Microdosing psychedelics: More questions than answers? An overview and suggestions for future research

Abstract

Background: In the past few years, the issue of ‘microdosing’ psychedelics has been openly discussed in the public arena where claims have been made about their positive effect on mood state and cognitive processes such as concentration. However, there are very few scientific studies that have specifically addressed this issue, and there is no agreed scientific consensus on what microdosing is. Aim: This critique paper is designed to address questions that need to be answered by future scientific studies and to offer guidelines for these studies. Approach: Owing to its proximity for a possible approval in clinical use and short-lasting pharmacokinetics, our focus is predominantly on psilocybin. Psilocybin is allegedly, next to lysergic acid diethylamide (LSD), one of the two most frequently used psychedelics to microdose. Where relevant and available, data for other psychedelic drugs are also mentioned. Conclusion: It is concluded that while most anecdotal reports focus on the positive experiences with microdosing, future research should also focus on potential risks of (multiple) administrations of a psychedelic in low doses. To that end, (pre)clinical studies including biological (e.g. heart rate, receptor turnover and occupancy) as well as cognitive (e.g. memory, attention) parameters have to be conducted and will shed light on the potential negative consequences microdosing could have.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers

“…Potential effects on memory and learning should be explored in a clinical population that would not be prone to ceiling effects. While these results contradict reports of enhanced cognition in the context of recreational use (Fadiman 2011;Kuypers et al 2019), it should be noted that not all pharmaceutical drugs that target cognitive and behavioral impairments have nootropic effects on healthy participants. For example, atomoxetine for ADHD (Bidwell et al 2011) and memantine for AD (Repantis et al 2010) do not enhance cognition in non-impaired individuals.…”

“…This liability is dose-dependent, however, and anti-inflammatory effects associated with psychedelics may be therapeutically applicable at sub-perceptual doses in humans as they are in animal models (Yu et al 2008;Nau et al 2013). Furthermore, a number of anecdotal uncontrolled reports associate the ingestion of sub-perceptual doses, or "microdoses" as called by some, of LSD, with enhanced mood and cognition (Fadiman 2011;Kuypers et al 2019). Although these reports must be viewed with caution as they are uncontrolled (Friedman 2017), they suggest possible therapeutic effect in cognitive decline associated with AD at sub-perceptual dose levels of LSD.…”

Psychedelics as a Treatment for Alzheimer’s Disease Dementia

“…The 5HT2A-R is found in high concentrations in regions of the brain vulnerable to dementia such as the prefrontal cortex and aforementioned hippocampus (Wood et al, 2012;Catlow et al, 2013;Bryson et al, 2017). Psychedelics induce brain plasticity and modify connectivity between brain regions and there is considerable anecdotal evidence of cognitive benefits from micro-dosing-a dose that does not cause perceptual change or impair functioning (Carhart-Harris et al, 2012;Wood et al, 2012;Catlow et al, 2013;Muthukumaraswamy et al, 2013;Zhang and Stackman, 2015;Griffiths et al, 2016;Carhart-Harris and Goodwin, 2017a;Carhart-Harris and Nutt, 2017;Johnstad, 2018;Fadiman and Korb, 2019;Kuypers et al, 2019;Lea et al, 2020a). This mini-review will explore the role of classical psychedelics psilocybin and Lysergic acid diethylamide (LSD) in treating AD with a focus on sub-perceptual-or ''micro''-dosing.…”

Treatment of a Complex Personality Disorder Using Repeated Doses of LSD—A Case Report on Significant Improvements in the Absence of Acute Drug Effects

“…Overall, the case resembles some features which have been described for "microdosing" of psychedelics, e.g., the repeated use of small doses of serotonergic hallucinogens in order to transiently improve mood, energy and other domains (16). It is believed that small doses below the threshold for "typical" hallucinogenic effects still can induce relevant stimulation of the serotonin 2Areceptor, resulting in positive mental effects which last for a few days (16). Somehow, this resembles our case, where only minor acute effects, but transient improvements in several domains were observed.…”