Combined DMT-harmine formulation reduces negative self-referential emotions during social self-evaluation: a randomized placebo-controlled trial in healthy volunteers

RATIONALE AND OBJECTIVES: Negative self-referential emotions such as embarrassment and shame play a key role in the psychopathology of psychiatric disorders but are often insufficiently addressed by standard treatments. Psychedelics such as ayahuasca - an Amazonian plant decoction containing the psychedelic N,N-dimethyltryptamine (DMT) and harmala alkaloids, have been proposed to positively modulate self-referential processing. The aim of this study was to investigate the effects of an ayahuasca-inspired harmine+DMT formulation and harmine on embarrassment and shame. METHODS: In this randomized, double-blind, placebo-controlled crossover trial (N = 28 healthy males), the effects of combined 100mg harmine and 100mg DMT (HAR/DMT), harmine alone (HAR), against placebo (PLA) on self-referential processing was investigated using a karaoke paradigm, where participants listened to recordings of their own singing (Self = S) and control vocal tracks (other bad = OB; other good = OG) and rated emotional responses. Acute emotions were assessed with visual analogue scales (items: pleasant, unpleasant, embarrassing, funny, and objective quality) and the Experiential Shame Scale (ESS). RESULTS: HAR/DMT compared to placebo significantly reduced embarrassment in the Self condition (EMM=-16.83, p=.001), but not in the two other conditions (OB: EMM=-4.38, p=.628; OG: EMM= 2.14, p=.894). HAR/DMT-HAR or HAR-PLA contrasts for embarrassment were not significant for any condition. HAR/DMT compared to placebo reduced ESS global score (F(df)= 4.26(2, 54); p=.019) and ESS emotional subscale (F(df)=5.11(2, 54); p=.009), while harmine alone showed no significant effects. CONCLUSIONS: These findings suggest that HAR/DMT acutely modulates negative self-referential emotions and may, thus, offer a promising therapeutic approach, which should be further investigated in clinical populations.