The psychedelic brew ayahuasca is both more complex and less studied than many other psychedelic compounds, including one ayahuasca constituent, N,N-dimethyltryptamine, or DMT. But a new study on ayahuasca use at a Peruvian retreat center not only adds to the growing evidence that ayahuasca treatments can provide lasting relief from conditions such as depression, it suggests changes to gene expression may be responsible for ayahuasca’s efficacy.
“This is the first study to look at any psychedelic and epigenetics, so it’s completely novel,” said Dr. Simon Ruffell, a psychiatrist at King’s College in London and now Ph.D. candidate in psychology, as well as the lead author of the paper published in June in Frontiers in Psychiatry.
The new study builds on previous work by Ruffell and his collaborators looking at the effects of ayahuasca on personality traits among participants at an Ayahuasca Foundation retreat center near Iquitos in Peru. That study looked at measures of neuroticism and openness in retreat participants.
The new observational study examined more aspects of mental health, with 63 self-selected participants completing questionnaires assessing levels of depression, anxiety, childhood trauma, and other conditions before beginning the retreat. Measures aside from childhood trauma, which was only assessed at the beginning of the retreat, were repeated following participation in the retreat and use of ayahuasca, and again at a six-month follow-up conducted by email.
Participants also gave saliva samples before and following the retreat to measure potential epigenetic changes, with samples from a total of 48 participants included in the final analysis.
Retreat participants showed improvements in depression and anxiety scores that persisted through the six-month check-in, a result consistent with past research on psychedelics and mental health, and the researchers’ expectations. What was new was the finding of a correlation between decreases in measures of participant depression and increased signs of epigenetic regulation of the SIGMAR1 gene, which provides the genetic code for making the non-opioid sigma-1 receptor.
The sigma-1 receptor has been associated with mental health conditions such as depression and dementia, and agonists such as fluoxetine (Prozac) and even simple ammonium salts have been shown to have antidepressant activity in rodents.
Ruffell and his colleagues were inspired to look at the SIGMAR1 gene by a 2018 theoretical paper in Frontiers in Pharmacology that hypothesized that sigma-1 receptor activation, and the resulting neuroplasticity and epigenetic changes, might be mechanisms through which ayahuasca exerts its therapeutic effects, which include relief from depression and anxiety related to childhood trauma.
The genetic analysis conducted in collaboration with the University of Exeter found a small but statistically significant increase in methylation — a molecular marker of changes in gene activity — of the SIGMAR1 gene, an average of 2.1%, in measurements taken after the retreat. Importantly, participants who scored higher on measures of childhood trauma had higher methylation scores following the retreat. The results are not conclusive, and Ruffell admits most epigenetic studies feature hundreds of subjects. “While we can’t say for sure that ayahuasca is causing a change in the expression of SIGMAR1, it certainly suggests that we should be investigating this area further,” he said.
The researchers also examined another gene, FKBP5, which has been associated with stress-related disorders but found no statistically significant changes in its activity after the ayahuasca sessions.
The study was funded through the UK Government’s Medical Research Council, with some additional funding from King’s College, London. But going forward, the Grant Town Foundation will also fund follow-up work by Ruffell and his colleagues Nige Netzband, and WaiFung Tsang, who now operate as independent researchers based at the Ayahuasca Foundation. “We are not financially involved and we try to keep independent from the center as much as possible,” Ruffell said.
In upcoming research, Ruffell and colleagues hope to dig deeper into the epigenetic effects of ayahuasca and SIGMAR1, while also examining different measures. In the most recent study, for instance, the childhood trauma scale identified major traumas such as sexual and physical abuse. But an upcoming study will measure experiences that are potentially less severe, but still traumatic, as identified by the individual. “So, for example, divorce of parents, death of a loved one or anything that was deemed traumatic in the eyes of the participant,” he said. “We are aiming to look at more everyday traumas.”
Image: Nicki Adams using adapted photo by Chubbyrain74