@Ismene2 Yes chronic use of 5‑HT₂B agonists can cause cardiac vulvuopathy. I think fenfluramine was the first drug where they identified this problem - it was used as a prescription weight loss/appetite suppressant drug until they figured out that it was causing damage to people's heart valves because of chronic 5‑HT₂B stimulation. Psychedelic effects mostly get attributed to 5‑HT₂A receptor activity (although it's probably more complex than that), but most of these drugs are also agonists on the 5‑HT₂B receptor. This is one of the reasons I'm wary of chronic microdosing psychedelics.
en.wikipedia.org
As I understand it, only a subset of users experienced valvulopathy, which makes the conventional hypothesis seem too simplistic. Perhaps there is a genetic susceptibility to it, but more generally, I think the observations suggest some underlying pathologies which 5-HT2B stimulation can amplify. I say "can amplify" because not every 5-HT2B "agonist" will necessarily do so in the first place. Similarly, some kinds of 5-HT2B agonism may amplify pathological fibroses in tissues in other parts of the body too. This area deserves far more research than it's gotten, and instead 5-HT2B agonism has become a kind of "taboo" in pharmacology, which if violated results in further attention being shutdown.
I any case, I believe it's highly likely that 5-HT2B interaction is a major contributor to the effects of many psychedelics drugs. Some evidence suggests 5-HT2B activation is critical to the effects of MDMA too and may play a bigger role in enhancement of serotonin transmission than interactions at the 5-HT transporter. By boosting overall serotonin release (in the brain, not sure about anywhere else in the body), 5-HT2B agonists may function somewhat indirectly as 5-HT1A agonists by boosting overall serotonin release. This could lead to softening or mellowing of psychedelic effects, reduction in body load, and so on. Hence, 5-HT2B may mediate the apparent entactogenic effects that many psychedelics possess.
I have other reasons to be wary about regular microdosing of psychedelics. Serotonin and by extension its "substitutes" are very powerful hormones, and I suspect that overly frequent activation (especially daily or continuous) over time will tend to produce profound shifts in epigenetic profile with all kinds of potential consequences that may be harmful and maybe very difficult to reverse. I'm even a bit wary about taking psychedelics weeks apart. The cascading effects of a single dose are apparent days, weeks, and even months into the future. In so far as my body seems to "remember" the effects of psychedelics for a long time, I can't help but wonder if even dosing every 2-3 weeks is too much.
It was from a professor in a journal club I took. He said it accounts for both surface area and metabolic differences (rodents are scavengers and tend to have metabolic enzymes which are more fully cranked than ours). That being said, it isn’t gospel, and there are quite a few exceptions .
Interesting. I purposely avoided getting into discussion about dose equivalencies above because I think the whole notion is under-determined in many cases. For example, do we want to equate based on peak intensity (PI) or area under the curve (AUC)? As a psychonaut deciding on a dose, I probably care a lot more about PI, and if I want a very strong experience, I might be very happy smoking some DMT because it's so powerful yet it's essentially over in 15 minutes. On the other hand, if I'm using psychedelics to treat my chronic health conditions, I might care a lot more about AUC, and I may prefer a low peak intensity dose of some long-acting substance which gives me medically beneficial effects without disrupting my life too much. This is rather simplistic reasoning for the sake of examples. In reality every drug has a multitude of effects throughout the body, the "strength" of each of which may correlate based on PI, AUC, some other potential axis. When we're looking at some kind of composite effect (i.e., life extension as a consequence of semi-regular psilocybin dosing in mice), there's simply no obvious choice of what axis to use to equate them. I would say that to the mouse, psilocybin is a lot more like DMT is in humans with stronger peak effects versus duration, but to echo what I already wrote, it's also difficult to decide how to equate passage of time between species, and something like 30 minutes of tripping may still "feel like" six hours of tripping for a human. These are fundamentally difficult problems, IMO.
www.nature.com
Snake oil indeed!
