# DMT, pharmacogenetics and cetera

# [DMT MoA](https://readwise.io/reader/shared/01gx4939hjb7mtt5074b0zk1j2/)

An awesome take by Andrew Gallimore on DMT's MoA. I'd reckon it generalizes on a wider range of psychedelics, e.g. 5-MeO-DMT and psilocin/other tryptamines at least.

## Takeaways:

Our brain is an error-reducing Bayesian predictive machine. Yeah.

![](https://substackcdn.com/image/fetch/w_1456,c_limit,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F4899cbfe-46fa-4183-bda2-39cab051cc8e_454x288.png align="center")

### Brain connectivity

**Structural**: *actual physical “wiring” of the brain, the synaptic connections between neurons;*

**Effective**: *the way activity in one cortical area causes an effect on the activity in another area. Depends on structural connectivity, at least in part;*

**Functional**: *connections* ***in time***\*. When, for example, the brain is encoding an object in the visual field, neurons in the areas that represent the features of that object are simultaneously active: those areas are functionally connected.\*

![](https://substackcdn.com/image/fetch/w_1456,c_limit,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2Fca6106d5-fcba-4a78-b16e-522195593e2f_1080x720.jpeg align="center")

### High-order networks

![](https://substackcdn.com/image/fetch/w_1456,c_limit,f_auto,q_auto:good,fl_progressive:steep/https%3A%2F%2Fsubstack-post-media.s3.amazonaws.com%2Fpublic%2Fimages%2F7f39fd0c-42e2-4e90-a3cc-25831f3ccd03_933x420.jpeg align="left")

**CEN**: activated during attention-demanding goal-directed tasks, such as solving a mathematical problem or writing a letter, and is important in holding and manipulating information in working memory.

**DMN**: activated during daydreaming, when thinking about the future or reminiscing about the past, or just letting the mind wander, and is often considered the resting state of the brain (hence *default* mode network).

**SAN:** helps the brain switch between the CEN and DMN according to demand.

<mark>⬇️ CEN ⇢ ⬆️ DMN</mark>, and vice versa.

### Enter DMT

1. ⬇️ ***within-network*** *functional connectivity (FC), also referred to as “network integrity”. In other words, high-order networks, such as the DMN, are disrupted and become more disorderly.*
    
2. ⬆️ ***between-network*** *FC or decreased “segregation”. Networks that are usually well segregated from each other show more functional connectivity between each other.*
    
3. *A globally hyperconnected brain state. On average, each cortical area shows greater functional connectivity to other areas —* ***more cortical areas are “speaking to each other”****.*
    

A great and self-explanatory [qEEG image on hyperconnected states](https://www.semanticscholar.org/paper/QEEG-STUDIES-OF-THE-ACUTE-EFFECTS-OF-THE-VISIONARY-Acosta-Urquidi/69519617a5bffa264510f7392acaa69145f21a11):

![QEEG STUDIES OF THE ACUTE EFFECTS OF THE VISIONARY TRYPTAMINE DMT |  Semantic Scholar](https://d3i71xaburhd42.cloudfront.net/69519617a5bffa264510f7392acaa69145f21a11/8-Figure3-1.png align="left")

Also, it looks like [theta oscillations' power is somewhat correlated with mystical experiences](https://www.frontiersin.org/articles/10.3389/fpsyt.2021.720066/full).

# [Pharmacogenetics](https://readwise.io/reader/shared/01gzqwtkzv1a5767mee834gnwf)

Another take by Mr. Phelps.

![](https://cdn.jamanetwork.com/ama/content_public/journal/jama/938948/joi220065va_1656698531.71575.png?Expires=1687258979&Signature=y3PzemWGAUacKRduRsPDq8-PvPJAQqC5XX7cosxJZvMrJbJZg3-0J5bXZhGGJRZcnpaUpXhL-d1KCFmG7mvDkr0DxXhLSYEaym~Uj6E505oQ~~OjPbidRCUfB8ggiUqoR9U30an2agg3k6X7yeyOsd2VSOEvsEr6081CWiPNkwJRagt0vuojpsq8c-5tke6Vd4Soxnm6ntsHP0CGKpnylbgiEqNkUQxorxQJ~iWOpByBd9ygU5~qHcdPCugD7~vkS0ptQMLPKaOP9pSYO0lHGsho-gji-3Kj5LBkSAU9LzVaHs34YT~jhcuA7dNYz25aNT~h0RjDI6w85rHUw02zfw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA align="center")

Looks great on pixels, doesn't it? Let's dive.

At 24 weeks, as JP (James Phelps) had rightfully mentioned, there was almost no absolute difference:

![](https://cdn.jamanetwork.com/ama/content_public/journal/jama/938948/joi220065t4_1656698531.90011.png?Expires=1687258979&Signature=kRAFqYyJHanXw-Xu2RqdIkLjyBwhB9O-skqGxI22fNKS-Ni9MxLoPhGbnQJODJyIuXSd~DS5dwoc-rCglef2QU~Aqu5ZqRxtJnUGmcZetj1tD2Obz9ulSL2E7hdCqYoy~kJFDJq4MSIhjmL6By~aAUn41oy7OnkRWpb~BJ8Rl88qqDn5HuPXKOjYg6qI6x2QNAQKG~ThHoDXUhY9~KHHsdqCKqIMxvWx8E15VSaFo4mkNkNvNewIJXxeBAuvuwwWp2NScViUqZwfvP8hVcLuOPYY6eEdbT3xAgPKA7Lubr3ebzSJZDF5Xsefg9X-i0FxYULykCU~38rKcoAe6N5KUw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA align="center")

And while, yeah, a $2000-high testing is awesome, doing it by yourself and looking at genes like [ABCB1 (Multiple Drug Resistance, or P-glycoprotein/BBB gene)](https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2015.14050680) or [P450](https://psychopharmacologyinstitute.com/section/pharmacogenomics-in-psychiatry-antidepressant-metabolism-2352-4548) can bring more merit and be basically cheaper.

![FIGURE 2.](https://ajp.psychiatryonline.org/cms/10.1176/appi.ajp.2015.14050680/asset/images/large/appi.ajp.2015.14050680f2.jpeg align="center")

*As one can see, ABCB1 can influence therapy a LOT*

* Basic logic with P450: if your antidepressant is metabolized by, say, CYP2C19 (let's take clomipramine) ⇒ you've got a super-active form of it ⇒ you'll have relatively higher levels of desmethylclomipramine (metabolite), which is more of an NRI compared to clomipramine.
    
* Another point: some genes, like [CYP2C19](https://www.sciencedirect.com/science/article/pii/S0165178122001494), can also [influence antidepressant response and effifacy](https://www.frontiersin.org/articles/10.3389/fphar.2019.00099/full) (spoiler: you want a faster form to benefit from some SSRIs like escitalopram)
    
* As prudent now, augmenting my BS engine with *chirping generative birds*:
    

| Gene | Function | Effect on antidepressant response | SNP |
| --- | --- | --- | --- |
| ABCB1 | Transports antidepressants across the blood-brain barrier | Variants that ⬇️ transporter activity may ⬆️ brain exposure to antidepressants and ⬆️ response | rs1045642 |
| FKBP5 | Modulates glucocorticoid receptor function and stress response | Variants that ⬆️ FKBP5 expression may ⬇️ glucocorticoid receptor function and ⬇️ response | rs1360780 |
| BDNF | Involved in neuroplasticity and neuronal survival | Variants that ⬇️ BDNF expression or activity may ⬇️ neuroplasticity and ⬇️ response | rs6265 |
| CYP450 | Metabolizes antidepressants and affects their blood levels and efficacy | Variants that alter enzyme activity may affect antidepressant pharmacokinetics and pharmacodynamics | rs3892097 (CYP2D6), rs12248560 (CYP2C19) |
| TPH2 | Involved in serotonin synthesis | Variants that ⬇️ TPH2 expression or activity may ⬇️ serotonin production and ⬇️ response | rs4570625 |
| AUTS2 | Involved in human psychological functions and neurobehavioral disorders | Variants that affect AUTS2 expression or function may affect antidepressant response | rs7785360, rs12698828 |

## [Cannabis is fun](https://psychopharmacologyinstitute.com/publication/medicinal-cannabis-and-the-psychiatric-patient-clinical-harm-vs-novel-treatment-interview-2681?utm_medium=email&utm_source=email&utm_campaign=EC044&ck_subscriber_id=201967303), until it's not

![Thumbnail Image ](https://designerapp.officeapps.live.com/designerapp/document.ashx?path=/a4b811e5-899f-4d94-8a47-6f1be74214e5/UserAssets/dalle0251717332131136754800.jpg&dcHint=IndiaCentral&fileToken=1488803a-a52b-4e29-89bd-4996654b30c6 align="left")

There's an interesting line here: *'Approximately 1.5% of cannabis users have a heart attack.'*

<s>Being not-so-pro-cannabis, I decided to explore this filter bubble and sprinkle it with confirmation bias.</s>

| Receptor | Location | Function | Effect of cannabis |
| --- | --- | --- | --- |
| **CB1** | Brain, nervous system, heart, blood vessels, platelets | Psychoactive, cardiovascular, platelet aggregation | **Increase heart rate, blood pressure, clotting** |
| CB2 | Immune cells and tissues, heart, blood vessels | Anti-inflammatory, immune modulation, cardiovascular protection | Reduce atherosclerosis, cardiac fibrosis |
| **GPR55** | Heart, blood vessels, various tissues | Blood pressure, vascular tone, cardiac contractility | **Cause arrhythmias, vasospasm** |

* As one can see, **CB1** and **GPR55** are not so good for our CVS;
    
* Looks like [**CBD**](https://en.wikipedia.org/wiki/Cannabidiol#Pharmacology) can block CB1 receptors non-competitively and enhance endocannabinoid signaling, and [**THCV**](https://en.wikipedia.org/wiki/Tetrahydrocannabivarin#Description) is a minor cannabinoid that can act as an antagonist of CB1 receptors and a partial agonist of CB2 receptors;
    

### Takeaways

1. Cannabis products such as concentrates, BHO, high-dose edibles etc are [not very good](https://www.youtube.com/watch?v=nQzbeZ83CnM);
    
2. Same goes for [high-THC and low-CBD products of any kind](https://med.stanford.edu/news/all-news/2022/04/marijuana-heart-disease.html);
    
3. Not using synthetic cannabs such as [JWHs (e.g. JWH-018) and -INACAs (e.g. AB-FUBINACA or ADB-FUBINACA)](https://www.nature.com/articles/s41598-021-90167-w/tables/1) is useful for your health!
    

---

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