Immunomodulatory and behavioral effects of ayahuasca and N, N-dimethyltryptamine in a rat model of lipopolysaccharide-induced depression

Metab Brain Dis. 2025 Jun 11;40(5):220. doi: 10.1007/s11011-025-01650-6.

ABSTRACT

Ayahuasca (Aya) is an Amazonian beverage traditionally used as medicine by Indigenous people in South America to treat various illnesses and have shown a potential to treat depression. This study aimed to investigate the antidepressant effects of fluoxetine, Aya and N, N dimethyl tryptamine (DMT), a component of the beverage, focusing on the modulation of inflammatory serum cytokine profiles and behavior of Wistar rats subjected to lipopolysaccharide (LPS)-induced depression. In total, 126 rats were randomly assigned to seven groups: saline control, LPS, fluoxetine, three ayahuasca groups (dosed at 0.5, 1, and 2 times the usual ritualistic dose, Aya0.5, Aya1 and Aya2), and one DMT treatment group. The rats received LPS every other day from day 1 to 13 and fluoxetine, Aya and DMT daily from day 2 to 14. At day 15, the rats were submitted to open field and forced swimming tests, plasma samples were collected and the animals were euthanized. The LPS group showed lower body weight grain and higher plasma levels of pro-inflammatory cytokines IL-1α (p < 0.001), TNF-α, and IL-12p70 compared to control, which were significantly reduced by the treatment groups (p < 0.05 up to p < 0.0001), indicating a potential for modulation of the inflammatory state seen in depression. The Aya2 group exhibited increased locomotion in the open field arena compared to the fluoxetine (p < 0.05) and DMT (p < 0.01) groups, with a significantly higher percentage of entries into the center than the control group (p < 0.01). Furthermore, treatments with fluoxetine, Aya, and DMT significantly increased swimming time compared to the LPS group (p < 0.01), and fluoxetine and the Aya0.5 groups displayed higher climbing times compared to LPS and control (p < 0.05). Although the LPS model did not consistently induce depressive-like behaviors, the results highlight the potential of ayahuasca and DMT to modulate the immune system and reduce pro-inflammatory cytokine levels associated with depression, which could have significant implications for treating inflammation-related aspects of depression.

PMID:40498206 | DOI:10.1007/s11011-025-01650-6