Beyond the Psychedelic Effect: Ayahuasca as Antidepressant

Ayahuasca is a psychoactive beverage that has long been used by indigenous people in South America in religious ceremonies and tribal rituals. In recent years, the beverage has emerged as a strong candidate for implementation into psychiatric care, particularly for patients with treatment-resistant depression.

Studies have shown that taking ayahuasca is associated with an improvement of depressive symptoms. In a study published on December 5, 2022, in Frontiers in Psychiatry, a team of researchers from Brazil’s Federal University of Rio Grande do Norte (UFRN) describe an experimental ayahuasca session. They found that specific emotional and physiologic parameters were critical moderators of improvement in major depression biomarkers, mainly serum brain-derived neurotrophic factor (BDNF) and serum cortisol (SC), 2 days after ayahuasca intake.

Nicole Leite Galvão-Coelho, PhD, professor of physiology and behavior at UFRN, is one of the authors of that study. She is also a researcher at the NICM Health Research Institute at Western Sydney University, Sydney, New South Wales, Australia. Galvão-Coelho spoke with Medscape Medical News about her team’s work.

A total of 72 people volunteered to participate in the study. There were 28 patients, all of whom were experiencing a moderate to severe depressive episode at screening. In addition, they had been diagnosed with treatment-resistant depression and had not achieved remission after at least two treatments with antidepressant medications of different classes. These patients had been experiencing deprssion for about 10.71 ± 9.72 years. The other 44 volunteers were healthy control participants. All the participants — both in the patient group and the control group — were naive to any classic serotonergic psychedelic such as ayahuasca.

In each group, half received ayahuasca, and the other half received a placebo. The dosing session was performed at UFRN’s Onofre Lopes University Hospital and lasted about 8 hours.

All volunteers underwent a full clinical mental health evaluation and medical history. Blood and saliva samples were collected at baseline, approximately 4 hours before the dosing session, and 2 days after the dosing session. During the dosing session, saliva samples were collected at 1 h 40 min, 2 h 40 min, and 4 h after ayahuasca intake.

The study showed that some acute measures assessed during ayahuasca dosing moderated the improvements in major depressive disorder (MDD) biomarkers 2 days after the session in patients with treatment-resistant depression. Larger acute decreases of depressive symptoms moderated higher levels of SC in those patients, while lower acute changes in SC levels were related to higher BDNF levels in patients with a larger clinical response.

The UFRN research team has been investigating the potential antidepressant effects of ayahuasca for approximately 12 years. According to Galvão-Coelho, the work reported in the most recent article — one in a series of articles that they wrote — provides a step forward as a pioneering psychedelic field study assessing the biological changes of MDD molecular biomarkers. “There have indeed been observational studies and open-label clinical studies. We were the first team, though, to conduct placebo-controlled clinical studies with ayahuasca in patients with treatment-resistant depression,” she explained. She noted that the work was carried out in partnership with Dráulio Barros de Araújo, PhD, a professor at UFRN’s Brain Institute, as well as with a multidisciplinary team of researchers in Brazil and Australia.

Galvão-Coelho said that in an earlier study, the UFRN researchers observed that a single dose of ayahuasca led to long-lasting behavioral and physiologic improvements in an animal (marmoset) model. In another study, there was improvement in depression severity for patients with treatment-resistant depression 7 days after taking ayahuasca.

As for biomarkers, Galvão-Coelho said that there is a long history of research on cortisol (the “stress hormone”) with respect to patients with depressive symptoms, given the link between chronic stress and depressive disorders. “In our patients with treatment-resistant depression, we found that before being dosed with ayahuasca, they presented hypocortisolemia,” she said. She noted that low levels of cortisol are as harmful to one’s health as high levels. According to her, the goal should be to sustain moderate levels. “In other studies, we’ve shown that patients with more recent, less chronic depression have high cortisol levels, but after a little while, the [adrenal] glands get overworked, which seems to lead to a situation where they’re not producing all those important hormones. That’s why chronic conditions of depression are marked by low levels of cortisol. But,” she pointed out, “after patients with treatment-resistant depression take ayahuasca, we no longer see hypocortisolemia.”

Another biomarker analyzed by the research team, the protein BDNF, has the capacity to induce neuroplasticity. Indeed, Galvão-Coelho mentioned a theory that antidepressant drugs work when they increase levels of this protein, which would stimulate new connections in the brain.

Because several earlier studies indicated that other psychedelic substances would promote an increase in BDNF, the UFRN researchers decided to explore the potential effects of ayahuasca on this biomarker. “We observed that there was actually an increase in serum BDNF, and the patients who showed the greatest increase [of this marker] had a more significant reduction in depressive symptoms,” Galvão-Coelho explained.

Considering all the previous findings, the team wondered whether acute parameters recorded during an ayahuasca dosing session could in some way modulate the responses of certain key MDD molecular biomarkers. They then conducted their study that was published last December.

Galvão-Coelho said that the results of that study show that acute emotional and physiologic effects of ayahuasca seem to be relevant to an improvement of key MDD molecular biomarkers (namely, SC and BDNF). She also noted that the results revealed that larger reductions of depressive symptoms during the dosing session significantly moderated higher levels of SC in patients 2 days after ayahuasca intake. In the case of BDNF, the positive correlation between clinical response and day-2 BDNF levels only occurred for patients who experienced small increases of cortisol during the experimental session. These were individuals who did not have such an intense response to stress and who felt more at ease during the session.

The findings showed which factors that arise during the psychedelic state induced by ayahuasca modulate biological response associated with the antidepressant action of these substances in patients with major depression. “We realized, for example, that to bring about a sense of comfort and trust, to get a good acute response, the dosing session had to be extremely well thought out. That seemed to be relevant to the results on the other days,” Galvão-Coelho explained.

For her, there was another take-away from the research: new antidepressant treatments should be complemented by a more comprehensive view of the case at hand. “We have to think about the patient’s overall improvement — including, therefore, the improvement of biomarkers — and not focus solely on the clinical symptoms.”

This article was translated from the Medscape Portuguese Edition.

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