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.

• Findings show that both LSD (10-20 mcg) and psilocybin (1-3mg) have subtle (positive) effects on cognitive processes (time perception, convergent and divergent thinking) and brain regions involved in affective processes. Regarding 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.

An Overview of Current Literature

Lysergic acid diethylamide (LSD) and psilocybin are prototypical classical psychedelics. These psychoactive substances typically produce perceptual distortions and mind-altering effects, mainly by agonistic action at the serotonin (5-HT) 2A brain receptor.

Psychedelics are seen as a class of substances scoring relatively high on physiological and psychological safety when used under supervision in a controlled setting. In general, they do not induce dependence, or adverse effects that would not be manageable when given in appropriate doses, and in the presence of someone who can provide psychological support, if needed.

• Recent placebo-controlled experimental studies have also shown that LSD and psilocybin increase self-rated positive mood and social behaviour, enhance emotional empathy, and reduce recognition of negative emotional states (e.g., sadness and fear).
• Moreover, preliminary findings and anecdotal reports suggest that psychedelics even show therapeutic potential in substance use disorders.

In addition, current research is investigating therapeutic applications of these substances in psychiatric disorders, with a focus on affective disorders. While the intensity or quality of the psychedelic experience seems to contribute to its therapeutic effect, anecdotal evidence also suggests that repeated use of smaller doses without the psychedelic experience (microdosing) is efficacious self-treatment for people suffering from affective disorders.

What is Microdosing and What are the Benefits?

In general, a microdose is considered to be one tenth of a dose normally causing hallucinogenic effects. The reported short-term benefits of microdosing include an increase in positive mood, a decrease in negative mood, and an improvement in relationships with others and their environment, which seems to be in line with the effects of full psychedelic doses, though without the perceptual effects.

When individuals are under the influence of these psychedelics including psychological (increased anxiety) or physiological (discomfort) changes. Interestingly, this increased anxiety is suggested to be linked to the surface emergence of latent emotional content by microdosing. Along the same lines, it is reasoned that this could accelerate a healing process in a therapeutic context because these emotions can then be used.

• Interestingly, Albert Hofmann, the discoverer of LSD and its hallucinogenic effects, stated decades ago that very small doses, perhaps 25 micrograms, could be useful as an antidepressant. This seems to be confirmed in the reports of people self-treating with micro-doses of psychedelics to combat symptoms of affective disorders such as depression and anxiety disorders.

Recent Research with LSD & Psilocybin

Study in Patients with Treatment-resistant Depression & Depression Associated with Life Threatening Illnesses

• Quick Inventory of Depressive Symptoms (QIDS) and Snaith-Hamilton Pleasure Scale (SHAPS) anhedonia scores significantly improved from baseline to 1 week and 3 months post-treatment, with maximum effect at 2 weeks. At 3-months follow-up, 58% of patients continued to meet criteria for response (defined as ?50% reduction in Beck Depression Inventory (BDI) score relative to baseline). Supplementary State Trait Anxiety Inventory (STAI) trait scale (STAI-T) scores also significantly improved with treatment.
• A 6-month follow-up study, in which a further 8 male participants were enrolled, found that the anti-depressant and anxiolytic effects of psilocybin were sustained and remained significant at 6 months post-treatment, according to QIDS, BDI and STAI-T.

• Additionally, Psilocybin produced significant anti-depressant and anxiolytic effects according to the Hamilton Anxiety Rating Scale (HAM-A) and GRID-HAM-D. 83% and 79% of patients continued to meet the criteria for response at 6 months according to HAM-A and GRID-HAM-D, respectively. These positive results were supported by significant improvements

Therapeutic Effects of Classical Psychedelics: An Overview

Psychedelic administration has been shown to have statistically significant reductions in depression and anxiety symptoms. These findings corroborate the limited previous research conducted in animal studies and healthy volunteers, as well as anecdotal evidence describing improved mood and reduced feelings of apprehension following psychedelic administration.

• Improvements were consistently observed across a variety of rating scales, and this is suggestive of a genuine therapeutic effect rather than a specific scale’s tendency to show a positive effect.

• Moreover, the lack of equivalent symptom reduction in control patients indicates that the anti-depressant and anxiolytic effects can be attributed to psychedelic intervention.

• Participants also described the experience as spiritually meaningful, resulting in decreased disease-related demoralisation and hopelessness as well as improved quality of life.

Summation

It is yet unclear whether psychedelic microdosing is of therapeutic value for depression due to the limited number of studies (with small sample sizes) that have been conducted. Nonetheless, the aforementioned effects on selective cognitive processes, resembling in a milder way the effects of full psychedelic doses, and without impairing cognitive processes, suggest that low doses of psychedelics could play a role in depression.

• Some underlying cognitive mechanisms of action, deduced from the observed effects, that is, increased divergent thinking and slowed down time perception, could be the induction of respectively increased cognitive flexibility, and the production of a heightened experience of being more in the present or mindful, which could lead to lessened ruminative thinking and more self-compassion, decreasing depressive symptoms.

• Regarding its safety, it was demonstrated that low doses are well tolerated and have no-to-minimal effects on physiological parameters.

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.

Overall, this (microdosing) psychedelics research field is still in its infancy, preliminary findings indicate that low doses of both LSD and psilocybin affect assessed biological processes. A first study showed changed connectivity in brain areas involved in affective behaviour, after a single dose of LSD (13 mcg tartrate). Interestingly these changes were also related to positive mood effects, which suggests this might be a potential mechanism underlying alleged therapeutic effects in depression. The proposed research will give new insights into the potential of future alternative psychiatric treatment forms that are fiercely needed.