Nick Jikomes, PhD Profile picture
Feb 17 16 tweets 9 min read
🧵#ScienceBreakdown: "Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors"

Interesting new paper by @DEOlsonLab, @LinTianPhD, et al. looking at why some serotonin 2A receptor agonists promote neuroplasticity, but others do not.

1/
Various small molecules, from endogenous neurotransmitters like serotonin to tryptamine #psychedelics, activate 5HT2A receptors... and yet they can lead to very different effects.

Getting at why this is was one of the basic motivations for this study.

2/
One idea here is that various compounds have distinct physical/chemical properties, despite all activating 5HT2A receptors.

For example, they differ in fat solubility. Some can cross cell membranes to get *inside* cells, and some can't...

3/
In cultured neurons, they measured compounds' ability to induce plasticity. Bathe cells in cmpds, then assessed plasticity by counting # of "spines" (places where synapses are) or dendritic complexity (# of times dendrites cross each other).

Did so for multiple cmpds:

4/
Graphs show that some cmpds induce more structural plasticity than others. This is tied to chemical properties.

Cmpds with more "N-methylation" induce more plasticity. This is includes #psychedelics like 5-MeO-DMT, which induces more plasticity than serotonin or tryptamine.

5/
Basically, the more fat soluble a 5HT2A receptor agonist is, the more plasticity you see.

(there's some more complicated stuff going on here related to how cmpds different molecular signaling pathways, which I'm skipping over).

6/
"Psychoplastogen" is a new term referring to compounds, like classic #psychedelics, which can rapidly induce neuroplasticity.

For background on this, see my convo w/ @DEOlsonLab: mindandmatter.substack.com/p/podcast-46-d…

For criticism, see my convo w/ Gul Dolen: mindandmatter.substack.com/p/gul-dolen-so…

7/
So, more fat soluble cmpds seem to be more plasticity-inducing. Idea is that perhaps this is b/c they're actually going inside cells to activate 5HT2A receptors, rather than doing so via receptors on the outer cell membrane (which is what we normally think of drugs doing).

8/
5HT2A receptors are GPCRs (a general type of receptor). Most of the time, you find, GPCRs on outer cell membranes, but there are some known to be localized inside of cells.

Next step is to see where 5HT2A receptors are localized in these neurons. Outside, inside, or both?

9/
Figure is kind of tough to explain, but they find evidence for 5HT2A receptors localized inside of neurons.

That does not mean 5HT2A receptors are *only* on the inside of neurons, but a sizable pool of these receptors appears to be inside of the neurons they looked at.

10/
Must these cmpds actually go inside of cells to have their plasticity-inducing effect? To test this, they chemically modified DMT, psilocin, etc. so they had reduced membrane permeability, but could still activate 5HT2A receptors.

11/
When DMT & psilocin modified to be less fat-soluble, didn't induce as much plasticity unless "electroporation" was used to force them inside cells.

Indicates that plasticity from cmpds like DMT & psilocin largely due to crossing cell membrane & activating 5HT2A inside cells

12/
What about the opposite? Can a cmpd like serotonin, which can't naturally cross membrane, be somehow forced into neurons? And if so, will it then induce plasticity similar to more fat soluble #psychedelics like DMT & psilocin?

13/
Skipping details, the answer appears to be, "Yes."

If you force serotonin into cells, it now induces structural plasticity more than it otherwise would.

14/
Effects of #psychedelics on neuroplasticity are related to their observed antidepressant effects.

Since forcing serotonin inside of cells made it "look like" #psychedelics in terms of plasticity effect, can this also enable it to induce antidepressant effects similar to psychs?
Short answer appears to be, "Yes."

That's all I have time to unpack here, but this is a really cool study worth checking out if you're interested in the details of how #psychedelics work in the brain at the cellular/molecular level to induce their effects.

16/16

• • •

Missing some Tweet in this thread? You can try to force a refresh
 

Keep Current with Nick Jikomes, PhD

Nick Jikomes, PhD Profile picture

Stay in touch and get notified when new unrolls are available from this author!

Read all threads

This Thread may be Removed Anytime!

PDF

Twitter may remove this content at anytime! Save it as PDF for later use!

Try unrolling a thread yourself!

how to unroll video
  1. Follow @ThreadReaderApp to mention us!

  2. From a Twitter thread mention us with a keyword "unroll"
@threadreaderapp unroll

Practice here first or read more on our help page!

More from @trikomes

Feb 10
🧵I've done several episodes about #COVID, including the origins of the #SARSCoV2, the biological & epidemiology of the virus, and how mRNA vaccines work.

Here are a few good ones, and a long-from article, that focus on these topics:

1/7
"The Mystery of SARS-CoV-2 & the Origins of COVID-19" with @Ayjchan:

Listen here: mindandmatter.substack.com/p/podcast-45-a…

2/7
"The Origins of the SARS-CoV-2 Virus" with @mattwridley:

Listen here: mindandmatter.substack.com/publish/post/6…

3/7
Read 7 tweets
Mar 28, 2022
🧵Mind & Matter content series on @Leafly.

A written content series with a new article each month exploring the relationship between humanity and psychoactive drugs.

In this thread, I will collect links to each article in the series.

All articles: leafly.com/news/tags/mind…

1/
"Death and psychedelics: How science is reviving this ancient connection"

Explores the relationship between #psychedelics & death. It integrates the perspective of thinkers ranging from Timothy Leary to Aldous Huxley to @BrianMuraresku.

Read here: leafly.com/news/science-t…

2/
"Would psychedelic therapy work w/o tripping?"

Inspired by convos w/ scientists like David Nichols, @DEOlsonLab & others, explores the question of whether #psychedelics subjective effects are required for any of their therapeutic benefits.

Read here: leafly.com/news/science-t…

3/
Read 7 tweets
Mar 27, 2022
Just learned that fluvoxamine, a common SSRI used to treat depression and other psychiatric conditions, increases the half-life of caffeine in the bloodstream.

Like, to an absurd degree:

1/ Image
Fluvoxamine does this by inhibiting a cytochrome P450 enzyme that metabolizes caffeine. Caffeine levels remain elevated for way longer than normal.

This would be bad for sleep.

2/ Image
When people feel tired from sleep disruption, they often naturally use more caffeine, which can lead to dependency, i.e. you will get withdrawal symptoms if you stop.

3/
Read 6 tweets
Jan 16, 2022
🧵"Psychoplastogens" = drugs that rapidly induce physical changes in the brain (neuroplasticity).

Examples: ketamine, psilocybin, LSD, DMT, MDMA.

Neuroscientists can literally watch new connections sprout overnight, as in the example below.

Movie:

1/
There are other plasticity-promoting psychoactive drugs, such as SSRIs, that are not psychoplastogens because they induce plasticity on a slower time scale (weeks).

Psychoplastogens can stimulate plasticity when exposed to neurons for <1 hour.

pubs.acs.org/doi/abs/10.102…

2/
I first learned about this term from the work of @DEOlsonLab.

I discussed his research with him in a recent podcast conversation, including his work on #psychedelics like ibogaine.

Listen here:

3/
Read 6 tweets
Jul 7, 2021
#ScienceBreakdown:

"The Phytochemical Diversity of Commercial #Cannabis in the United States."

This is a preprint for a study I recently completed with collaborators at @CUSystem: @bkeegan, @cannagenomics.

Descriptive summary of the study below.

biorxiv.org/content/10.110…

1/
Some questions we asked:

How diverse is #cannabis in the US in terms of cannabinoid + terpene content?

Are similar or distinct chemical phenotypes (chemotypes) seen across US states?

What are the most common chemotypes we reliably see and about how many are there?

...

2/
Do industry labelling systems align w/ underlying chemistry? Any systematic difference, above chance levels, for samples labelled Indica vs. Sativa?

How about strain names? Are any reliably associated w/ certain chemotypes or are they random w/ respect to product chemistry?

3/
Read 42 tweets
Dec 14, 2020
#ScienceBreakdown: A group of scientists (@DEOlsonLab) created an ibogaine analog lacking nasty properties of ibogaine but retaining desirable ones. It is also claimed to be non-hallucinogenic.

Background and dissection of study below.

Full study: sci-hub.st/https://www.na…

1/ Image
Background:

Ibogaine is an alkaloid found in iboga, a shrub from West Africa. It's a dissociative psychedelic and can induce intense hallucinations that last for many hours.

Prelim evidence suggests it may help treat addiction, but it can also have serious side-effects.

2/ Image
You obviously don't want a drug to have severe side-effects, and ibogaine has some, including cardiotoxicity (heart damage).

There's also a push in the psychedelic drug space to develop psychedelic analogs that retain therapeutic properties but don't induce hallucinations.

3/
Read 25 tweets

Did Thread Reader help you today?

Support us! We are indie developers!


This site is made by just two indie developers on a laptop doing marketing, support and development! Read more about the story.

Become a Premium Member ($3/month or $30/year) and get exclusive features!

Become Premium

Don't want to be a Premium member but still want to support us?

Make a small donation by buying us coffee ($5) or help with server cost ($10)

Donate via Paypal

Or Donate anonymously using crypto!

Ethereum

0xfe58350B80634f60Fa6Dc149a72b4DFbc17D341E copy

Bitcoin

3ATGMxNzCUFzxpMCHL5sWSt4DVtS8UqXpi copy

Thank you for your support!

Follow Us on Twitter!

:(