A recently published study that administered ayahuasca to participants with treatment-resistant depression sheds new light on how ayahuasca affects mood and brain chemistry.

This study conducted in Brazil was a high-quality randomized double-blinded placebo-controlled trial looking at the effects of ayahuasca versus placebo and comparing the effects between 28 depressed and 45 non-depressed participants.

The study specifically focused on people experiencing the hardest to treat depression, known as treatment-resistant depression, which generally is defined as depression that is not alleviated by at least 2 different anti-depressant medications. In this study, depressed participants had tried an average of 3.8 different anti-depressant medications with no meaningful improvement in their depression.

The study also collected and evaluated important biological samples for all participants, before, during, and after their ayahuasca dosing session, including salivary and blood levels of cortisol, Brain-derived neurotrophic factor, and C-Reactive Protein, to see what role these important biological markers may play in ayahuasca’s effects on depression.

Findings

The study showed that after a single administration of ayahuasca in a controlled hospital setting, depressed participants experienced larger and significant reductions in depressive symptoms than were found in the group that received a placebo. Because the study only followed participants for 7 days, we don’t know how long this anti-depressant effect lasted but it did showed rapid and clinically significant antidepressant effect after a single session with ayahuasca.

According to one of the principal investigators, the participants were all administered a relatively weak ayahuasca tea with lower levels of DMT then might be found in a ceremonial settings. This was done purposefully because all of the participants were psychedelic-naive and did not have any prior experience with ayahuasca or other psychedelics. So even with this relatively weak ayahuasca dose, depressed participants experienced significant reductions in their depression.

Session Intensity

One interesting finding was that the the anti-depressant effects were positively correlated with the intensity of “psychedelic perception.” In other words, those who had a stronger visionary and psychedelic state during their ayahuasca session tended to have bigger reductions in depressive symptoms.

Cortisol Levels

While cortisol is a stress-related hormone and high cortisol levels can cause all kinds of negative mental and physical symptoms, it is well established that chronic and severe depression is often accompanied by low cortisol levels upon awakening. And the group of depressed participants in this study indeed had reduced blood plasma and salivary cortisol levels at baseline.

During their ayahuasca session, salivary cortisol levels shot up dramatically, which is to be expected in an intense psychedelic experience. But the interesting finding was that 48 hours after dosing, the awakening cortisol levels in the depressed group had risen significantly and looked similar to levels detected in non-depressed controls. In other words, 2 days after ayahuasca, their cortisol levels normalized to similar levels of non-depressed people.

C-Reactive Protein

C-reactive protein (CRP) is a protein produced by the liver in response to inflammation. High levels of CRP in the blood are looked at as markers of systemic inflammation. People with severe depression often have higher blood levels of CRP. Following a single session with ayahuasca, both depressed and non-depressed participants showed a significant reduction of C-reactive protein levels. And for the group with depression, there was a significant correlation between lower CRP levels and reduced depressive symptoms. Those with the biggest reductions in CRP levels experienced the largest reductions in depression symptoms, suggesting that lowering inflammation may be a one factor in ayahuasca’s anti-depressant effects.

Brain-derived neurotrophic factor (BDNF)

Brain-derived neurotrophic factor (BDNF) is a brain protein that is essential for neuronal development and survival, synaptic plasticity, and cognitive function. It is considered an important marker for neurogensis and brain plasticity, the brain’s ability to grow new neurons and adapt over time in response to new experiences. Dysregulation of BDNF signaling is involved in several disorders, including Alzheimer’s disease and chronic severe depression. Several studies have shown that people suffering from depression often have lower brain levels of BDNF.

In the present study, higher BDNF levels in both the depressed group and the control group were found after a single ayahuasca session compared to those administered a placebo. And this increase in BDNF levels were associated with reduction in depressive symptoms for the group with treatment-resistant depression.

These findings are consistent with research on other psychedelics that showed that increasing neuroplasticity may be an important pathway in psychedelics’ mental health benefits.

Conclusion

This study on ayahuasca and depression is significant due to both its design and the resulting findings. The design was of high quality and included not only a placebo (which included ingredients that mimic ayahuasca’s purging effect), but also a control arm of non-depressed participants. Both depressed and non-depressed groups were split into an active and placebo subset, allowing the researchers to examine ayahuasca’s effects on the depressed and non-depressed groups and compare the effects to a legitimate placebo.

The study also collected biological samples from all participants before, during, and after their ayahuasca dosing session, allowing the researchers to examine interactions between ayahuasca, depression symptoms, and these biological markers.

Finally, the study focused on people with the most severe and hardest-to-treat form of depression.

While this was a small study and only followed participants for 7 days, it demonstrated that ayahuasca has fast-acting anti-depressant effects even for severe cases of depression and that these effects are correlated with positive changes in cortisol levels, inflammation levels, and BDNF, suggesting that ayahuasca’s affect on inflammation, neurogenesis, and the central nervous system may all play a role in its anti-depressive affects.