Nicole Galvão-Coelho has long had an interest in studying the treatment of depression, particularly alternative treatments to traditional antidepressants such as lifestyle interventions, to improve the mental health of patients.
But the associate professor of Physiology and Behavior at the Federal University of Rio Grande do Norte in Brazil says she was surprised when she received an invitation from a research colleague in 2011. Dráulio B. Araújo, a professor of neurosciences at Federal University of Rio Grande do Norte asked Galvão-Coelho if she would like to join his team to conduct a clinical trial for the treatment of depression with ayahuasca, a psychedelic brew created by Indigenous peoples in Brazil and other South American countries.
“When Dráulio invited me, I never heard about ayahuasca,” Galvão-Coelho says. “It’s a little bit funny because people outside of Brazil think that in Brazil, everybody drinks ayahuasca and it’s not true.”
Indigenous people use ayahuasca for healing and spiritual purposes, and some contemporary churches use ayahuasca as a sacrament in religious ceremonies. Unlike LSD and other classical psychedelics, ayahuasca has been legal for religious use in Brazil since 1987.
“No one uses ayahuasca to get high,” Galvão-Coelho says. “This is why I had never heard about ayahuasca.”
In 2016, Galvão-Coelho and Araújo’s team in Brazil conducted a first of its kind placebo controlled clinical trial using ayahuasca to treat depression. The findings were very similar to the results of studies in the U.S. and UK using psilocybin, the psychedelic compound in magic mushrooms. The researchers found that in a double blind trial with a placebo, ayahuasca reduced depression in the research subjects. The results of the ayahuasca study were published in 2019 in the journal Physiological Medicine.
“We were the first group to do a double blind trial with a classic psychedelic for depressive patients,” Galvão-Coelho says. “The other studies when they were double blind, were done with cancer patients, or they were open trials with depressive patients.”
Galvão-Coelho recently gave a series talks in the U.S., including stops at the University of California San Francisco and Berkeley campuses — to discuss her team’s ongoing work with ayahuasca and its key component, N, N-Dimethyltryptamine, more commonly known as DMT. The group’s research not only suggests DMT and ayahuasca may provide some of the same benefits documented for psilocybin in U.S. and UK clinical trials, it also provides a template for how to work with the substance in clinical settings.
Some of Galvão-Coelho’s research also adds a tantalizing data point to the question of whether the subjective content of a psychedelic experience is an important component of its therapeutic effects. During her discussions with researchers at UC Berkeley, it was also noted that research subjects who come from disadvantaged communities in Brazil may report improved mental health as a result of receiving meals and lodging during the research period.
What is Ayahuasca?
Ayahuasca is a beverage created by boiling an array of plants containing known psychedelic compounds. The exact recipe varies depending on the group making the brew, their traditions and the botanicals available to them. Most ayahuasca includes at least one plant containing DMT. The ayahuasca Galvão-Coelho and her colleagues studied included the DMT-containing leaves of the Psychotria viridis plant, a flowering shrub native to South America that’s part of the Rubiaceae family, a cousin to coffee.
Unlike either psilocybin or LSD, DMT is readily broken down in the body by the enzyme monoamine oxidase when consumed by mouth, which means DMT is not orally active. Isolated or synthetic DMT can be smoked — the preferred route of administration for the late psychedelic writer Terence McKenna — while some scientific research has utilized intravenous injections of DMT.
The traditional ayahuasca practice, however, is to add plant admixtures that contain monoamine oxidase inhibitors, which temporarily block the action of the enzyme and allow DMT to persist in the body after being swallowed. These typically come from adding segments of the tropical South American vine, Banisteriopsis caapi, which contains the monoamine oxidase inhibitors (MOAIs) harmine and harmaline.
While DMT is considered the primary psychedelic ingredient in ayahuasca, harmine and harmaline are reportedly psychoactive in their own right, if not to the colorful extent of DMT. Studies investigating harmine also reveal anti-tumor properties, and an ability to stimulate the growth of new nerve cells. This suggests that there may be more to the healing properties of ayahuasca than the psychedelic effects alone.
Clinical Research on Ayahuasca
Galvão-Coelho, Araújo and their team became interested in the growing membership of churches using ayahuasca as a sacrament and for healing. Churches such as the Santo Daime and União do Vegetal have congregations throughout the world including in the U.S. They also noted the groundswell of research on the antidepressant effects of classical psychedelics such as psilocybin, and some studies using ayahuasca that showed reductions in patient depression scores.
To conduct their 2016 study, researchers obtained ayahuasca brew from a branch of the Barquinha ayahuasca church in Ji-Paraná-RO, Brazil and recruited 29 patients currently suffering from depression. They gave ayahuasca to 14 of these patients in a hospital setting, but 15 received a placebo, something Galvão-Coelho and her colleagues note previous studies using ayahuasca lacked.
“There’s always an extensive discussion about placebo and various types of active placebo,” says Matthew Johnson, a psychiatrist and professor in psychedelics and consciousness at Johns Hopkins University, who has conducted research using psilocybin at the university. While placebos in many drug trials are inert sugar pills, psychedelics researchers sometimes opt for “active placebos,” that is, substances that produce some sort of noticeable subjective effect, so that subjects don’t immediately recognize they haven’t taken the psychedelic. Johnson has used both low dose psilocybin and a chemical relative of ketamine as an active placebo when studying higher dose psilocybin in patients.
Ayahuasca poses a unique challenge, in that it is both a complex, not great tasting beverage, and one that is renowned for instigating vomiting and sometimes diarrhea in those who take it. Galvão-Coelho’s team hit upon a recipe — they would use yeast, citric acid and food coloring to copy the brownish tint and bitter-sour taste of ayahuasca, along with zinc sulfate to engender “mild gastrointestinal distress.”
“That’s certainly a very clever way to go about controlling for that aspect of ayahuasca,” Johnson says.
Of the 15 patients in the placebo group, Galvão-Coelho says, five believed they had received ayahuasca.
The patients who actually received ayahuasca showed the most immediate reduction of depression symptoms as measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), an effect that persisted over time. “We found improvement in depression severity for all patients in the ayahuasca group seven days after dosing,” the researchers write in the paper, “while four patients in the placebo group have worsened their symptoms.”
The study also showed that the more intensely patients perceived the psychedelic experience, particularly their sense of “transcendence of time and space,” the larger the change in their subsequent MADRS scores.
“We found that psychedelic perception, the intensity of psychedelic perception, was important to clinical response,” Galvão-Coelho says. “Bigger intensity, larger response.”
How Much Does the Ceremonial Experience Matter?
After the 2016 investigation, Galvão-Coelho and her research team moved on to further studies of ayahuasca in both humans and animals.
In a March 2022 paper published in Frontiers in Behavioral Neuroscience, they found that treatment with ayahuasca had a prophylactic effect in preventing depression. Their research showed that the amount of stress experienced by socially isolated marmosets if the ayahuasca was reduced if given prior to the isolation.
That result not only aligns with claims of members of ayahuasca churches who consume ayahuasca for well being and healing from past traumas, it simultaneously bolsters the idea that the subjective psychedelic experience — a “spiritual” experience — is not entirely necessary for psychological benefits.
“It’s not just the spiritual context,” Galvão-Coelho says. “The substance, by itself is important too, ’cause in marmosets we saw that ayahuasca helps to avoid the depressive-like state.”
The researchers also found evidence for dissociating at least some of ayahuasca’s positive effects from the subjective psychedelic experiments in humans. In their subsequent November 2022 paper published in Frontiers in Behavioral Neuroscience, the researchers found that depressed patients who showed a better response to ayahuasca also exhibited higher levels of Brain Derived Neurotrophic Factor, or BDNF, a protein known to modulate neuroplasticity in the brain.
Those higher levels of BDNF were correlated with lower stress levels during the ayahuasca experience as measured by levels of the stress hormone cortisol in patients’ saliva. “We did not find any relationship between psychedelics perception and biological response,” Galvão-Coelho.
Her interpretation? Psychedelics, including ayahuasca, may have benefits for combatting stress, inflammation, or other health conditions regardless of the subjective psychedelic experience. This may be good news for companies and researchers hoping to develop psychedelic medicines without altered states of consciousness.
But when it comes to mental health conditions involving rumination such as depression, Galvão-Coelho says, “I have a guess that psychedelic effect is important.”
Can Ayahuasca Be Medicine?
The shift from psychedelics as purely spiritual sacraments to psychedelics as medicine is already underway in the U.S. with drug development companies such as COMPASS Pathways pursuing FDA approval for psilocybin therapies and the Multidisciplinary Association for Psychedelic Studies (MAPS) generating promising initial results from a Phase 3 clinical trial of MDMA to treat post traumatic stress disorder. Could ayahuasca be taken down the same path?
“You’re not going to have FDA approval of just oh, you know, take leaves off the Psychotria viridis plant and boil them,” Johnson says. The FDA will want specific dosage information for DMT and other active components. But with traditional ayahuasca, “it’s the equivalent of brewing up coffee, you can’t know exactly how much caffeine is in it. You’d have to do assays of that particular pot of coffee to know exactly.”
Clinical trials with ayahuasca are also complicated by the nausea and vomiting commonly induced by ayahuasca, a phenomenon not seen nearly as often with psilocybin, according to Johnson. Although he says there is the prospect of using freeze dried ayahuasca, as Spanish MAPS researcher Jordi Riba attempted, who subsequently found that participants had very little nausea.
“Perhaps because the freeze drying process killed off microbes that are present in ayahuasca,” Johnson says. “Freeze drying is a form of concentrating it; you’re basically sucking all of the possible water out of it, getting it down into a fine product and you standardize it,” which could make it easier to get approved medical use.
At the same time, Draulio Araujo says it’s not yet clear if eliminating the unpleasant aspects of taking ayahuasca is a good idea. “Even in our clinical trials, it seems that purging and setting are important for the positive outcome,” he says.
Araujo began researching ayahuasca in 2006 out of pure curiosity, and never had any intention to develop the brew into a medication, even if other research groups go that route.
“The possibility of ayahuasca becoming a medicine seems closer and closer to me,” Araujo says. “We never invested in this idea because we believe that, first, the indigenous populations, inventors of this technology, should be consulted and reimbursed.”
At the same time, Galvão-Coelho’s research team has shifted to researching DMT on its own rather than in the form of ayahuasca.
“Because it has a faster effect than ayahuasca, then, if it also shows a good clinical response in patients,” it would be easier and cheaper to develop a clinical protocol for its use, Galvão-Coelho says. While the goal is to study DMT in a clinical population, she adds that more research must first be done before possibly developing DMT — or ayahuasca — as a treatment for depression.
“At the moment,” says Galvão-Coelho, “we are focused on understanding the cognitive and neurobiological response of DMT in healthy volunteers.”