# Motivation and emotion/Book/2024/Ayahuasca and the brain

* Multimedia presentation (3 min)

## Overview

* Figure 1. Ayahuasca being prepared in Ecuador
* Scenario
* Imagine you are at the point in your life where your career is thriving, and everything is falling into place the way it should. Then, on a fateful day, you receive a cancer diagnosis. Once the shock of such news dissipates, you are left with a novel of questions –
* “Am I going to die?” “What does this mean for my future?” “Do I have a future?” “What about my family?” “What about my career?” “What about me?”
* These are just a few questions that would whirlwind through one’s mind after such a diagnosis, which was no different for Margaret de Wys. In 1999, at the peak of her career, Margaret’s life was seemingly on the right path until she was tragically diagnosed with breast cancer. All she knew was that she did not want to die. On a mission to seek healing, Margaret was invited to a Mayan ceremony. To this day, Margaret does not know why she said yes; all she knows is that she felt a pull – an attraction of sorts that was prompting her to go. So, off Margaret went. No one at this ceremony knew that Margaret had just received such a fateful diagnosis. Though a man named Carlos, a Shuar healer from the Amazon Jungle looked at Margaret and said[grammar?],
* “I see inside you—your veins, organs, blood, and cells. Black smoke is trapped in your breast. Come to Ecuador, and I will heal you.” (Louis, 2010)
* This decision would forever change Margaret’s life. To the point where she claims it saved her life and cured her of her cancer[grammar?].
One of the sharmic treatments given to Margaret was Ayahuasca (see Figure 1.=), a traditional South American psychoactive beverage. Many individuals have claimed that Ayahuasca saved their lives and cured them of physical and or mental ailment/s. Ayahuasca's methodology is a somewhat contentious topic in the Western world, as there is yet to be an established basis for what it does beyond influencing one's psyche as is yet to be evidenced beyond individual testimony[grammar?]. Psychedelic use raises a multitude of questions, but primarily, what are the neurological effects of ayahuasca on the brain?
* Focus questions:
* What is ayahuasca?
* What are psychedelics?
* What are the neurological effects of ayahuasca on the brain?
* Why do people seek out ayahuasca as a form of treatment?

## What is ayahuasca?

Ayahuasca is a potent South American plant with a rich cultural history. Indigenous populations of the Amazon have used it for centuries for spiritual and medicinal purposes (Domínguez-Clavé et al., 2016). Ayahuasca is made from a unique combination of two ingredients, typically the Banisteriopsis caapi vine and the leaves of the Psychotria Viridis plant. The Banisteriopsis caapi acts as a monoamine oxidase inhibitor (MAOI), and the leaves of the Psychotria Viridis plant contain high levels of N, N-dimethyltryptamine (more familiarly known as DMT). When brewed together, the inhibition of MAOI by banisteriopsis caapi acts as a bioactivation for the DMT in the Psychotria Viridis leaves (Malcolm & Lee, 2017, p. 43), promoting anti-depressant effects. Once consumed, ayahuasca causes intense psychological experiences, typically come in the form of hallucinations and emotional insight[factual?].

## How do psychedelics effect the brain?

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### What are psychedelics?

Psychedelics are a class of psychoactive substances known for their ability to alter perception, mood, and cognitive processes. Commonly referred to as "hallucinogens," these substances can induce profound changes in consciousness, often leading to experiences characterised by altered sensory perceptions, vivid visual or auditory hallucinations, and shifts in thought patterns (Kelmendi et al., 2022).
Table 1.
Caption Goes Here
| Most common psychedelics | What they are derived from | Their chemical compound |
| LSD (lysergic acid diethylamide) | Ergot fungus | Figure 2. Structural formula of LSD |
| Psilocybin | Psilocybin mushrooms (also known as "magic mushrooms") | Figure 3. Structural formula of psilocybin |
| Mescaline | Several species of cacti, such as peyote | Figure 4. Structural formula of mescaline |
| DMT (dimethyltryptamine) | A various plants, including but not limited to virola elongata bark and anadenanthera peregrina | Figure 5. Structural formula of DMT. |

### How do psychedelics work?

The effects of psychedelics are attributed to their interaction with the brain’s neurotransmitter systems, particularly serotonin. The primary serotonin receptor that is affected by psychedelics is the 5-HT2A receptor (Johnson et al., 2019). This receptor is a subtype of the serotonin receptor family. It is primarily located in the brain’s cerebral cortex and other cognition, emotion, and perception regions. It is closely linked to the characteristic effects of psychedelics, such as heightened sensory perception, emotional shifts, and altered thinking patterns. When consumed, psychedelics act as agonists at the 5-HT2A receptor. This binding leads to a cascade of intracellular events that result in altered neurotransmitter release and enhanced synaptic communication[factual?].

## The neurological effects of ayahuasca

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### Increased neuroplasticity

Ayahuasca activates neurotransmitter systems, particularly serotonin receptors. The activation of the 5-HT2A receptor, in particular, enhances synaptic signalling and communication between neurons. Due to this, it is believed and reported that ayahuasca promotes functional and structural neuroplasticity (Mallaroni et al., 2023).
Neuroplasticity is the brain’s ability to reorganise itself. It does this by forming new synapses and strengthening existing ones. This can be due to life experiences, building on skills or learning new ones, or, as new research developments are suggesting, external sources, such as psychedelics.
In their 2021 study, Cato M. H. de Vos and colleagues investigated this by performing a systematic review of the biological dynamics of psychedelics. Due to gaps and relevancy, only 20 studies were used out of their initial 344. Their review found that “expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity” (de Vos et al., 2021, p. 1). BDNF is a protein and it plays a significant role in neuron survival and adaption, especially in regulating neurotransmitters and neuroplasticity (Bathina & Das, 2015, p.1164).
* Thinking time!
* It could be hypothesised that due to the “new life perspective” that many ayahuasca users claim to experience, they are encouraged to change their behaviour or emotional approach to specific situations due to the psychedelic impact on BDNF, resulting in neuroplasticity.

### Changes in default mode network (DMN)

The Default Mode Network (DMN) is a network of brain regions: the prefrontal cortex, insular cortex, inferior parietal lobule, lateral temporal cortex, posterior cingulate/retrosplenial cortex, the extended hippocampal formation, dorsomedial prefrontal cortex, and ventromedial prefrontal cortex) (Buckner, 2013, p. 351-352) (see Figure 6.). It is most active when a person is at rest and not focused on the external environment. It is associated with daydreaming, narrative identity, and mind wandering.
In their 2022 systematic review, James J. Gattuso and colleagues found that across psychedelics, including ayahuasca, there is a “consistent disruption in resting-state connectivity within the DMN and increased functional connectivity between canonical resting-state networks” (p. 155).
This disruption in DMN activity appears to be one of the reasons why those who partake in ayahuasca experience psychedelic phenomena such as ego death, insight and sensory perceptions, and shifts in perspective and habitual thoughts.

### Altered perception

When using psychedelics, it is very common to experience sensory-perceptual alteration - a chnage[spelling?] in how sensory stimuli are experienced, accompanied by an atypical reaction to those stimuli. This can manifest as heightened, diminished, or distorted perceptions in a person's hearing, vision, touch, smell, or kinaesthetic response (Khan & Khan, 2021). It can also impact perception of time and emotional responses.

#### Visual and auditory hallucinations

Visual and auditory hallucinations (such as seeing geometric shapes, complex imagery, bright colours, and sounds and music that are not present) are the most common side effects of psychedelic use due to increased neural activity and altered processing in visual and auditory pathways. This further plays into warping one’s perception of time, as hallucinations may feel long-lasting or like the person is moving slowly.

##### "Grandmother" ayahuasca

A common phenomenon among ayahuasca users is interacting with "Grandmother Ayahuasca." Grandmother Ayahuasca is regarded as a benevolent spirit who is consistently wise and maternal yet firm in its personification.
Though [grammar?] arguably a hallucination, Grandmother Ayahuasca is often described as a spirit or entity encountered during ayahuasca experiences, guiding participants through their “trip”. Each encounter with Grandmother Ayahuasca and its perceived form depends on the user’s beliefs and the context of their experience (see Figure 7.).
In her 2017 book "Listening to Ayahuasca: New Hope for Depression, Addiction, PTSD, and Anxiety", Dr Rebecca Harris conducted a questionnaire-based observational study that measured the long-term therapeutic effects of ayahuasca. Many individuals she interviewed reported significant improvements in mental health issues, substance abuse problems, and traumatic experiences. Harris also recounted her own experiences with ayahuasca, particularly with Grandmother Ayahuasca. Harris credited Grandmother Ayahuasca for providing her with wisdom and insight into past traumas and guidance and research concepts for this book.
After encountering Grandmother Ayahuasca, many people in Harris' study felt that they had gained great insight into themselves, were able to heal from ailments (mental and physical), gained wisdom and guidance for their life plans, and gained a deeper understanding of their lives and traumas. Many attributed these breakthroughs to Grandmother Ayahuasca and continue believing they have a lifelong connection and solitude with this mysterious spirit.

#### Cognitive flexibility and mindfulness

Harris’s 2017 book is not the only body of work that has come across consistent evidence of psychedelics showing great therapeutic potential.
Many studies are investigating the therapeutic effects of ayahuasca use and are finding that it has much potential to be investigated. Such studies include A Murphey-Beiner and K Soar's 2019 piece, where 48 participants' cognitive flexibility and mindfulness were measured before and after consuming ayahuasca. Results showed that both cognitive flexibility and mindfulness had significantly improved in the 24 hours after ayahuasca use compared to before participants had taken it (p. 1165).
These results showed great promise in what is considered the “afterglow” period after using psychedelics.

## Lingering effects after ayahuascaa

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### Psychedelic afterglow

In drug use, "afterglow" refers to the positive feelings and heightened emotional or mental clarity that often follow the primary effects of a psychoactive substance. Few studies have investigated the adverse effects of afterglow; however, many positive aspects have been documented.
In their 2023 systematic review, Ricarda Evens and colleagues found that across "48 studies, summing to 1,1774 participants, reductions in psychopathological symptoms; increases in well-being, mood, mindfulness, social measures, spirituality, and positive behavioural changes; mixed changes in personality/values/attitudes, and creativity/flexibility" (p. 1). These effects lasted for different periods depending on what was measured (i.e., stress, depression, grief). Typically, afterglow effects last anywhere from one day to a month.
None of the studies that provided multiple "subacute assessment points reported opposing findings (e.g., decreased depression at one and increased depression at another subacute assessment point)" (p.13), making it difficult to gauge the true impact of afterglow.

## Why do people seek out ayahuasca as a form of treatment?

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### Mental health and therapeutic insights

People seek out ayahuasca for several reasons, some of which have been mentioned. Traditionally, ayahuasca is used in cultural ceremonies by South American communities and tribes. Though [grammar?] in more modern, westernised times, it is more commonly sought to aid in resolving mental health issues and therapeutic insights.[factual?]

#### Depressive disorders

Depression is one of the most commonly diagnosed mental health disorders, coming in many forms and varieties (see Figure 8.). Unfortunately, researchers do not know precisely where depression is localised in the brain, though it is hypothesised that it is active in many brain regions simultaneously (Pandya et al., 2012, p. 641).
In an attempt to simplify the complexity of this disorder, Dean and Keshavan (2016) consider depression as a “united syndrome” (p. 101) and raise the most common neurological trends of most (if not all) depressive disorders, such as altered neurotransmission, HPA axis abnormalities, reduced neuroplasticity, and general network dysfunction - all aspects mentioned earlier that are increased under ayahuasca intake.
To truly put ayahuasca's therapeutic potential to the test, in 2018, Fernanda Palhano-Fontes and colleagues conducted a "parallel-arm, double-blind, randomised, placebo-controlled trial in 29 patients with treatment-resistant depression" (TRD) (p. 655). Fourteen participants received a single dose of ayahuasca, and the remaining 15 received a single dose of the placebo. Their study found evidence that in both groups, depression severity changed considerably, though [grammar?] more profoundly in the ayahuasca group. They speculate that this success could be due to the MAOI present in the brew and also acknowledge limitations in this study, such as comorbid conditions of TRD, socioeconomic status (SES), and lack of previous studies into TRD and ayahuasca treatment.

### Physical health ailments

Recent discoveries have revealed that DMT is also an agonist to the sigma-1 receptor. The sigma-1 receptor is not only involved in the pathological process of major depressive disorder (MDD), but its agonists can regulate neuroinflammation, neurogenesis, and mitochondrial function (Wang et al., 2022, p. 3).
The multi-effect activation of the sigma-1 receptor is starting to be considered a treatment method for neurodegenerative conditions such as Parkinson’s and Huntington’s (p. 3). This is due to its neuroprotective aspects that regulate and modulate calcium levels and glial cells. In addition, activation of sigma-1 receptors is starting to be associated with BDNF and improving mitochondrial functions.
However, this is not the reason why (as far as current research suggests) people seek out ayahuasca as a form of treatment for their physical health ailments. Many are simialr[spelling?] to Margaret de Wys and seek extreme measures as a last resort. Alternatively, they are seeking the increasingly proven therarapeutic[spelling?] benefits of ayahuasa[spelling?] during their trying times.

## Conclusion

Ayahuasca is a South American drug that causes many neurological effects. It holds a deep, traditional history within Indigenous tribes and communities in South America, as well as modern day purposes for Western communities. When properly brewed, ayahuasca produces N, N-dimethyltryptamine (DMT), a psychedelic that induces auditory and visual hallucinations, altered perception of self and time, mood, cognitive processes, and more. Ayahuasca enhances neuroplasticity through several fundamental mechanisms, primarily related to its active compounds, particularly DMT and the MAO inhibitor found in the Banisteriopsis caapi vine. Its agonists, such as the 5HT2A receptor and the sigma-1 receptor, show great promise in treatments for mental health disorders, such as depression and neurodegenerative diseases, such as Huntington's. Research is still quite limited in the therapeutic mechanisms of DMT-based psychedelics, particularly ayahuasca. Still, as the research continues to grow, the potential of its treatment grows with it.