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Comment by esseph | Hacker News Reader

I know people personally that psilocybin, LSD, and other substances do nothing for. All of them also have existing mental health disorders (extreme generalized anxiety, depression, bipolar, etc.).

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That could be an interaction with the meds they take for those conditions, couldn't it? I seem to recall that SSRIs in particular could mitigate the effects of the hallucinogen.

Yes, also that was accounted for with doctors notice and slow tapers off medications over months.

Nothing as in there is no outside noticeable change in behavior and they report no change in speaking, or nothing as it relates to the topic of this thread, in that they have no profound or spiritual experiences?

They might get a slight body high even on what would otherwise be considered heroic doses for their weight.

Things like lemon-tek to make the psilocybin more bioavailable were also not impactful to them, while being apparently extremely impactful for others.

It may be worth noting that antidepressant medication has a strong suppressing effect on psychedelics.

Depends on the type! Generally might be true for SSRIs but not always for TCAs or lithium which can have the opposite effect. https://pubmed.ncbi.nlm.nih.gov/8788508/ (just one example)

Well aware and accounted for.

If they’re doing high doses of psychedelics and only experiencing a body high, then they’re either on a drug blocking its effects, or they’re not taking a 5HT2-A agonist. They simply do not just produce a body high at high doses, you will know when you’re tripping.

This isn't completely true. Tolerance to psychedelics is a thing, and can often ve extremely long lasting. I have a friend that when given heroic doses of 2C-B(50mg or more, orally), hardly experienced more than threshold level effects. This was 2C-B tested and confirmed to have 95% purity, and it affected me exactly as expected. He was not on any drugs except hash, which is typically synergistic.

In his case, according to him he yad used 2C-B very heavily many years previously, and it seems he developed an extremely high level of tolerance which remained unchanged for many years of non-use.

In the cases discussed in the thread, it's possible that something similar was happening. Indeed, many antidepressants also alter serotonin receptor expression over time, and it's plausible that in some people, these effects could linger for a long time.

I agree in that case, long-term SSRI and psychedelic use complicates things. But in general, I would not say the literature points to tolerance being long lasting. Tolerance is built up quickly, and then quickly lost. There have been many (reproduced) studies on the effects of psychedelics and tolerance build up, and they show it doesn't last for more than a few weeks (psilocybin / LSD).

I'd be interested to see those studies. I think there could be a couple different types of tolerance, one of which only occurs with rather heavy use. It's something I've seen reported anecdotally from a number of people who've used psychedelics very heavily. It might not show up in human studies because of ethical concerns. There could be some interesting pharmacological differences too, where this only occurs with specific drugs. The psychedelics are quite varied in terms of pharmacodynamics beyond just the 5-HT-2 receptor subfamily.

Here's the OG tolerance study done on psilocybin and LSD: https://link.springer.com/article/10.1007/BF00407974

We need more studies on the long term effects of heavy psilocybin use. We know how chronic use of alcohol and cannabis affect people fairly well at this point. We also know a lot about regular psilocybin use, but not a whole lot about what happens to people if they take it for 20 years.

Imagine being on a med for 30-50 years.

I'd call that a case of the drug(s) they were on blocking the effect due to an apparently permanent change to their brain chemistry.

Some of them were younger, in their 20s with long lasting depression and no history of medication in the last ~2y.

This wasn't some like, "weekend experience" but more multi-decade "experiments" with some extremely well educated friends, coworkers, etc.

Group size of around 30.

Fwiw I find that, due to my antidepressants, i need 3x the dose to have the equivalent experience as my friends.

I find mushrooms in particular delightful, just not deep.

Higher dose.

EXACTLY! The same to most of the posters with “meh-effects”: up the dose! LSD and psilocybin can be very psychedelic and hallucinogenic

Many psych meds diminish/block psychedelic effects.

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