de Araujo, D. B. | bioRxiv Science

bioRxiv2017

Short term changes in the proteome of human cerebral organoids induced by 5-methoxy-N,N-dimethyltryptamine

Dimethyltryptamines are hallucinogenic serotonin-like molecules present in traditional Amerindian medicine (e.g. Ayahuasca, Virola) recently associated with cognitive gains, antidepressant effects and changes in brain areas related to attention, self-referential thought, and internal mentation. Historical and technical restrictions impaired understanding how such substances impact human brain metabolism. Here we used shotgun mass spectrometry to explore proteomic differences induced by dimethyltryptamine (5-methoxy-N, N-dimethyltryptamine, 5-MeO-DMT) on human cerebral organoids. Out of the 6,728 identified proteins, 934 were found differentially expressed in 5-MeO-DMT-treated cerebral organoids. In silico systems biology analyses support 5-MeO-DMTs anti-inflammatory effects and reveal a modulation of proteins associated with the formation of dendritic spines, including proteins involved in cellular protrusion formation, microtubule dynamics and cytoskeletal reorganization. Proteins involved in long-term potentiation were modulated in a complex manner, with significant increases in the levels of NMDAR, CaMKII and CREB, but a reduction of PKA and PKC levels. These results offer possible mechanistic insights into the neuropsychological changes caused by the ingestion of substances rich in dimethyltryptamines.

neuroscience↗

bioRxiv2017

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double-blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery-[A]sberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0{middle dot}019; Cohens d=0{middle dot}98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0{middle dot}04; at D7, p<0{middle dot}0001). Between-group effect sizes increased from D1 to D7 (D1: Cohens d=0{middle dot}84; D2: Cohens d=0{middle dot}84; D7: Cohens d=1{middle dot}49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4{middle dot}95; p = 0{middle dot}04; NNT = 2{middle dot}66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.

clinical trials↗