The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro
Jose A. Morales-García, Mario de la Fuente Revenga, Sandra Alonso-Gil, María Isabel Rodríguez-Franco, Amanda Feilding, Ana Perez-Castillo & Jordi Riba
Scientific Reports, 2017, 7, 5309
Banisteriopsis caapi is the basic ingredient of ayahuasca, a psychotropic plant tea used in the Amazon for ritual and medicinal purposes, and by interested individuals worldwide. Animal studies and recent clinical research suggests that B. caapi preparations show antidepressant activity, a therapeutic effect that has been linked to hippocampal neurogenesis. Here we report that harmine, tetrahydroharmine and harmaline, the three main alkaloids present in B. caapi, and the harmine metabolite harmol, stimulate adult neurogenesis in vitro. In neurospheres prepared from progenitor cells obtained from the subventricular and the subgranular zones of adult mice brains, all compounds stimulated neural stem cell proliferation, migration, and differentiation into adult neurons. These findings suggest that modulation of brain plasticity could be a major contribution to the antidepressant effects of ayahuasca. They also expand the potential application of B. caapi alkaloids to other brain disorders that may benefit from stimulation of endogenous neural precursor niches.
Ayahuasca is the Quechua name used to designate Banisteriopsis caapi, a jungle liana of the Malpighiaceae family that is native to the Amazon and Orinoco river basins1. The term is also applied to the tea that is obtained by infusing in water the stems of B. caapi, alone or in combination with other plants2. The ayahuasca tea is a central element in the ancient shamanic practices and rites of passage of the indigenous inhabitants of northwestern South America. More recently, ayahuasca has become a central sacrament in the rituals of Brazilian syncretic religious groups. These so-called “ayahuasca religions” have popularized ayahuasca use with the expansion of their activities to North America and Europe3.
Ayahuasca has a complex chemistry and pharmacology. B. caapi contains high amounts of harmine and tetrahydroharmine (THH) and to a lesser degree harmaline, three indole alkaloids with β-carboline structure4. These alkaloids are reversible monoamine-oxidase-A (MAO-A) inhibitors5, while THH can also inhibit serotonin reuptake6. Although B. caapi can be the sole ingredient of the tea7, up to 100 different plants have been described as admixtures to ayahuasca. These plants contain a wide variety of psychotropic substances such as nicotine (from Nicotiana spp.), scopolamine (from Brugmansia spp.), caffeine (from Ilex guayusa and Paullinia yoco), cocaine (from Erythoxylum coca) and N,N-dimethyl-tryptamine (DMT, from Psychotria viridis and Diplopterys cabrerana)2, 8.
In recent years, non-traditional use of ayahuasca has expanded worldwide, especially the version of the tea that combines B. caapi with P. viridis, due to the visionary effects induced by DMT, a psychedelic serotonin-2A agonist9. This expansion and reports of health benefits derived from its use have stimulated research into the pharmacology and therapeutic potential of ayahuasca10. Two recent studies found that a single dose of ayahuasca rapidly reduced depressive symptoms in treatment-resistant patients11, 12. Remarkably, clinical improvement was maintained for up to three weeks. With the resurgence of research on psychedelics13, the β-carbolines of B. caapi have been considered to play a minor role in the overall pharmacology of ayahuasca preparations. However, this is probably a narrow view. B. caapi is the common ingredient to all ayahuasca brews, and chemical analyses have shown that while the β-carbolines are present in all ayahuasca samples, this is not always the case for DMT14, 15. For instance, an ayahuasca sample from the Brazilian Church União do Vegetal, a group known to regularly combine B. caapi with P. viridis in their ayahuasca, was found to contain no DMT at all16.
Due to their ubiquitous presence in ayahuasca, it can be hypothesized that the β-carbolines contribute to the CNS effects of the tea. Studies in animals have shown that harmine has antidepressant effects in behavioral animal models of depression17, 18. Responses after harmine in the forced swim and open field tests are analogous to those obtained with ayahuasca infusions prepared from B. caapi and P. viridis and containing DMT19, 20. These findings suggest that DMT is not essential for the behavioral responses observed in animals. Additionally, in contrast with more traditional antidepressants such as imipramine, harmine increases BDNF levels in the hippocampus after both acute and chronic administration18, 21. These data suggest that harmine and potentially the other β-carbolines present in B. caapi contribute to the therapeutic effects of ayahuasca observed in clinical studies involving patients with depression11, 12.
At the cellular level, antidepressant drug action has been linked to the ability of drugs to stimulate adult neurogenesis22. Neurogenesis is the process of generating functional neurons from progenitor cells. In the adult brain of mammals, neurogenesis occurs in two main niches: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone of the dentate gyrus of the hippocampus (SGZ). Neural stem cells in these areas can be induced to asymmetrically divide, generating new stem cells, and astrocytes, oligodendrocytes or neurons23, 24. These newly generated neurons have the capacity to migrate and integrate into existing neural circuits. The activity and phenotypic fate of neural stem cells is determined by both endogenous and exogenous factors25. Beyond understanding the mechanisms of adult neurogenesis, we are ultimately interested in its therapeutic capacity. Specifically, despite their various mechanism of action, clinically-effective antidepressants share the common feature of inducing neural stem cell proliferation and differentiation into new neurons26–28.
Here, we investigated the capacity of the three main β-carbolines present in B. caapi to induce neurogenesis in vitro using neural progenitor cells from adult mice. We decided to focus on the alkaloids found in all ayahuasca brews, rather than on nicotine, DMT, scopolamine or other psychoactive compounds that can be present in ayahuasca following the addition of the admixture plants mentioned above. To this end neurospheres were prepared from stem cells obtained from both the SVZ and the SGZ and treated with harmine, THH, harmaline, and harmol. The latter is present only in small amounts in B. caapi but is readily formed in vivo in humans via O-demethylation of harmine, which undergoes extensive first-pass metabolism4, 29, 30. As shown below, results showed that the B. caapi β-carboline alkaloids present in ayahuasca directly regulate proliferation, migration and differentiation of neural stem cells.