Preliminary report on the effects of a low dose of LSD on resting-state amygdala functional connectivity

In this double-blind, placebo-controlled study, a microdose of LSD (13 µg) was found to increase and decrease connectivity in various areas of the brain. One of these effects correlated positively with mood increases, but overall mood changes were variable.

Abstract

Background: The practice of “microdosing,” or the use of repeated, very low doses of lysergic acid diethylamide (LSD) to improve mood or cognition, has received considerable public attention, but empirical studies are lacking. Controlled studies are needed to investigate both the therapeutic potential and the neurobiological underpinnings of this pharmacologic treatment.

Methods: The present study was designed to examine the effects of a single low dose of LSD (13 μg) versus placebo on resting-state functional connectivity and cerebral blood flow in healthy young adults. Twenty men and women, 18 to 35 years old, participated in 2 functional magnetic resonance imaging scanning sessions in which they received a placebo or LSD under double-blind conditions. During each session, the participants completed drug effect and mood questionnaires, and physiological measures were recorded. During the expected peak drug effect, they underwent resting-state blood oxygen level-dependent and arterial spin labelling scans. Cerebral blood flow, as well as amygdala and thalamic connectivity, were analyzed.

Results: LSD increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and cerebellum and decreased amygdala connectivity with the left and right postcentral gyrus and the superior temporal gyrus. This low dose of LSD had weak and variable effects on mood, but its effects on positive mood were positively correlated with the increase in amygdala–middle frontal gyrus connectivity strength.

Conclusions: These preliminary findings show that a very low dose of LSD, which produces negligible subjective changes, alters brain connectivity in limbic circuits. Additional studies, especially with repeated dosing, will reveal whether these neural changes are related to the drug’s purported antidepressant effect.”

Authors: Anya K. Bershada, Katrin H. Preller, Royce Lee, Sarah Keedy, Jamie Wren-Jarvis, Michael P.Bremmer & Harriet de Wit

Notes

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

Summary

Low dose LSD improves resting state amygdalar functional connectivity. Controlled studies are needed to investigate the therapeutic potential and neurobiological underpinnings of this pharmacologic treatment. A low dose of LSD (13 micrograms) altered resting-state functional connectivity and cerebral blood flow in healthy young adults. This low dose of LSD had weak and variable effects on mood, but its effects on positive mood were positively correlated with the increase in amygdala – middle frontal gyrus connectivity strength.

Depressive disorders are among the most prevalent psychiatric conditions. Existing antidepressant medications have a number of limitations and therefore new medications are needed to manage symptoms of depression. Low doses of lysergic acid diethylamide (LSD) taken once every 3-4 days have been reported to have therapeutic effects, including enhanced mood, improved cognition, as well as relief from migraine headaches, pre-menstrual symptoms and traumatic brain injury. However, the effects of low doses of LSD on brain function are also not known. At very low doses, little is known about the actions of LSD. However, at higher doses, the effects are more apparent.

A low dose of LSD (13 g) increased global brain connectivity in the amygdala and medial prefrontal cortex, and reduced negative bias experienced by depressed patients. This study was designed to examine the neural effects of a low dose of LSD on resting state cerebral blood flow and connectivity in healthy adults.

This study used a within-subject, double blind design with 20 healthy young adults receiving 0 (placebo) or 13 g of LSD in two sessions. Subjective mood states and physiological measures were recorded at baseline, 60 min intervals after drug administration, and 90 min after peak drug effect. Subjects were told they might receive a placebo, stimulant, sedative, or hallucinogen drug, and were required to abstain from drugs and medications for 48 hours before and 24 hours after each session.

Subjects attended two 5-hour sessions beginning at 9 am, separated by at least 7 days. After compliance to drug abstention was verified, baseline measures of subjective state and cardiovascular function were obtained, and LSD was administered sublingually 30 minutes after arrival under double-blind conditions. A drug was manufactured by Organix, Inc. (MA), and prepared in solution with tartaric acid by the University of Chicago Investigational Pharmacy. Subjective drug effects were assessed using the Drug Effects Questionnaire (DEQ), the Addiction Research Center Inventory (ARCI), and the Positive and Negative Affect Schedule (PANAS).

The PANAS contains 20 items, including subscales for positive affect and negative affect, and the 5D-ASC contains 25 items. A 3T MRI scanner was used to measure neural responses during rest, and to assess for perfusion alterations that might qualify any fMRI changes observed. Peak change-from-baseline values were calculated for each subject on each repeated subjective and physiologic measurement.

fMRI data were analyzed using the CONN functional connectivity toolbox 18.b (26), which included functional realignment and unwarping, slice-timing correction, co registration, structural segmentation and normalization into a standard stereotactic space, functional normalization, outlier detection, and smoothing with a 8 mm full width at half maximum Gaussian kernel. The between-conditions contrast LSD>Pla was computed on the 2 nd level using seed-to-voxel connectivity maps. The 1 st eigenvariate of significant clusters was extracted for each participant and correlated with changes in positive and negative mood assessed with the PANAS questionnaire directly after scanning.

We preprocessed and quantified 9 ASL data and used FSL’s BASIL toolbox to assess between-drug change in CBF. The resulting statistical parametric maps were evaluated at a significance threshold of P 0.05 FWE corrected. LSD produced few subjective or physiological effects, but significantly increased scores on the sedation scale PCAG of the ARCI and increased systolic blood pressure. Men and women did not differ on most measures, although women reported experiencing the drug effect earlier than men.

LSD increased thalamus connectivity in the cerebellum, amygdala connectivity in the angular gyrus, middle frontal gyrus and cerebellum, and decreased amygdala connectivity in the postcentral gyrus and superior temporal gyrus. This increased amygdala connectivity was correlated with positive mood.

A very low “microdose” of LSD increased amygdala seed-based connectivity with the right angular gyrus, right middle frontal gyrus, and the cerebellum, and decreased connectivity with the left and right postcentral gyrus and the superior temporal gyrus. This study investigates the effects of a very low dose of LSD on resting state connectivity and CBF. The results are consistent with previous work showing reduced amygdala system modulation, including lower amygdala activation and decreased amygdala connectivity to the frontal pole.

The viewing of angry faces decreased connectivity between the amygdala and the superior temporal gyrus in the LSD group. Amygdala hyperreactivity has been associated with a host of psychiatric disorders involving negative processing bias, and SSRIs are known to dampen amygdala responses. Moreover, increased connectivity between the amygdala and middle frontal gyrus, right angular gyrus, and cerebellum was observed in LSD users.

A microdose of LSD did not alter thalamo-cortical connectivity, but changed information processing in emotional networks, but did not induce psychedelic symptoms or an altered state of consciousness. Our study had several limitations, such as including only healthy volunteers, investigating effects of only a single administration of LSD, and not examining subjects’ responses to behavioral tasks implicated in mood-enhancing effects of drugs. Here we report the results of the first study to investigate the effects of a very low dose of LSD on resting state functional connectivity in healthy human volunteers.

Figure 1 shows that participants exhibited stronger amygdala seed-based connectivity in the LSD condition compared to the Pla condition.

LSD and Pla induce alterations in the amygdala seed-based connectivity, which is correlated with changes in positive mood.

The mean values for the effects of the drug are shown in Table 2. The 5D-ASC is a retrospective report completed only at the end of the session.

Study details

Compounds studied
LSD

Topics studied
Microdosing Neuroscience

Study characteristics
Placebo-Controlled Double-Blind Within-Subject Randomized

Participants
20 Humans

Authors

Authors associated with this publication with profiles on Blossom

Harriet de Wit
Harriet de Wit is a Professor of Psychiatry and Behavioral Neuroscience at the University of Chicago. Her research focuses on the physiological, subjective (i.e., mood-altering), and behavioral effects of drugs in healthy human volunteers.

Institutes

Institutes associated with this publication

University of Chicago
Research with psychedelics is taking place at the Human Behavioral Pharmacology Lab at the University of Chicago.

Linked Clinical Trial

Mood Effects of Serotonin Agonists
The purpose of this study is to determine the effects of very low doses of serotonergic agonists on depressed mood in human volunteers.

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