This review of the effect of microdosing on depression found that there still isn’t much evidence available, but points towards increased cognitive flexibility and decreased rumination of possible mechanism.

Abstract

“Microdosing psychedelics is the repeated use of small doses of, for example, lysergic acid diethylamide (LSD) and psilocybin, typically for a few weeks. Despite the popular and scientific attention in recent years, and claims by users that it has therapeutic value in affective disorders like depression, little scientific knowledge is available to back this. The purpose of this review was to investigate whether there are scientific grounds to state that this practice could be helpful in the treatment of affective disorders, and safe to use repeatedly. To that end, the literature (PubMed, MedLine) was searched, looking for (controlled) experimental studies with low doses of LSD and/or psilocybin, in healthy volunteers and patient samples. After a selection process and the addition of relevant articles, 14 experimental studies entered this review. Findings show that both LSD (10–20mcg) and psilocybin (<1–3mg) have subtle (positive) effects on cognitive processes (time perception, convergent and divergent thinking) and brain regions involved in affective processes. Besides the pleasant experience, increased anxiety and a cycling pattern of depressive and euphoric mood were also found. With regard to safety, it was demonstrated that low doses are well tolerated (in healthy volunteers) and have no-to-minimal effects on physiological measures. While it is yet unclear whether psychedelic microdosing is of therapeutic value for depression, the aforementioned effects on selective processes suggest that low doses of psychedelics could play a role in depression by inducing some kind of cognitive flexibility, which might lead to decreased rumination. While previous studies were conducted mostly in small samples of healthy volunteers, future placebo-controlled clinical trials in depressed patients are required to understand the therapeutic value of microdosing psychedelics, how this differs from therapy using full psychedelic doses, and whether different psychedelics have different effect patterns. The proposed research will give new insights into the potential of future alternative psychiatric treatment forms that are fiercely needed.”

Author: Kim P. C. Kuypers

Summary

Introduction

Lysergic acid diethylamide (LSD) and psilocybin are prototypical classical psychedelics that produce perceptual distortions and mind-altering effects. They also increase self-rated positive mood and social behaviour, enhance emotional empathy, and reduce recognition of negative emotional states.

Psychedelics are seen as a class of substances scoring relatively high on physiological and psychological safety when used under supervision in a controlled setting. Some studies even suggest that psychedelics may show therapeutic potential in substance use disorders.

Microdosing LSD and/or psilocybin-containing mushrooms has been shown to improve positive mood, decrease negative mood, and improve relationships with others and their environment, though without the perceptual effects. LSD is more associated with cognitive and/or stimulating effects, while psilocybin with emotional or well-being effects.

The positive effects of psychedelics can be accompanied by acute negative effects, such as increased anxiety or discomfort. However, the latent emotional content of these psychedelics can also be used to accelerate a healing process.

Despite positive claims of microdosers, no clinical trial has focused on the question whether repeated administration of psychedelics in low doses can serve therapeutic potential in affective disorders.

Methods

A search of the databases PubMed and MedLine yielded 23 hits, which were reduced to 12 by de-duplication and removal of irrelevant articles. These 12 articles were localized in a book about microdosing psychedelics, a review paper describing the long-term effects of psychedelics, and in my personal experience.

A total of 14 experimental studies in humans were reviewed, of which 4 were harvested from the bibliographic database of the Multidisciplinary Association for Psychedelic Studies and 8 were obtained via google scholar.

Experimental research with LSD

In the past, a number of studies were conducted on LSD and its effects on cognition, subjective perception and brain activity. Five recent studies were identified and included in this review.

Older research with LSD

Abramson and colleagues combined data from 141 experimental sessions with 31 participants to provide a clear view of the mental effects caused by different doses of LSD. They found that the effects of low doses of LSD on the selected parameters seem to be very mild or placebo-like.

Isbell and colleagues published six experiments with LSD, in which the dose-response effect, the test-retest value of a series of mental and physiological measures, and tolerance after repeated doses of LSD were investigated. They found that daily microdosing is not efficient, but that an abstinence period of 3 days is long enough to reinstate the mental response.

Greiner et al. conducted a dose-effect study with five different doses of LSD and placebo administered to 14 healthy male volunteers. They found that 20 mcg of LSD had a threshold effect on mood, but participants did not experience the cycling pattern of depressed and euphoric mood states.

McGlothlin et al. tested the long-lasting effects of repeated administration of a high dose of LSD on measures of anxiety, attitude and value, aesthetic sensitivity, creativity and personality in healthy volunteers. The results suggest that LSD (25 mcg) has a similar effect pattern as the stimulant amphetamine (20 mg) in the mentioned doses.

Statistics were conducted between low and high LSD dose, and between 25 mcg LSD and amphetamine, and between participants who stated to have long-lasting effects at the 6 month follow up.

Recent research with LSD

In a study, elderly subjects received different doses of LSD tartrate repeated 6 times every 4 days for a period of 21 days. Cognition was tested at different times and with different measures. Blood was collected to determine LSD concentrations after doses 1 and 6. The average half-life was 8.25 7.5 h, and there were no significantly more adverse events in the LSD groups compared with the placebo group.

Bershad et al. found that low doses of LSD were safe and had no effect on mood, cognitive skills or social behaviour. However, they did find that blood pressure increased and that there was a slight increase in basal body temperature.

In a recent functional imaging study, participants who took LSD tartrate had increased connectivity in the limbic system, which was related to changes in positive mood.

Gasser and colleagues investigated the safety and efficacy of LSD-psychotherapy in patients with anxiety related to life-threatening diseases.

After the treatment blind was broken, more people experienced drug-related adverse events in the high dose condition compared to the low dose condition, but self-rated anxiety decreased after two high dose sessions with LSD, and increased after the open-label crossover to LSD 200 mcg.

An uncontrolled, naturalistic study

One of the included experimental studies showed that taking psilocybin-containing truffles improved convergent and divergent thinking. However, placebo-controlled experimental studies are needed to confirm these results.

Controlled, experimental studies

Hasler and colleagues tested the effects of different doses of psilocybin on subjective experience and cognition. They found that the lowest dose caused a decrease in heart rate 6 h after ingestion.

In a recent positron emission tomography study, Madsen and colleagues demonstrated that the degree of 5-HT2A receptor occupancy is related positively to the intensity of the psychedelic experience.

Study in obsessive compulsive disorder patients

Moreno and colleagues administered psilocybin to 9 patients with obsessive compulsive disorder. The symptoms reduced after treatment with a low dose, suggesting that psilocybin could help balance habitual behaviour and cognitive control.

Discussion

This article reviewed experimental evidence that low doses of LSD and psilocybin have no effect on mood state, selective cognitive processes, or brain regions involved in affective processes.

Low doses of psychedelics may have a role in depression due to their effects on selective cognitive processes, such as increased divergent thinking and slowed down time perception, which may lead to lessened ruminative thinking and more self-compassion, decreasing depressive symptoms.

The cause of effects: expectancy and underlying biology

Despite positive media coverage, scientific evidence shows that microdosing has no significant effects on social behaviour, creativity, or productivity. In addition, people expecting certain effects might stop with microdosing because the practice was not deemed effective, or the effects did not meet their expectations.

Future studies could consider presenting participants with options of substances they could receive, or using additional ‘active’ treatments to control for expectancy and placebo effects. They might also want to compare the effects of low doses between groups of people with experience and those who are drug-naive.

Preliminary findings indicate that low doses of both LSD and psilocybin affect assessed biological processes. These effects are probably due to a change in connectivity in brain areas involved in affective behaviour, and may be a potential mechanism underlying alleged therapeutic effects in depression.

The authors labeled the effects of LSD as ‘non-substantial’, but further studies could reveal the role of other 5-HT receptors and neurotransmitter systems in the psychedelic-induced effects and potential therapeutic mechanism.

Adverse effects

Users report to experience negative effects when asked about microdosing psychedelics, but these are generally limited to the dosing days when physical discomfort and increased feelings of anxiety can arise.

Family and colleagues demonstrated no LSD-related effects on heart rate or basal body temperature after a single dose of LSD. However, they advise to monitor heart parameters after repeated doses of LSD due to concerns about substances that act on the 5-HT2B receptor.

Lessons learned and future perspective

Psychological support is needed during a microdose, as increased anxiety is mentioned in anecdotal reports and in findings of reviewed experimental studies. This support might also contribute to an enhanced state of mindfulness and cognitive flexibility, thereby facilitating the therapeutic process.

The reviews do not provide robust evidence in favour of a specific dose, but rather give a range in which psychedelics show subtle (beneficial) effects without producing extreme perceptual distortions. The studies used LSD base or LSD tartrate, except one.

According to one recent study, repeated LSD doses do not affect psychological and cognitive functions, and two dose-free days in between are sufficient to curb the tolerance. Therefore, daily dosing is probably not efficacious, and two to three dose-free days in between would be sufficient. Research shows that full psychedelic doses can relieve depression after one or two doses, and the quality of the psychedelic experience is predictive of the therapeutic outcome.

Future research should compare the effect pattern of LSD and psilocybin in repeated low doses, in one study, and see if they have different, and perhaps a complementary, effect pattern that could be employed successively to treat different symptoms (‘cognitive’ or ‘affective’) observed in one psychiatric disorder.

Conclusion

While preliminary findings demonstrate the therapeutic efficacy of full psychedelic doses in the treatment of depression, anecdotal reports suggest that lower doses, without the psychedelic experience, are beneficial too.