Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers

This double-blind, placebo-controlled, within-subject study (n=20) found that a microdose of LSD (up to 26 μg) elicited dose-dependent subjective effects during the ‘peak’ of the experience but not at the follow-up (48 hours).

Abstract

“Background: Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100–200 μg) positively bias emotion processing. Yet, the effects of such subthreshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single, very low doses of LSD (0–26 μg) on mood and behaviour in healthy volunteers under double-blind conditions.

Methods: Healthy young adults (N = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in randomized order at 1-week intervals. During the expected peak drug effect, they completed mood questionnaires and behavioural tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed.

Results: LSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 μg). At the highest dose, the drug also increased ratings of vigour and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected.

Conclusions: Single microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.”

Authors: Anya K. Bershad, Scott T. Schepers, Michael P. Bremmer, Royce Lee & Harriet de Wit

Notes

This paper was included in a systematic review of microdosing psychedelics by Ona & Bouso (2020).

Summary

Healthy young adults received 0 (placebo), 6.5, 13, or 26 mg of LSD in randomized order at 1-week intervals and completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed.

Microdosing lysergic acid diethylamide (LSD) to improve mood and cognitive function has received widespread coverage in the media. Although few controlled studies have been conducted, there have been several naturalistic studies.

LSD has been shown to have effects on the serotonin system, specifically the 5-HT2A receptors, although it also binds to several other serotonin receptors and dopamine D2 receptors. Its effects last for a long time, which may account for its therapeutic value.

LSD has been used as an antidepressant for a long time, but many early studies lacked adequate control groups and did not isolate drug effects from effects of psychotherapy itself. More recent studies have shown that high doses of LSD are effective in reducing psychiatric symptoms.

Several recent controlled studies have shown that high doses of LSD produce beneficial emotional effects, such as reduced reactivity to fearful faces and increased feelings of trust and closeness to others.

LSD has been reported to improve cognitive function in animal models of depression, and this is consistent with cellular findings that LSD increases dendritic arbor complexity, promotes growth of dendritic spines, and stimulates formation of synapses.

Several studies have examined the effects of low doses of psychedelic drugs in human volunteers, including a controlled setting with LSD (0, 5, 10, and 20 mg) and a naturalistic setting with psilocybin or psilocin. Participants reported transient enhanced mood and well-being.

In a double-blind, within-subject placebo-controlled laboratory study, 3 low doses of LSD altered mood, cognition, and affective responses to stimuli with emotional valence.

Study Design

Healthy young adults received 0 (placebo), 6.5, 13, or 26 mg of LSD in 4 sessions, and completed behavioral tasks assessing cognition and affective responses to emotional stimuli.

Subjects

Subjects were recruited from the community and were required to have a high school education, a body mass index of 19 to 26, no current or past year DSM-5 disorders, and no regular medication aside from birth control.

Subjects were instructed to abstain from drugs and medications for 48 hours before and 24 hours after each session, as well as from cannabis and alcohol for 24 hours before and 12 hours after each session.

Procedure

Subjects attended four 8-hour experimental sessions beginning at 9:00 AM and separated by at least 7 days. They were tested for compliance to drug abstinence instructions, subjective state, cardiovascular function, and mood 48 hours after each session.

Drug

The drug was manufactured by Organix and prepared in solution with tartaric acid by the University of Chicago Investigational Pharmacy. It was administered sublingually at doses below the threshold for hallucinatory effects.

Subjective and Cardiovascular Drug Effects

The Drug Effects Questionnaire consists of 5 questions assessing subjective drug effects using 100-mm visual analog scales.

A POMS was administered before and after drug administration to assess mood, and a POMS Depression scale was used 48 hours after each session.

5 Dimensions of Altered States of Consciousness

The 5D-ASC Questionnaire measures 5 aspects of the psychedelic experience: Oceanic Boundlessness, Dread of Ego Dissolution, Visionary Restructuralization, Acoustic Alterations, and Vigilance Reduction.

Physiological, Behavioral, and Cognitive Measures.

The dual n-back, digit symbol substitution, cyberball, emotional images, and remote associations tasks were administered during the sessions.

Statistical Analyses

Analyses were conducted using SPSS, version 25 (IBM Corp., Armonk, NY). Behavioral data were analyzed using repeated-measures analysis of variance with dose and time as within-subjects factors.

Subjective Effects

LSD (13 and 26 mg) significantly increased ratings of “feel drug”, “feel high”, “like drug” and “dislike drug” on the Drug Effects Questionnaire. There was a trend toward a dose3 time interaction on “want more”.

LSD (26 mg) increased scores on the LSD subscale compared with placebo (Figure 1B). There were no significant drug effects on the other subscales.

LSD significantly increased ratings of Vigor, Friendliness, and Anxiety on the Profile of Mood States (POMS). It did not significantly affect Elation, Depression, Anger, Fatigue, and Confusion.

LSD dose-dependently increased ratings on the 5D-ASC Questionnaire on the subscales of Experience of Unity, Blissful State, Impaired Control and Cognition, and Changed Meanings of Percepts. There were no significant linear drug effects on Disembodiment, Anxiety, Elementary Imagery, and Audiovisual Synesthesia.

Physiological Effects

LSD (13 and 26 mg) significantly increased blood pressure, and diastolic blood pressure, but did not affect heart rate or basal body temperature.

Emotion Processing Tasks

LSD had little effect on task performance, except for a marginal decrease in positivity ratings for positive pictures.

Drug Identifications

14 participants correctly guessed that they had received placebo, 6 participants correctly guessed that they had received a hallucinogen, and 2 participants incorrectly guessed that they had received a stimulant, sedative, opioid, or cannabinoid.

DISCUSSION

In this study, very low microdoses of LSD produced measurable modest increases in ratings of drug effect scales and subtle effects on behavioral tasks in healthy young adult volunteers.

LSD produced measurable subjective and physiological effects at doses of 13 and 26 mg. The dose that produced the most pronounced effects was 26 mg, which increased blood pressure but did not affect temperature or heart rate.

Some evidence suggests that higher doses of LSD combined with psychotherapy can have beneficial effects on mood. However, the effects of repeated microdoses of LSD in clinical populations of symptomatic volunteers remain to be determined.

Single large doses of LSD have been shown to improve mood, but few studies have examined smaller doses administered at regular intervals. Anecdotal reports suggest that repeated microdoses of LSD improve mood and reduce ratings of depression.

Although some previous studies have suggested improvements in cognition, we did not detect these in our study. We did find that LSD marginally increased the number of attempted trials on a measure of creativity.

Several studies using higher doses of LSD have shown acute effects on emotion processing, but we did not observe similar effects in our sample. We speculate that increased global connectivity in the brain may affect perception of valenced stimuli, leading subjects to rate positive images as less positive.

In a controlled laboratory setting, we tested 3 doses of LSD and compared them with placebo. We concluded that the 13-mg dose would be optimal for a repeated dosing study because it produced minimal subjective, behavioral, affective, and cognitive effects that might interfere with normal function.

The effects of low doses of LSD should be investigated in individuals who report negative affect and in those who take the drug repeatedly. This will advance our understanding of the neural and behavioral processes underlying depressed mood and could lead to new treatments.