This review (2021) examines the antioxidant, anxiolytic (anxiety), and antidepressant effects of ayahuasca, with a particular emphasis on its anti-inflammatory action yielding therapeutic benefits for disorders related to neuroinflammatory factors.
Abstract
“Review: Ayahuasca is a decoction with psychoactive properties, used for millennia for therapeutic and religious purposes by indigenous groups and the population of amazonian countries. As described in this narrative review, it is essentially constituted by β-carbolines and tryptamines, and it has therapeutic effects on behavioral disorders due to the inhibition of the monoamine oxidase enzyme and the activation of 5-hydroxytryptamine receptors, demonstrated through preclinical and clinical studies. It was recently observed that the pharmacological response presented by ayahuasca is linked to its anti-inflammatory action, attributed mainly to dimethyltryptamines (N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine), which act as endogenous systemic regulators of inflammation and immune homeostasis, also through sigma-1 receptors. Therefore, since neuroinflammation is among the main pathophysiological mechanisms related to the development of neurological and psychiatric diseases, we suggest, based on the available evidence, that ayahuasca is a promising and very safe therapeutic strategy since extremely high doses are required to reach toxicity. However, even so, additional studies are needed to confirm such evidence, as well as the complete elucidation of the mechanisms involved.”
Authors: Marina G. da Silva, Guilherme C. Daros & Rafael M. de Bitencourt
Summary
Ayahuasca is a decoction with psychoactive properties, used for millennia by indigenous groups and the population of amazonian countries. It has been observed that this decoction has an anti-inflammatory effect, which makes it a promising and very safe therapeutic strategy.
- Introduction
The inflammatory response can cause a series of problems to the body, including neuropsychiatric problems, such as depression, anxiety, cognitive disorders, and neurodegenerative diseases. Ayahuasca, an ancient psychoactive plant beverage of Amazonian origin, has been shown to perform anti-neuroinflammatory actions quite promising for the treatment of various neuropsychiatric disorders.
This narrative review will address the anti-inflammatory effects of ayahuasca and its possible implications as a pharmacotherapeutic alternative for different neuropsychiatric disorders.
- Ayahuasca: cultural and pharmacological aspects
Ayahuasca is a decoction with psychoactive properties composed of two plants, primarily the stem of Banisteriopsis caapi and the leaves of Psychotria viridis.
Ayahuasca is used by indigenous groups and the population of amazonian countries for therapeutic and religious purposes. It has been legalized in Brazil for religious and non-profit purposes only.
Ayahuasca’s somatic effects (nausea, paresthesia, increased body temperature) appear 20 min after ingestion, followed by its cognitive effects (intense perceptual, cognitive, emotional, and affective changes). Its acute psychoactive effects last for about four hours.
B. caapi and P. viridis are plants found in the Amazon and tropical zones of South America and the West Indies, respectively, and have active ingredients such as -carbolines and DMT.
- Synchronous use of plants
The psychotropic properties of ayahuasca are mainly attributed to the high amount of DMT, which is metabolized by the enzyme monoaminoxidase. However, some substances can act as inhibitors of this enzyme, preventing the degradation of DMT present in P. viridis, allowing its arrival at the systemic circulation and the central nervous system.
-carbonyl alkaloids are derived from the amino acid tryptophan and have a broad spectrum of action on human organs, including the ability to inhibit the activity of MAO in the liver and intestine and to exert selective inhibitory effects on serotonin reception.
The harmine has a moderate affinity for the 5-HT2A receptor and a low affinity for the 5-HT2C receptor, and increases the electrically evoked dopamine efflux in the rats’ nucleus accumbens.
- Active substances of P. viridis
DMT, a tryptamine metabolite, crosses the blood-brain barrier and induces anxiolytic and antidepressant effects due to its agonist action on the 5-HT1A receptor. It also induces hallucinogenic effects due to its binding to 5-HT2A receptors.
This molecule interacts with several non-serotonergic molecular targets, and can also promote neuroplasticity through the formation of the dendritic column. It is also involved in the modulation of several neurotransmitter systems, and can also act as an endogenous systemic regulator of inflammation and immune homeostasis.
When administered intravenously, DMT reaches its maximum blood levels after 2 min, and its half-life is 259 min.
- Ayahuasca’s action on inflammatory mechanisms
For a long time, the CNS was seen as immunologically privileged, but today it is known that despite the protective barriers, the CNS is subject to pathogenic events and immunological surveillance.
Neuroinflammation occurs in response to stress related to the CNS, and is characterized by the production of proinflammatory mediators by specialized macrophages, neurons, astrocytes, cytokines, chemokines, and the complement system.
Microglia are immune cells in the brain that exhibit a deactivated phenotype under physiological conditions. However, chronic activation of microglia is associated with harmful consequences.
Ayahuasca’s therapeutic potential is probably linked to its anti-neuroinflammatory action, which is modulated by the nuclear factor of activated T-cells (NFAT) and nuclear factor kappa B (NFkB) pathways.
Studies have shown that 5-MeO-DMT inhibits brain pathways associated with cell death and promotes neuroplasticity, inflammation, and neurodegeneration, suggesting that the substance has a potential neural protection role.
- Neuroinflammation: pathophysiological mechanism related to the development of neurological and psychiatric diseases
Neuroinflammation is a main pathophysiological mechanism in several neurological and psychiatric diseases, including chronic degenerative diseases and diseases related to acute injury. Besides, pro-inflammatory cytokines have configured possible biomarkers in several clinical conditions, such as depression.
Acute infections can lead to depression, and patients with chronic inflammatory disorders have a higher prevalence of depression. Ketamine, an NMDA receptor N-methyl-D-aspartate antagonist, has a rapid antidepressant effect in animal models.
Although depression has received the most attention, inflammation is also related to anxiety disorders. Chronic minocycline treatment reduces anxiety-like behaviors induced by repeated restraint stress.
TNF-, IL-6 and 8 are involved in the progression of Alzheimer’s, Parkinson’s disease, and ALS, respectively, and are responsible for the inflammatory response caused by extracellular amyloid plaques.
- Therapeutic applicability
Ayahuasca has therapeutic applicability in several neurological and psychiatric disorders, however, a possible bias should be considered due to its use related to the religious context.
Researchers have investigated the effects of DMT and ayahuasca on anxious and depressive behavior in rats, zebrafish, and mice. They have found that these substances have a biphasic effect, with high doses reducing locomotion and increasing parameters related to animal anxiety.
Researchers in Brazil found that ayahuasca reduced depressive symptoms in hours after administration, and that cerebral blood perfusion was increased in the subgenual area, nucleus accumbens, and insula, reinforcing the antidepressant activity of this compound.
Ayahuasca’s antidepressant effects are also related to the modulation of cortisol levels. In a study with non-human primates, ayahuasca was able to reverse behavioral parameters related to depression and normalize fecal cortisol levels. A study published by de Almeida et al. (2019) demonstrated an interaction between serum cortisol and BDNF levels, and ayahuasca treatment reduced depressive symptoms and decreased C-reactive protein levels in patients with treatment-resistant depression.
Ayahuasca can be used to treat cognitive disorders, such as dementia, by reducing the expression of proteins involved in degeneration and brain injury, and by enhancing the expression of proteins important for learning and memory.
- Toxicity
In an animal model, ayahuasca was given in doses up to 8x the usual dose for 70 days. Two of the animals died after receiving the highest dose.
- Conclusions and future perspectives
Several studies demonstrate that ayahuasca can offer therapeutic benefits for disorders related to neuroinflammatory responses, highlighting anxiety and depression disorders. However, additional studies are still needed to confirm such evidence.
Acknowledgements
M.G.S., G.C.D. and R.M.B. are supported by research fellowships from CAPES and PUIC, and they are grateful to the indigenous people for their contribution to scientific knowledge.