Ayahuasca accelerates fear extinction via its effect on serotonin receptors

A recent study sheds light on the neural mechanisms that might underlie the therapeutic benefits of the traditional psychoactive brew known as ayahuasca. The study found that the powerful concoction helps to reduce the fear response in rats, working equally well on both new and old fear memories. This effect appears to be caused by ayahuasca’s interaction with specific serotonin receptors in the brain.

The findings have been published in the British Journal of Pharmacology.

Ayahuasca is typically made from the leaves of the Psychotria viridis bush and the vines of the Banisteriopsis caapi. This brew, revered in many South American cultures for its powerful psychoactive properties, primarily owes its effects to the compound N,N-dimethyltryptamine (DMT) found in P. viridis and the β-carbolines (harmine, tetrahydroharmine, and harmaline) in B. caapi. The latter compounds inhibit enzymes that would otherwise degrade DMT, allowing it to exert its psychoactive effects, including alterations in perception, emotion, and consciousness, by affecting serotonin receptors in the brain.

Despite anecdotal evidence of ayahuasca’s psychological benefits, including its use in traditional healing ceremonies to promote emotional and mental well-being, there was a lack of scientific understanding of its effects on fear memory extinction, a critical process in the treatment of anxiety and trauma-related disorders such as PTSD. Fear memory extinction refers to a psychological process through which the response to a previously learned fear-inducing stimulus decreases over time, typically through repeated exposure to that stimulus without any negative outcomes.

“Our rodent lab investigates the brain and molecular mechanisms underlying memory formation during threatening or stressful experiences. We focus on developing pharmacological approaches to weaken the expression of aversive memories,” said study author Leandro Jose Bertoglio, a full professor of pharmacology at the Federal University of Santa Catarina.

“Collaborators within our network are studying ayahuasca, a popular brew in Brazil and the Amazon, for its potential to treat depression and ethanol dependence. Given our expertise in fear extinction – the process where a neutral memory suppresses an aversive one – we are exploring ayahuasca’s impact on this process. The extinction likely forms the biological foundation for some psychotherapies.”

The researchers conducted a set of experiments using 331 Wistar rats, both male and female, to assess the effects of orally administered ayahuasca on the extinction of fear memories. Fear memories were induced using a contextual fear conditioning procedure, and extinction was measured as a reduction in fear response, quantified by the amount of time spent freezing.

The researchers evaluated different doses of ayahuasca and included control treatments to ensure the reliability of the findings. Advanced techniques, including the use of specific antagonists, were employed to investigate the neural mechanisms underlying ayahuasca’s effects.

They found that ayahuasca facilitated the extinction of both recent and remote fear memories without inducing anxiety or affecting the general exploratory behavior of the subjects. This outcome was consistent across different doses of ayahuasca and was observed in both male and female rats.

The findings pinpointed the activation of serotonin receptors in the infralimbic cortex, a brain area known to regulate fear, as a critical component of ayahuasca’s action. Specifically, the 5-HT2A and 5-HT1A receptors played significant roles in mediating the extinction-enhancing effects of ayahuasca. This suggests that ayahuasca, through its interaction with these receptors, may influence the balance between excitation and inhibition in the infralimbic cortex, thereby modulating the fear extinction process.

“Orally administered ayahuasca accelerates fear extinction and its retention in female and male rats,” Bertoglio told PsyPost. “This effect is associated with N,N-dimethyltryptamine (DMT) and involves the activation of two serotonin receptor subtypes (5-HT1A and 5-HT2A) in the infralimbic cortex. This brain region, homologous to the ventromedial prefrontal cortex in humans, is crucial in regulating memory extinction.”

The 5-HT2A receptors are known for their role in the mechanism of action of many psychedelic substances. 5-HT1A receptors are widely distributed in the brain, including areas such as the hippocampus, raphe nuclei, and cerebral cortex, but less is known about their relationship with psychedelic substances.

“Compared to the 5-HT2A receptor, the participation of the 5-HT1A receptor in the effects of ayahuasca and other classical serotonergic psychedelics (e.g., psilocybin and LSD) has been less explored,” Bertoglio said. “Our research aimed to elucidate the role of both receptors, demonstrating that DMT’s action on both 5-HT1A and 5-HT2A receptors contributes to enhanced fear extinction.”

By demonstrating that ayahuasca can facilitate fear memory extinction, the study opens the door for future research into its potential as a therapeutic tool for treating anxiety and trauma-related conditions. Furthermore, the identification of specific neural mechanisms involved in ayahuasca’s effects offers a promising direction for the development of novel psychiatric treatments that target these pathways. In particular, further investigations will focus on more severe and widespread fear memories, which are associated with PTSD.

“Our goal is to advance understanding of how and where psychedelic substances act when modulating the expression and persistence of aversive memories,” Bertoglio explained. “These studies foster collaborations and their findings encourage related studies with humans.”

The study, “Ayahuasca-enhanced extinction of fear behaviour: Role of infralimbic cortex 5-HT2A and 5-HT1A receptors,” was authored by Isabel Werle, Laura M. M. Nascimento, Aymee L. A. dos Santos, Luciane A. Soares, Rafael G. dos Santos, Jaime E. C. Hallak, and Leandro J. Bertoglio.