Reward-related neural activity after low doses of LSD in participants with depressed mood

A new study suggests that low doses of the psychedelic drug lysergic acid diethylamide, better known as LSD, can enhance how the human brain processes emotional rewards.

A new study suggests that low doses of the psychedelic drug lysergic acid diethylamide, better known as LSD, can enhance how the human brain processes emotional rewards. New research published in the Journal of Psychopharmacology, points to specific shifts in electrical brain activity following the administration of a small dose in patients experiencing mild depression. These neural changes corresponded with an improved mood that lasted for days after the initial exposure.

The study's primary discovery is that low-dose LSD acts as a neurobiological corrective for "depressive blunting" the reduced emotional response to outcomes often seen in depression. This provides some of the first controlled evidence for the "microdosing" or very low dose hypothesis that sub-hallucinogenic doses of LSD can have antidepressant effects by modulating how the brain processes rewards and emotional feedback. The researchers suggest that by amplifying the "emotional sting" of negative outcomes and the salience of positive ones, the brain is better able to update its expectations and engage with the environment, countering the apathy associated with depression

Abstract

“Background:

Lysergic acid diethylamide (LSD) has been considered as a potential treatment for depression for over 75 years, but its therapeutic potential has only recently been considered in mainstream psychiatry. Repeated ingestion of low doses of LSD (“microdoses”) is thought to reduce depression, but the neurobiology underlying this effect is unknown. We previously reported that low doses of LSD increased event-related potentials (ERPs) during receipt of monetary rewards in healthy adults. LSD also produced more positive subjective effects in participants with mild-to-moderate baseline symptoms of depressed mood, compared to controls.

Aim:

In this report, we examined the effects of LSD on reward ERPs in participants with mild-to-moderate depressed mood and in non-depressed controls.

Methods:

Participants with subclinical mild-to-moderate depression (N = 20) or controls with minimal symptoms (N = 19) received LSD (26 μg tartrate) or placebo on two sessions. Primary measures were ERPs during a reward task, and secondary measures included self-reported mood during and 48 hours after the sessions.

Results:

LSD (vs placebo) increased late positive potential (LPP) amplitude to loss (vs win) reward feedback only in participants with higher baseline depressed mood, suggesting enhanced affective processing given the role of LPP in emotional valuation of reward. This effect of LSD on LPP was associated with its acute positive mood effects, and with lower depressed mood 48-hour after the LSD (vs placebo) session. In the full sample, LSD (vs placebo) decreased feedback-P3 and LPP amplitude to reward (vs neutral) feedback.

Conclusion:

Although findings must be interpreted with caution, results support the idea that low doses of LSD have potential anti-depressant effects.

Glazer J, Molla H, Lee R, Nusslock R, de Wit H. Reward-related neural activity after low doses of LSD in participants with depressed mood. Journal of Psychopharmacology. 2026;0(0). Read Paper

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