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

A low dose of LSD (26 micrograms) altered brain responses to reward feedback in people with mild-to-moderate depression, compared to those without depression. In depressed participants, LSD increased a brain signal called the late positive potential (LPP) when they received loss feedback, suggesting enhanced emotional processing of rewards. This change was linked to immediate positive mood and lower depressed mood two days later. Across all participants, LSD reduced other reward-related brain signals. The findings cautiously support the idea that low-dose LSD may have antidepressant effects.

Study at a glance

Abstract

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