Ayahuasca vine and its anti-inflammatory effects in microglia
Santos et al. open new doors into our perception of the liana
Few things before we begin:
Welcome to another edition of The Tab, where I break down scientific papers and important concepts related to psychedelics. We will delve into another ayahuasca paper this week. You will learn a bit more about how components of the B. caapi vine benefit an important brain cell.
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Components of Banisteriopsis caapi, a Plant Used in the Preparation of the Psychoactive Ayahuasca, Induce Anti-Inflammatory Effects in Microglial Cells
Why they did it
Banisteriopsis caapi is a species of liana plant found in South America. It’s on our radar because it is one of the two main ingredients of ayahuasca. It contributes β-carbolines to the brew. 🍵
β-carbolines stop the body from breaking down DMT (For a quick explanation of this, see this previous issue), allowing DMT molecules to shimmy up to the brain for a dance with our neurons.
There is mounting evidence that ayahuasca can treat central nervous system disorders such as depression, PTSD, Parkinson’s disease, and Alzheimer’s disease. 🧠
β-carbolines could be playing an important role this therapeutic potential.
There are lots of β-carbolines in B. caapi, yet, we have not seen a thorough examination of their true diversity in B. caapi, nor their full therapeutic value
This paper zooms in on the effect β-carbolines have on microglia, the resident-immune cell in the brain.
Microglia have many jobs, including responding to injury, promoting repair, triggering and controlling immune response to pathogens, and cleaning up waste throughout the brain. ⛑
Like our actual immune system, microglia can be over-activated for various reasons. When this happens, they release molecules which cause inflammation. Inflammation can cause/contribute to the aforementioned CNS disorders.
The neuromodulatory action of β-carbolines may enable us to reign in the activation of microglia, and thus, help treat CNS disorders. 🥼
What they did
The first steps they took were to extract, separate, and identify the compounds present in a sample of B. caapi collected from Brazil.
Extraction is fairly simple; the plant is dried, powdered, macerated with methanol, and filtered through a very tight sieve. 🌿
The compounds in B. caapi were separated with high-performance liquid chromatography (HPLC). This is a process of using high pressure to push a mixture through a column of adsorbent material. Atoms move through the column at a different rates depending on their mass and charge. Atoms flowing at different rates are thus separated (this is called “fractioning”), and thus can be collected and analyzed separately.
The fractions were analyzed separately using mass spectrometry coupled with time-of-flight (TOF) measurements. These instruments provide a mass/charge ratio ideal for identifying unknown organic compounds.
They then ran four experiments with cultured microglial cells to test the effect of the extracts on various parameters of cell survival and function.
In each experiment, they tested:
The entire B. caapi extract
Each of fractions 1-5 from the HPLC run
Harmine, Harmaline, and tetrahydroharmine (THH) analytical standards purchased from a chemical vendor
Each of these treatments were applied to microglia cultures in these four experiments:
Cell viability - A measure of the physical and physiological health of cells in response to a treatment. 💪
Apoptosis/necrosis assay - Apoptosis is a process of “intentional” cell death which does not elicit inflammation, while necrosis refers to “accidental” or externally triggered cell death which does elicit inflammation. This test also measures healthy cells. ☠️
Reactive oxygen species (ROS) production - ROS are highly reactive molecules which, among many things, can induce apoptosis or necrosis, cause inflammation, damage DNA, and alter gene expression. ⚛
Cytokine Production - Cytokines are a loose category of small signaling proteins. They help regulate both the endocrine and immune systems. 😷
What they found
From the separation of B. caapi components, the researchers found:
Harmine, harmaline, and THH. These were expected and confirmed by comparison to the analytic standards.
Three compounds previously described in the literature, harmalinic acid, procyanidin, and epicatechin.
Five unidentified fractions, named F1-F5. They attempted to resolve the structure of the compounds in these fractions but the results were inconclusive due to low amounts present.
Cell Viability
B. caapi extract , F3, F4, and F5 did not have any significant impact on microglia viability. F1 & F2 increased microglia viability at higher concentrations, as seen in Fig. 1.
The known β-carbolines affected viability differently. Notably, harmine increased cell viability at 8 μg/mL, and then viability drastically drops at higher concentrations.
Apoptosis/Necrosis
The most notable result here is that F4 decreased viable cells and increased necrotic cells at 42.8 μM and 342 μM, suggesting a significant action of some unknown β-carboline in this fraction.
Harmine had similar effects at different concentrations (Fig. 2).
ROS production
F4 and harmine steal the show here again, with F4 increasing ROS production at all concentrations, and harmine all but the highest concentration. This latter result may be due to the cells losing function at such a high dose (Fig. 2).
Cytokine production
Most treatments had anti-inflammatory effects on the microglia, though the largest effect came from harmaline, THH, F4, and F5.
This was observed through a decrease in pro-inflammatory cytokines IL-6, IL-17, TNF, and/or IFN-γ, and an increase in anti-inflammatory cytokines IL-4 or IL-10.
Check the paper (linked below) for the exact matchup between the treatments and significant effects on cytokine production.
My Take
This study is fairly straightforward. Compounds found in B. caapi do have anti-inflammatory action on microglia, and this is promising for developing therapeutics. However, this paper also opens many pressing questions about (1) the identity of the unknown compounds in fractions F1-F5, (2) the mechanisms behind the dose-dependency of the effects of these compounds on different cell populations, and (3) how the compounds for which significant effects were found can be translated into therapeutics for humans. I am especially curious to know about F4, as this compound had some effect across all of the assays, with contradictory effects. Namely, it seems to decrease viability/increasing necrosis at some concentrations, but has anti-inflammatory effects at both the same and different concentrations. It will be interesting to see an identification of the compound and how it shapes up in further testing on cells and in whole organisms. 🧪
As always, I am super stoked whenever a new psychedelic paper involving glial comes out. It is one of my most anticipated areas of research in the space. Here’s a previous issue about DMT, psilocin, and microglia. 🧫
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📃 Here’s the paper:
Santos, B. W. L., Moreira, D. C., Borges, T. K. dos S. & Caldas, E. D. Components of Banisteriopsis caapi, a Plant Used in the Preparation of the Psychoactive Ayahuasca, Induce Anti-Inflammatory Effects in Microglial Cells. Molecules 27, 2500 (2022).
Available here.
From Around the Psychosphere
🔬 Research
Kambô is a frog-secreted, psychedelic-adjacent drug originating from the same region as ayahuasca, but with very different effects. Check out this new paper on the ritual, effects, dosage, and risks of its use.
A new qualitative analysis of the phenomenology and content of the smoked DMT experience, using reports from r/DMT.
Mind & Matter Episode with Andrew Chadeayne on: Chemistry of Magic Mushrooms, DMT Analogues, Entourage Effects in Cannabis & Fungi, Novel Psychedelic Medicines, Psychedelic Startups
Free webinar on June 22nd: “Mapping the Future of Psychedelics: Deconstructing Powerful Drugs to Make Better Medicine” presented by Boris Heifets
The Olson Lab receives $2.7 million to study non-hallucinogenic psychoplastogens.
Great thread on underappreciated areas of psychedelic research:
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🔮 Culture
Owsley Stanley’s Troll House up for sale in Berkeley.
Psychedelic activists arrested at DEA headquarters for protesting for access to psilocybin for terminal cancer patients.
Shayla Love on the hotly-debated paper mentioned last issue.
And an insane connection between a meme and the dispute:
📈 Industry
A new newsletter from PsyMed Ventures is a great way to stay up to date on industry news, interviews with peeps in the space, as well as the investments/philosophies of PsyMed.
Updated job board from the rebranded Psychedelic Alpha (formerly Psilocybin Alpha)
ATAI CEO named as one of highest paid CEOs in Biopharma. Harbinger of industry success or inequality?
Tunes for your next flow state
🔥 Kingfish Tiny Desk Concert 🧈
🤟🏽 Have a swell weekend friends 👽