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Comment by trgv | Hacker News Reader

Assuming that psilocybin is effective at treating depression, I find myself wondering whether actual conscious experience (that is, being high) is an essential part of its effectiveness or not.

To put this another way, imagine someone takes whatever dose of psilocybin and then is rendered unconsciousness until the perceptual effects wear off. Will there be any difference in its effectiveness as a treatment for depression?

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Being conscious during the trip is an essential part of the healing process. In fact, healing comes from the realization of what consciousness really is, that death is not the end, how my little self is just a stubborn part of a larger infinite consciousness that is the Universe thinking itself into existence, etc. You 'remember' what you really are and that's liberating.

One theory that I subscribe to is that the drug increases the brain's neuroplasticity, allowing for new pathways to be created between sometimes unrelated parts of the brain.

Being conscious allows one to guide (but not control heh) this process, where the user can pick a subject to think about and immerse oneself into a audiovisual/emotional/cognitive hallucinatory experience that follows related to that subject. Inevitably the most pressing issues of one's life will surface, allowing the user to examine them from all these different angles - accept, forgive, love and heal.

Psychedelics absolutely increase neuroplasticity, via triggering the release of BDNF. They are also extremely potent anti-inflammatories.

Regarding the value of the trip itself, you pretty much hit the nail on the head. It always makes me chuckle when scientists talk about trying to isolate the antidepressant effect from the psychedelic nature of the experience. That is a sure sign that the people studying the compound lack significant first-hand experience with it.

I believe we already have an answer for this - which is that most of the benefits of psilocybin on depression (and most other things) rely on the patient being conscious so that they are able to have a 'mystical-type experience.'

In almost all psilocybin studies, the effect is mediated by the degree to which the participant has a 'mystical-type experience.'

I don't imagine this could be experienced while unconscious, and so assuming that's correct, then it would be substantially less effective if someone was unconscious.

I would expect a small anti-depressant effect of psilocybin alone, possibly related to the serotonin 2A receptor and it's impact on well-being. But, to be very clear - the active experience of a 'mystical trip' is what causes a reduction in depression.

See:

http://journals.sagepub.com/doi/full/10.1177/026988111773127...

'Determinants of enduring effects were psilocybin-occasioned mystical-type experience'

http://journals.sagepub.com/doi/full/10.1177/026988111667551...

'The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.'

On the other hand, apparently electro-convulsive therapy still has an antidepressant effect even when patients are anesthetized for the treatment. So it's not like this is a dumb question to ask categorically.

Absolutely not a dumb question to ask, thanks for noting that. In fact, a really good question to ask, as like some other commenters noted that would actually be nice and convenient if it was the case. I just wanted to make sure the information was available on what we know, as I think research has already found the answer, to anyone who viewed the thread.

> In almost all psilocybin studies, the effect is mediated by the degree to which the participant has a 'mystical-type experience.'

> I don't imagine this could be experienced while unconscious, and so assuming that's correct, then it would be substantially less effective if someone was unconscious.

It's correlation, but to determine causation one would have to undergo simultaneous mystical-inducing-quantity psilocybin and be "naturally" unconscious (because e.g. stuff used for general anesthesia is likely to interfere with other brain processes). I have no idea how such an experiment could actually be carried out.

Overnight hospital stay with an IV drip to administer the psilocybin after the patient falls asleep?

Sounds like a good idea, provided that the patient is a good sleeper and is not sleep deprived - there is research showing sleep deprivation provides some short term relief for depression ... everything is confounding, nothing is intuitive about these things.

To refine your question further[0]: is this an effect of the psychological experience of tripping on mushrooms, or is this a physiological effect of the drug itself?

In either case, it may explain some habitual drugs users who are actually self-medicating. It could be that in a few years, they're doing the exact same thing but with a prescription to make it all morally upstanding.

[0]Correct me if I'm misunderstanding.

In regard to you second part, that has happened/is happening in the US on a state by state basis with marijuana.

I’m not going to look for references right now, but there is current research into the anti-inflammatory effects of classical psychedelics.

Anecdotally, it has been speculated by researchers that it is in fact this effect that produces many of the observed benefits, apart from the psychedelic experience itself.

And so people are looking at analogs that can have some of the same receptor affinity profiles without causing psychedelic effects, or with much diminished psychedelic effects.

Personally I think a protocol such as what you suggest is a better approach and would work.

I had a friend who had a historical condition caused by a spinal trauma in her childhood, while professionally practicing ballet.

It would be externalised as random pains associated with her back.

She went through several prescription painkillers when her doctor told her to try sub-recreational doses of shrooms to treat the pain (obviously not prescribed).

It worked well until I believe she tripped hard, which I suppose happens with street-quality drugs and specifically with mushrooms which if not extracted have a relatively large variablity in concentrations between mushrooms bodies.

So here's both the lesson of why she stopped doing them and the obvious fact of some doctors actually knowing of the effects; but they can not advise since there no specific research on this could be used as a medication this and whether that could even be regularly prescribed as a medicine.

I believe the ketamine anti-depressant experiments use a different anesthetic to put subjects under in order to split the trip experience from the lower-level chemical effects, and still find benefits. If the trip itself is not necessary for ketamine, that makes it more plausible that it's not necessary for psilocybin etc.

(Of course, this doesn't rule out the possibility that much of the benefit is coming from after the trip during regular life based on experiencing regular life with 'reset' neurons under the Carhart-Harris/Nutt interpretation.)

The experiments I've read about don't use any additional anaesthetic. They just give people a low but still noticeable dose intravenously. Some people reported mild and transient unpleasantness during the treatment due to the drug's effects.

Ketamine is used as a disassociative, though.

The categories aren't necessarily as clear cut as label -> effect, though, as in psychedelics (including psilocybin and its relatives) can be dissociating, and ketamine (and other dissociatives) can be psychedelic. That said, not because of particularly similar physiology; they certainly have different receptor targets.

Doubtful, but I'm sure you could find a way if you really tried, maybe with someone to talk to you while you sleep.

Euphoria is only one of several effects on the consciousness, and in many cases the deliberate cognitive processes that are enabled/invited by that combination of effects are the real treatment. This is when the issues causing the depression are thought patterns, which can sometimes be more effectively examined and dealt with under the influence of ego-fear-dissolving euphoria, dissociativity, form constant hallucinations, etc.

There's good evidence that the degree to which a person has a "mystical-type experience" is a good predictor of the benefit.

This is not surprising if you've taken it before. It's the experience itself that's liberating, much in the same way that other profoundly meaningful experiences in life depend on you actually "being there" to have any benefit.

Yep, this. See my reply to the poster for more info.

The effects of subthreshold doses of psilocybine would suggest that it's a cause of the drug, rather than the experience.

Yes, it would still work because the current hypothesis is that it's the resulting increase in neurogenesis which is responsible for the amelioration of depression.

Neurogenesis in general seems to be inversely proportional to experiences of depression.

That's assuming that the same neurogenesis still happens in the absence of a conscious experience. Do you have evidence that supports this?

Nope, the effect is mediated by the psilocybin induced mystical experience, which I don't believe could be experienced while unconscious. See my comment above.

Great question. Would love to see controlled studies on this, though the anaesthetic drug would be a confounding factor.

That makes me wonder: what if we gave people psilocybin and knocked them out with ketamine until the effects subsided? Hmm...

I'm not sure if your question was tongue-in-cheek, but a k-hole (high ketamine dose) is also considered by some to be a psychedelic experience. It was (is?) common in the rave culture to do exactly what you describe.

I would assume so, that it’d be akin to a strong one-shot antidepressant. Psilocybin is quickly metabolised to psilocin, which binds to serotonin receptors. It might be more of a risk for a bad trip, though, unless you have good dream control.

Also, you’d definitely need to be rendered unconscious, haha—I can’t imagine trying to sleep naturally on mushrooms, although when I take them I always have the most beautifully restful sleep after coming down.

Propofol would do the trick (in a clinical setting).

Putting someone under while on drugs that typically render it hard to sleep without disrupting the drugs seems considerably harder and riskier than keeping the trip a safe experience by having experienced psychiatrists and antipsychs on hand.

Michael Jackson disagrees.

Hallucinacions are part of the healing with any psychedelic for me. Set yourself in a pleasant environment with cool people, and the experience that you get will be long lasting and behavior changing. Not always life changing, but it always added something positive to my views, thinking or overall scence of wellbeing. At it is the same for mushrooms, lsd and ayahuasca

Serotonin and brain function: a tale of two receptors by Robin Carhart-Harris and David Nutt[1] suggests that the main affects are due to the conscious impacts on behavior, but that those impacts don't depend on the experience of being high so much as the long-lasting effects of the stimulation. It basically comes down to whether or not you believe them though.

[1] http://slatestarcodex.com/2017/10/10/ssc-journal-club-seroto...

well, in these studies, we are talking about really low doses. so no, "trip"

  The present study focused on changes in brain function before versus after psilocybin in 
  patients with treatment-resistant depression who received two doses of the drug 
  (10 mg followed by 25 mg, one-week apart) as part of an open-label clinical trial.

25mg of pure psilocybin, the equivalent of 3.3 - 5 grams of dried mushrooms (depending on strength), is certainly enough for a trip.

It would be interesting to see if pure psilocybin (or prodrugs thereof) elicited as similarly-successful a response. I wonder to what extent other alkaloids, that are also present in mushrooms, affect the after-effects crucial to anti-depression.

The introspection is crucial.

I guess what the parent comment was questioning was exactly this assertion. I tend to believe that the introspection is part of the reason these drugs help, but we won't really know for a fact until proper double blind experiments are done.

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