#21

Wow, the options for shrooms in the SF Bay Area have expanded even more than I had imagined.

Professor Michael Pollan, the famous author, wrote a book about psychedelics called “Change Your Mind” while also became a Netflix show. It’s a good watch and/or read, esp hearing about how pyschelics were first being explored in the 60s and 70s for their mental therapeutic value before the whole War on Drugs shut them down. Now they are back on the menu.

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#22

I have a friend who did not trust any of the sources available so grew their own. They now have a nice little supply for use on an as needed basis. :smile:

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#23

They are remarkably easy to grow from either spores or liquid culture; both are readily available. Many ‘how to’ videos on YouTube. Cut out the middleman. Rely on your own best friend, yourself!

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#24

Thanks for pointing out the potential association between psychedelics, 5HT-2b agonism, and valvular heart disease. I found this fully referenced inquiry to OpenEvidence (which only uses published medical research for its answers) to be extremely enlightening and easy to read. I’ll just post the link rather than dump it all here.

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#25

Is there an actual association study somewhere or is this only mechanistic speculation? Were the VHD drugs dosed only a few times and showed toxic effects?

#26

If you read the answers from OpenEvidence, it’s mechanistic speculation when it comes to psychedelics, which may not be an issue since they are usually dosed so infrequently “in the wild” compared to, for instance, fenfluramine which was dosed daily for indefinite periods of time.

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#27

Two drugs with the same binding can have widely different effects. That’s why some drugs that are a 5-HT2A receptor agonist have no effect while others are psychedelic.

I recommend this psychedelics neuroscience course on youtube for anyone interested in psychedelics.

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#28

And for all we know, a drug with activity at other serotonin receptor subtypes may not exhibit the same heart valve-damaging properties as another, even if activity at 5ht-2b were identical.

I’ve never seen any studies on long-term psychedelic use and heart valve defects, and I’d be surprised if any have been done since most researchers have been interested in psychiatric effects.

#29

Is there an actual association study somewhere or is this only mechanistic speculation? Were the VHD drugs dosed only a few times and showed toxic effects?

Fenfluramine was pulled from the market specifically because of its link to VHD and pulmonary hypertension. Other 5-HT2B agonists like the dopamine agonist cabergoline and pergolide have also been removed from the market for PD because of their association with VHD: Drug-associated valvular heart diseases and serotonin-related pathways: a meta-analysis

Additionally, carcinoid disease increases circulating 5-HT levels and dramatically increases risk of heart disease. As these tumors can often release 5-HT directly into the portal vein, they affect the right-sided valves, but the 5-HT is then metabolized in the lungs which spares the left-sided valves.

The pathophysiology of 5-HT2B activation in the heart valves has been extensively studied and while there are subtleties to GPCR activation (efficacy, functional selectivity, etc), the smart assumption is that excessive exposure to psychedelics (5-HT2A agonists) and enactogens (5-HT releasers) will cause heart disease. I’d also point out that Sasha Shulgin, by far the most influential researcher of psychedelics and entactogens, developed heart disease later in life that required surgery—potentially as a result of his frequent use of these substances.

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#30

You’re catching my drift.

It’s also a full agonist at 5-HT2A receptor without any psychedelic effects. So we should speculate the 5-HT2B agonism with heart disease is shared with psilocybin when the 5-HT2A agonism with psychedelic effects isn’t?

#31

Would mice develop the same VHD as humans in response to 5ht type compounds like psilocybin? I did not see anything about the mice developing heart problems. The psilocybin improved their survival.

#32

It’s also a full agonist at 5-HT2A receptor without any psychedelic effects. So we should speculate the 5-HT2B agonism with heart disease is shared with psilocybin when the 5-HT2A agonism with psychedelic effects isn’t?

It’s not mechanistic speculation, just basic Bayesian reasoning. We know multiple 5-HT2B agonists have been withdrawn for their connection to VHD, therefore it’s likely that other 5-HT2B agonists will do the same. Considering the possible outcome is disease, this not only the smart assumption but the safe one as well. Sure, certain psychedelics might display ‘special’ 5-HT2B signaling that doesn’t cause VHD, but this is complete speculation and you’ve provided no evidence for it. Drug development companies are designing psychedelics with no or minimal 5-HT2B activity, so they don’t share your optimism.

The other issue is a totally separate one, and the logical connection you’re drawing between them has zero connection with the physiology. While there are 2A partial agonists that lack psychedelic effects (the classic example is lisuride), this is contrary to our logical expectations and psychedelic pharmacology has been intensively trying to answer why for the past 30 years or so. There’s actually a very sweeping explanation for this that has emerged in the past couple years: psychedelic activity requires a minimum Gαq efficacy at the 5-HT2A receptor (see Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential)

Cabergoline has shown up as a full agonist, but only in second messenger assays. GPCR signaling is difficult to untangle due to the massive cross-talk (and other issues like signal amplification) that occurs at the post-receptor level, and in the case of cabergoline (very ‘dirty’, i.e. hits lots of different GPCRs) the second messengers don’t give reliable readouts of receptor activation. I’d bet money that cabergoline would act as a weak partial agonist in the BRET assays used by the Wallach lab the above paper.

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#33

Even if we conclude that psilocybin/psilocin is a 5-HT2B agonist in a similar way to cabergoline with no difference in functional selectivity, the half-life is 3 hrs for psilocin for while 70 hrs for cabergoline, and psychedelics except for microdosing isn’t dosed in a similar way. It’s not an apples to apples comparison.

If we get to the meat of the issue, association studies in humans show a reduction in heart disease, diabetes, and hypertension for lifetime use of classical psychedelics.

As illustrated below, lifetime classic psychedelic use was uniquely associated with a 23% lower odds of heart disease in the past year and a 12% lower odds of diabetes in the past year.

The results showed that respondents who reported having used a classic psychedelic at least once in their lifetime had significantly lower odds of hypertension in the past year after adjusting for several potential confounders (adjusted odds ratio, 0.86 [0.81–0.91]; P<0.0001

https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.120.16715

It’s functional selectivity that determines psychedelic effects at 5-HT2A receptor, not level of activation. In reality when something binds to a receptor the molecule physically changes the receptor according to the shape of it.

LSD even changes the receptor as such so a lid is over the molecule when the bound to the receptor which is why the effects are longer.

#34

Even if we conclude that psilocybin/psilocin is a 5-HT2B agonist in a similar way to cabergoline with no difference in functional selectivity, the half-life is 3 hrs for psilocin for while 70 hrs for cabergoline, and psychedelics except for microdosing isn’t dosed in a similar way. It’s not an apples to apples comparison.

If we get to the meat of the issue, association studies in humans show a reduction in heart disease, diabetes, and hypertension for lifetime use of classical psychedelics.

Refer to my orginal post where I said excessive usage.

It’s functional selectivity that determines psychedelic effects at 5-HT2A receptor, not level of activation. In reality when something binds to a receptor the molecule physically changes the receptor according to the shape of it.

The Wallach lab’s paper that I linked is by far the most convincing body of data on this and their hypothesis (minimum Gq efficacy) doesn’t agree with your mechanistic speculation. Perhaps start basing your conclusions on the primary literature rather than YT videos.

#35

As far as I can tell that’s subsequent to 5-HT2A activation and explains the functional selectivity of the 5-HT2A receptor of different 5-HT2A agonists (why some are psychedelic at the 5-HT2A receptor and others are not).

If it’s Andrew Gallimore’s course you’re talking about, he does bring up Gq activation, but the videos might be a bit old

#36

As far as I can tell that’s subsequent to 5-HT2A activation and explains the functional selectivity of the 5-HT2A receptor of different 5-HT2A agonists (why some are psychedelic at the 5-HT2A receptor and others are not).

While it’s true that β-arrestin biased 2A agonists would lack psychedelic activity, many psychedelics also strongly recruit β-arrestin. This means that signaling bias is unable to explain it, since as long as a 2A agonist has a minimum Gq efficacy, it could have a wide range of different β-arrestin efficacies and still produce psychedelic effects.

#37

Just an interesting note:

“In November 2020, the state of Oregon became the first U.S. state to both decriminalize psilocybin and also legalize it for supervised non-medical use after the Ballot Measure 109 passed.”

#38

Unfortunately, the 2020 Oregon ballot initiative was essentially repealed in 2024. Maybe not unfortunately when it comes to truly “hard drugs” like cocaine/heroin/meth.

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#39

With the 5-HT issues you mentioned. Do you think this would include SSRI, SNRI, MAOI, and other types of mental health medication on the market?

This was an interesting paper for people with Parkinson’s disease. Mianserin was the only mental health medication that improved lifespan.
www.neurology.org/doi/10.1212/WNL.0000000000213783

The study included 14,289 individuals with PD (mean age 72 at diagnosis, 59% male) and identified 23 drugs associated with reduced mortality risk at 8 years. These drugs included ranitidine (histamine-2 blocker); pantoprazole and esomeprazole (proton pump inhibitors); losartan (angiotensin receptor blocker); atorvastatin (for high cholesterol); tadalafil (for erectile dysfunction); levothyroxine sodium (thyroid hormone); phenoxymethylpenicillin, erythromycin, and azithromycin (antibiotics); 4 nonsteroidal anti-inflammatory drugs; combined codeine/paracetamol and tramadol (opioid analgesics); zopiclone and melatonin (sleep aids); mianserin (antidepressant); mometasone (nasal corticosteroid); 2 opium-derived cough medicines; and dexamethasone (ophthalmologic corticosteroid).

Which appears to be a mix of 5-HT antagonist, histamine antagonist, alpha antagonist, perhaps opioid agonist(kor?), and noradrenaline reuptake inhibitor.

Mianserin, the only antidepressant associated with reduced mortality in our study, distinguishes itself from other antidepressants by effectively and selectively elevating norepinephrine levels by both blocking its reuptake and stimulating its release

I thought that was interesting about the norepinephrine and longevity.
The opioid/opium medications were surprising as well.

A lot of the psychedelic/hallucinogen influencers were taken out by cancer: Leary(prostate), McKenna(brain), Shulgin(liver).
Though they might have used other substances as well. So it’s difficult to say it was directly psychs etc.

From Wikipedia:
"Around this time, Shulgin began showing early signs of dementia, mostly severe loss of short-term memory. With progression of the dementia since 2010, his wife, Ann Shulgin, had been trying to sell part of their property to raise more money to cover care costs. "

So it’s probably good to be using products that can protect against these issues: heart, cancer, dementia.

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#40

There is definitely a connection between SSRI use and mitral valve disease according to this article. The interesting part is the genotypic predisposition to the condition. If a person is pure recessive, long-long, for the 5-HTTLPR alleles they are more likely to develop mitral valve disease. The heterozygous genotype s/l and homozygous dominant s/s would be less likely to develop the disease.

It seems if antidepressants that increase chances of mitral valve disease are prescribed appropriately to those that have a predisposition to anxiety and depression( the heterozygous and homozygous dominant 5-HTTLPR ) then those patients would be at low risk of heart valve disease.

What does this mean for psychedelic use? A certain genotype may be more predisposed to heart valve issues from psilocybin or ergot derived compounds. This genotype would always be a large enough population in any randomized study to show a connection between SSRI’s, psychedelics, etc. and show a strong correlation between heart valve disease and these compounds

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