Study on LSD microdosing uncovers neuropsychological mechanisms that could underlie anti-depressant effects

by Eric W. Dolan  December 3, 2022 in LSDMicrodosing

A single, low dose of  lysergic acid diethylamide (LSD) can increase reward-related brain activity, according to new research published in Neuropsychopharmacology. The study indicates that the psychedelic drug alters neuropsychological processes that tend to be blunted in patients with depression.

The findings could have important implications for understanding the relationship between microdosing and mental health.

Microdosing is becoming increasingly popular as a means of improving productivity, creativity, or overall psychological wellbeing. The practice involves taking very small doses of LSD or other psychedelic substances on a regular basis. But there is little scientific evidence regarding the purported benefits of microdosing.

“After seeing the numerous media reports of the benefits of microdosing, I felt that there was a need for controlled studies,” explained lead researcher Harriet de Wit, a professor at the University of Chicago and director of the Behavioral Pharmacology Laboratory. “My laboratory is equipped to investigate whether very low doses of LSD produce changes in mood, behavior or, in this study, brain function.”

“The use of this drug under naturalistic conditions is influenced by strong expectancies of benefits by the users, and expectancies are known to affect responses to drugs. By studying the drug under double-blind, placebo controlled conditions we can determine what the drug itself does without the expectancies. In this particular study, we wanted to know whether low doses of LSD change the brain’s signature response to a rewarding stimulus.”

In the study, 18 healthy young adults participated in three five-hour laboratory sessions in which they received placebo, 13 μg of LSD, or 26 μg of LSD in randomized order. The sessions were separated by at least 7 days. Approximately 120 minutes after receiving placebo or LSD, the participants completed a monetary incentive delay task as the researchers recorded their brain activity using electroencephalography.

During the task, the participants responded as quickly as possible to target stimuli displayed on a computer screen, which signaled the potential opportunity to win small sums of money. They received positive or negative feedback after each attempt, based on their performance.

The researchers were particularly interested in three different patterns of electrical brain activity. Reward-Positivity reflects a hedonic effect that occurs after a person receives a reward, and it is thought to reflect the encoding of feedback about the success of reinforcement learning. Late-Positive Potential occurs after a person learns about an outcome, and it is thought to reflect the processing of emotional stimuli. Feedback-P3 occurs after a person receives feedback about their performance, and it is thought to reflect the updating of predictive models.

“In this study we showed that a low dose of LSD, in the range of doses that people use when they ‘microdose’ LSD, can increase the brain’s response to a rewarding stimulus,” de Wit told PsyPost. “Previous studies have shown that individuals with depression show a dampened brain response to reward. In our study, we found that a low dose of LSD increased the reward-related signal in a way that is consistent with possible anti-depressant effects. This may be related to the purported beneficial effects of microdosing.”

Compared to placebo, De Wit and her colleagues found that both doses of LSD increased Feedback-P3 amplitudes, but only 13 μg of LSD increased Reward-Positivity and Late-Positive Potential amplitudes when the participants were presented with a potential reward.

“One surprising finding was that the effects of the drug were not simply, or linearly, related to dose of the drug,” de Wit said. “Some of the effects were greater at the lower dose. This suggests that the pharmacology of the drug is somewhat complex, and we cannot assume that higher doses will produce similar, but greater, effects.”

Whether microdosing has any positive benefits remains unclear. In a previous study, de Wit and her colleagues failed to find evidence that taking low doses in LSD resulted in improvements to mood or cognition. The researchers said that more research is needed to determine the long-term effects of microdosing, and whether it holds promise as a safe and effective way to improve mental health.

“Many questions remain unanswered,” de Wit explained. “First, can this finding be replicated by others? Does the effect hold true in other subject populations, such as individuals who report low mood states? What happens if the drug is administered repeatedly – do the effects increase or decrease? And, does the drug improve psychiatric symptoms, and if so, how are these brain changes related to the possible clinical benefits?”

The study, “Low doses of lysergic acid diethylamide (LSD) increase reward-related brain activity“, was authored by James Glazer, Conor H. Murray, Robin Nusslock, Royce Lee, and Harriet de Wit.