken rather than a microdose. Furthermore, one-fifth of microdosing practitioners experience some type of adverse event, so more controlled studies are necessary to elucidate their safety profiles.

In four randomized, placebo-controlled trials, the alleged benefits of microdosing could be attributed to a placebo effect. Yanakieva et al. (2019) found delayed time perception in the absence of self-rated effects on perception, and Bershad et al. (2019) found no differences in mood, cognition, nor physiological parameters, while subjects reported notable subjective effects. Four clinical trials using LSD in similar doses suggest that individuals can avoid psychoactive effects and obtain noticeable benefits by taking less than 20 g of LSD. However, the mean age of the sample recruited by Yanakieva et al. (2019) and Family et al. (2020) was 62.9 years.

Researchers should conduct more controlled clinical trials and more naturalistic, non-gender biased, prospective observational research in order to overcome the limitations of survey-based studies. Microdosing with drugs other than LSD and psilocybin represents a novel, vast, and promising field of research. Ibogaine, ayahuasca, and DMT have been shown to have neuroprotective properties and may be used to treat PD.

Microdosing may have future clinical applications in the treatment of neurodegenerative diseases and in helping individuals to overcome opioid dependence. In most studies included in this review, participants used LSD and psilocybin, although other psychedelic and non-psychedelic drugs were also used to a lesser degree. The most common dose schedule was one day microdosing and two days off, but there were six studies in which the regimen was not specified.

Psychedelic microdosing benefits and challenges: an empirical codebook. Anderson, T., Petranker, R., Christopher, A., Rosenbaum, D., Weissman, C., Dinh-Williams, L.A., Hui, K., Hapke, E., Farb, N.A.S., 2019a, 2019b.

Psychedelic microdosing can be used to study the effects of psychedelics on the brain, including the effects of psychedelics on the memory, attention, and learning systems, as well as the effects of psychedelics on the brain.

A transition from injectable opioid agonist therapy to sublingual buprenorphine/naloxone for the treatment of opioid use disorder using a microdosing approach has been described, as well as the potential use of banisteriopsis caapi as a therapy for Parkinson’s Disease.

Several studies have shown that microdosing psychedelics may be safe and beneficial. These include studies on the effect of lysergic acid diethylamide (LSD) on anxiety associated with life-threatening diseases, and a study on the safety and efficacy of ayahuasca for treating depression.

Psilocybin reduces depression and anxiety in patients with life-threatening cancer, improves functional connectivity of the amygdala during emotional face discrimination, and reduces brain abnormalities in depression: evidence from a meta-analysis of fMRI studies.

Several studies have been conducted on the subject of microdosing with psychedelics, including motives and side-effects among users, self-rated effectiveness of microdosing for mental and physical health problems among microdosers, and neuroprotective potential of Ayahuasca and untargeted metabolomics analyses: applicability to Parkinson’s disease.

Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking. Microdosing psychedelics can promote structural and functional neural plasticity, and ibogaine administration modifies GDNF and BDNF expression in brain regions involved in mesocorticolimbic and nigral dopaminergic circuits.

Ayahuasca, a hallucinogen from the Amazon, has long-lasting analgesic effects. It has been shown to stimulate adult neurogenesis in vitro and to affect amygdala activity during processing of fearful stimuli in healthy subjects.

Psychedelics are considered safe and effective for treatment of depression and other mental illnesses. However, there is no clear evidence that psychedelics can be used to treat psychiatric conditions.