Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca
Nicole Leite Galvão-Coelho, Ana Cecília de Menezes Galvão, Raíssa Nóbrega de Almeida, Fernanda Palhano-Fontes, Isaac Campos Braga, Bruno Lobão Soares, João Paulo Maia-de-Oliveira, Daniel Perkins, Jerome Sarris and Draulio Barros de Araujo
Journal of Psychopharmacology, 2020, 1-9.
DOI : 10.1177/0269881120936486
Background : Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients (n = 28) and healthy controls (n = 45).
Aims : We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale.
Results : At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed (rho = –0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed.
Conclusions : These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.
Keywords : BDNF, biomarkers, cortisol, immune system, psychedelics
Pharmacological interventions are the most used therapeutic strategy to treat major depressive disorder (MDD). However, about 50% of treatments are unsuccessful in preventing relapse, leading to recurrent MDD (Aherne et al., 2017; Monroe and Harkness, 2011). MDD is a heterogeneous disorder and the understanding of its neurobiology is essential for the development of more efficient treatments (Jha and Trivedi, 2018; Mora et al., 2018).
Some depressive patients have higher blood levels of proinflammatory biomarkers, such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) (Jha and Trivedi, 2018; Mora et al., 2018). IL-6 is a specific inflammatory biomarker produced by immune and non-immune cells that has pleiotropic actions on the immune system, physiology processes, and behavior (Uciechowski and Dempke, 2020). CRP is a nonspecific inflammatory biomarker produced by hepatocytes, released mainly due to classic IL-6 signaling and, to a lesser extent, by stimulus of other pro-inflammatory factors such as IL-1β (Kramer et al., 2007). CRP is usually used in clinical routine to assess systemic inflammation due to its stability, prolonged half-life (about 20 hours), and its low cost of dosage (Ivashchenko et al., 2005).
The inflammation observed in a subset of depressive patients, such as treatment-resistant patients, is lower than that seen in typical inflammatory diseases, such as infections or autoimmune disorders (Chamberlain et al., 2019; Osimo et al., 2019; Raison and Miller, 2011). Drug-naïve depressive patients have showed similar levels of CRP or IL-6 to healthy controls (Cubała and Landowski, 2014; Zou et al., 2018). Therefore, some studies have identified an association between inflammation and depression
severity (Haapakoski et al., 2015).
The relationship between inflammation and antidepressant treatment is complex. A reduction in IL-6 after treatment has been observed, but not in CRP and TNF-α (Więdłocha et al., 2018), although these findings are not in consensus (Arteaga-Henríquez et al., 2019). In fact, the anti-inflammatory effects of antidepressants may be influenced by the pre-treatment level of inflammation (Arteaga-Henríquez, et al., 2019; Zhang et al., 2019).
There is consensus that the chronic stress response, associated with MDD, disrupts the balance between pro-inflammatory and anti-inflammatory pathways (Slavich and Irwin, 2014; Sousa et al., 2015). A further change induced by chronic stress is the reduction of brain-derived neurotrophic factor (BDNF), an important modulator of neurogenesis and neuroplasticity. The reduced level of BDNF is suggested to be associated with changes in brain volume in specific areas among patients with MDD, such as hippocampus (Foltran and Diaz, 2016; Jesulola et al., 2018). These biological alterations show multiple physiological interactions and have been associated with MDD (Dooley et al., 2018; Jesulola et al., 2018).
Due the low efficacy of antidepressants (Hengartner et al., 2018), there is a renewal interest in the use of classic serotonergic psychedelics for treatment of MDD (ayahuasca: Almeida et al., 2019; Galvão et al., 2018; Osório et al., 2015; Palhano-Fontes et al., 2015, 2018; Sanches et al., 2016; psilocybin: Carhart-Harris et al., 2016; Griffiths et al., 2016; Ross et al., 2016). These substances have been identified as potential fast-acting antidepressants, due to their short latency for clinical improvement (Almeida et al., 2019; Ramaker and Dulawa, 2017). Some studies have also proposed a direct anti-inflammatory effect of psychedelics via serotonin 2A receptors (5-HT2A) and sigma-1 receptor (σ1R) (Flanagan and Nichols, 2018; Szabo et al., 2014).
In this study we report blood levels of the pro-inflammatory biomarkers IL-6 and CRP from volunteers recruited for a randomized placebo-controlled trial of ayahuasca for treatmentresistant depression (Palhano-Fontes et al., 2018). In this trial patients received a single dose of ayahuasca or placebo and a significant antidepressant effect of ayahuasca was observed 1, 2, and 7 days after treatment (Palhano-Fontes et al., 2018).
We investigated the blood inflammatory biomarkers of these patients and of healthy controls in the pre-treatment phase, and tested if these levels were reduced after ayahuasca intake compared to placebo. We hypothesized that the changes in inflammatory markers and depressive symptoms would be correlated
and predictive of the antidepressant response and remission rates 48 hours after ayahuasca intake. We also explored the correlation between inflammatory biomarkers, cortisol and BDNF serum levels, which were previously evaluated from this clinical trial (Almeida et al., 2019; Galvão et al., 2018), and we expect to find negative relationship between them.