There has been a lot of attention on the Amazonian plant medicine Ayahuasca over the last few years, especially for its therapeutic potential. But, frankly, there has also been a lot of hype. Statements such as “its 10 years of therapy in 1 night” get bandied about regularly. And the psychedelic press makes big proclamations like “A Single Session Of Ayahuasca Defeats Depression” when new research is released. Meanwhile, the mainstream press relishes in the ayahuasca tragedy stories or overly sensational stories about the visions or the purging. In the end it creates a cloud of misinformation and confusion about what ayahuasca is and what it can do. The truth is that while rigorous clinical trials scientifically studying the effects on humans is scant, there is a lot of evidence, anecdotally, clinically, and neurochemically, in favor of ayahuasca as an anti-depressive agent.

Working with Ayahuasca: Anecdotal Observations

Based on my own professional experience working in Peru full-time as an ayahuasca retreat facilitator, guide, and apprentice shaman for the past 2 years I can unequivocally say that I know that ayahuasca *can* cure depression. During that time, I’ve worked with and met countless people who specifically sought-out ayahuasca to treat their depression. Part of the reason is journalist Kyra Sylak's 2006 National Geographic article on her experience attending an ayahuasca retreat in the Peruvian Amazon. In it, she chronicled her dramatic recovery from depression and PTSD. That article was one of the most viewed National Geographic articles of all time and led to a lot of publicity around ayahuasca as a miracle cure for depression. Many people suffering from life-long and treatment-resistant depression came down to Peru in search of that miracle.

What I saw was that ayahuasca can indeed cure depression in some people, but it is not a panacea for everything or everyone. I worked with several guests who reported complete remission of their depression, not to mention major changes in their outlook on life and the healing of life-long traumas and emotional wounds. I also met several people who had attended their first ayahuasca retreat many years ago and reported that it literally saved their life. They were back now to work on different things or because they really enjoyed the experience. One guest told me that she was literally about to commit suicide several years ago when someone gave her the National Geographic article and it gave her enough hope to try one last remedy. These kinds of stories are not uncommon.

But there are also people who after 1 terrifying ceremony, decide that this is not for them and leave in a hurry. And there are also people who feel and look great when they finish their retreat only to return 6 months or a year later reporting a significant backslide. Most often this is due to them returning to the same depressogenic environment and not being able to make the structural life changes needed. Sometimes this is because these changes seemed too painful, daunting or traumatic to undertake (eg getting out of a relationship, quitting a job, moving, setting limits with family members, etc.) and over time the effects of, say, living in a toxic relationship, took their toll. For others, ayahuasca will clear the depression cloud that has been hanging over them but they’re going to need to do their part in terms of lifestyle changes when they get home to really liberate themselves permanently from depression. The people who, from what I’ve seen, get the most out of their ayahuasca experience do just this, using it as a springboard to make some major life changes (quitting drinking/smoking, begin meditating, improve nutrition, career changes, etc.)

But perhaps most importantly, I’ve seen ayahuasca help heal the root issues at the core of people’s depressions. Things like childhood trauma, old negative beliefs and patterns of thinking, and pervasive feelings of alienation and meaninglessness. And these are things that can take a long time to heal in traditional psychotherapy. This to me is more impressive because we are talking about more than just depression, but about changing the fundamental way people relate to themselves and their world. This is where the power in ayahuasca medicine lies and, in my opinion, the relief from depression is simply a reflection of the profound transformation occurring underneath.

What Does The Research Show?

While there are mountains of anecdotal evidence, there have only been two serious clinical studies that have been conducted examining the effects of ayahuasca on depression. In both studies depressed subjects were recruited, provided ayahuasca in a controlled setting, and followed-up with afterwards.

The first was a a small study conducted in Brazil in 2016 that examined the effects of ayahuasca on people with recurrent Major Depressive Disorder. In the study, subjects were given a one-time administration of ayahuasca in a hospital setting while seated quietly in a dimly-lit room. The study showed that the average depression score for subjects dropped from 19.2 on the HAM-D scale, a standard depression measurement questionnaire, to 7.5 at 21 days of follow-up. That is the equivalent of going from a moderate depression to full remission, so these results are pretty dramatic. However, this study only had 17 subjects and was neither blind nor placebo-controlled. It also followed subjects for only 21 days so who knows how they were doing 6 months or 1 year later. It was a promising preliminary study but definitely not the final word on ayahuasca and depression.

The same Brazilian team of researchers followed up a year later with a more thorough double-blind placebo controlled study of 29 subjects with treatment-resistant depression (14 in the ayahuasca and 15 in the control). This study is a big deal because it is the first double-blind placebo controlled study conducted on ayahuasca. They also showed that average HAM-D scores of the subjects administered a single dose of ayahuasca dropped from 21.8 to below 10. At the 1-week follow-up, 36% of the ayahuasca-drinking subjects were in full remission while only 8% of the control group was in remission. Again, very promising. However, clinically speaking these groups are too small to draw any definitive conclusions from. Furthermore, due to high drop-out rates, the team wasn’t able to continue the study beyond 1 week. That is a serious limitation as treatment-resistant depression is a long-term condition.

But these 2 clinical studies confirm the results of previous exploratory studies that administered ayahuasca to small groups of clinically depressant research participants. They also showed similar 50-60% declines in HAM-D scores up to 28 days later.

For comparison, the average drop in HAM-D scores in clinical trials for all FDA-approved SSRI-based anti-depressants was approximately 40%. And these were achieved with trials that explicitly excluded the very difficult treatment-resistant clients which where the focus of the ayahuasca studies. So the ayahuasca results, while preliminary are definitely promising, especially since this was after only a one-time administration of ayahuasca while current pharmaceutical treatments require weeks to build up in the body and then must be taken daily on an ongoing basis.

The Hoasca Project

Other researchers have taken the approach of studying the psychological health of long-term ayahuasca drinkers. The most famous of these non-clinical studies on ayahuasca, is the Hoasca Project, also conducted in Brazil, which administered psychological, biochemical, and physiological tests to long-term members of the Uniao do Vegetal Church in Manaus, who drink ayahuasca regularly in a religious context as a sacrament. These subjects had been drinking ayahuasca for many years, in some cases hundreds of times. Researchers compared the results of their psychological and biological tests with the results from a control group of age- and gender-matched subjects from the community. Now this was also a small study with only 30 total subjects, 15 of which were in the control. But the results revealed that most members of the UDV group had battled with alcoholism, addiction and depression prior to their participation in the ayahuasca church but none of the members currently met the criteria for a psychiatric or substance abuse diagnosis. The UDV members had experienced remission in all their psychiatric conditions, including depression, over the course of their participation with the ayahuasca church. This compares with the control group where 2 members had active psychiatric diagnosis. Other similar retrospective studies have showed essentially the same thing: long-term drinkers of ayahuasca appear to be psychologically healthier than their age/gender-matched community counter-parts and have significantly lower levels of addiction and psychiatric conditions.

Perhaps the most intriguing finding of the Hoasca Project was that the long-term ayahuasca drinkers showed significant increases in serotonin (5HT) transporters levels. Serotonin transporters are intimately related to the regulation of serotonin levels in the brain and are the target site for SSRI-based anti-depressants, so this finding showed one potential pathway by which ayahuasca can treat depression.

Ayahuasca: A complex brew

Ayahuasca is not one individual plant but a combination of plants cooked together to create a drinkable brew. The two primary ingredients are the vine ayahuasca (Banisterias Caapi) and the leaves of the chacruna plant (Psychotria Viridis), although ayahuasqueros will often include many other medicinal plants in their cook or use analogs in lieu of chacruna. Each of these two primary ingredients has their own antidepressant compounds. For example, the ayahuasca vine contains a variety of psychoactive alkaloids known as beta-harmalines that are inhibitors of the Monoamine Oxidase (MAO) enzyme. MAO inhibitors were the first anti-depressants ever developed and the Harmine in ayahuasca is a powerful one. Studies of rats administered with Harmine show a variety of anti-depressant and anti-anxiety like effects and increases in BDNF, which is a protein that supports the growth and function of neurons. 

The chacruna plant contains significant quantities of Dimethyltryptamine (DMT), which is the compound responsible for the visual and visionary experience associated with ayahuasca. DMT strongly affects a variety of Serotonin receptors in the brain as they are very close cousins. One of the serotonin receptors that DMT activates is known as 5HT-2A. This is an important receptor for a lot of psychedelics/entheogens and is considered by some to be a primary neurochemical pathway for psychedelic/visionary experiences. And studies show that harmine also binds to the 5HT-2A receptor, so ayahuasca may be delivering a double dose of serotonin activation at the 2A receptor. 

Recent studies show that some of the very medications psychiatrists prescribe to supplement traditional anti-depressants when they aren’t effective are major 5HT-2A receptor agonists. So we know that targeting 5HT-2A receptors can have anti-depressant properties, especially for those with intractable treatment-resistant depression.  

Powerful anti-depressant compounds, but what else?

At a minimum, ayahuasca contains two very powerful psychoactive compound that have anti-depressant effects. But how can they lessen depression in one session while traditional anti-depressant medications targeting the same neurochemistry take weeks? This is still a mystery. But even the reductionist scientific understanding of ayahuasca shows that there may be more going on than serotonin receptor activation. For example, there is neuro-imaging evidence showing that ayahuasca causes marked reductions in activity and disruptions in connectivity in a network in the brain that is known to be over-active in people with depression.

My personal opinion is that the scientific understanding barely scratches the surface. A ceremonial ayahuasca experience includes a variety of ingredients (the individual, the setting, the peers and community, the shaman/facilitator, the specific constituents of the brew, the beliefs and understandings of how it works by the user, the spiritual nature of the experience for many, the physical purging that is a big part of the experience, etc.) and almost none of them have been examined scientifically. For example, only relatively recently have researchers discovered that psychedelic-caused mystical experiences can themselves have beneficial effects on mood, outlook, and personality.

Frankly, the scientific method does not lend itself well to examining such subjective experiences but that doesn’t mean that we can’t learn from the fruits of of that framework. However, it does mean that in many ways the scientific understanding is way behind the traditional Amazonian knowledge and wisdom that has been accumulated over hundreds of years and passed down from teacher to student. These traditions don’t have a western scientific theory for how Ayahuasca works, but they have tremendous practical knowledge and wisdom on how to wield ayahuasca effectively for maximum benefit.