Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms [pdf]

https://www.nature.com/articles/s41598-017-13282-7.pdf

by dtawfik1 • 9 years ago

227 103 9 years ago

DenisM• 9 years ago

From the abstract:

[...] Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. [...]

dtawfik12• 9 years ago

yeah, very interesting

discordance• 9 years ago

N=19 is a very small sample size. I would be careful forming opinions based on this study.

jessaustin• 9 years ago

Yes it is much better to enjoy psilocybin oneself.

pizza3• 9 years ago

even if it were e.g. sixteen or seventeen, for all of them to report lessened depression a week after is a fairly strong finding, at least enough to merit someone else attempting to reproduce the research. present depression medication barely works better than placebo

anythingnonidin14• 9 years ago

Please read 'A Prevalent Misconception About Sample Size, Statistical Significance, and Clinical Importance'

http://www.joponline.org/doi/abs/10.1902/jop.1972.43.3.181?j...

ComputerGuru• 9 years ago

Before self-medicating based on this combined with a self-diagnosis, consider that LSD and psilocybin have a nasty tendency of triggering latent psychological conditions if not taken in the appropriate dosage and in a controlled environment.

[ref: http://www.nationaldrugstrategy.gov.au/internet/drugstrategy... ]

dtawfik12• 9 years ago

Definitely. Probably is a good resource for psychiatrist as a treatment strategy rather than a protocol for patients to self direct.

wallace_f• 9 years ago

I can swear I came across a study I found, I believe, on Erowid, which noted this link had a lower instance of increased mental illness than religious "meccas" do.

In light of that evidence, it's entirely possible the human experience itself, and not some more mechanistic action or first order effect of the drug, cause the increase in mental illness.

I'm trying to find this source, but am coming up short and on mobile, but will look into it later.

lawpoop• 9 years ago

Actually, I think this is more a risk of marijuana, which in the US, is prescribable in several states, legal in a few, and decriminalized in most.

Which is not to say that I encourage recklessness with psychedelics, but that forasmuch as that is a concern with LSD or psilocybin, we're got bigger fish on our hands. Marijuana is much more available than either of those.

cheshire_cat• 9 years ago

I'd definitely advise anyone thinking about this to do their research but the risk doesn't seem to be as large as often suggested. There was a large US study that showed no correlation between lifetime psychedelic use and mental health problems.

"[...] lifetime use of LSD, psilocybin, mescaline, or peyote, or past year use of LSD, was not associated with a higher rate of mental health problems."

https://www.nature.com/news/no-link-found-between-psychedeli... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747247/

CardenB• 9 years ago

“Life time use” and “one time use triggering latent psychological conditions” are very different. Of course those who use over a long period of time aren’t showing adverse conditions. The ones who were triggered stayed away.

anythingnonidin14• 9 years ago

Yes, and also:

'Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population.'

https://www.ncbi.nlm.nih.gov/pubmed/25586402

benevol• 9 years ago

the risk doesn't seem to be as large as often suggested

The anti-depressant business model is genius: (a) They're sold at a very high price point, (b) they generally make you factually dependent for quite some time (and they're quite hard to quit). It's one of big pharma's preferred multi-billion cash cows.

Now you know who's interested in spreading fear, doubt and uncertainty regarding cheap and effective competing substances such as LSD and psilocybin. And this industry has the resources to effectively influence public discussion forums such as HN, Reddit, Slashdot, etc.

sdfin• 9 years ago

Is there proof that they have a tendency of triggering "latent" conditions, instead of generating the conditions? How can it be demonstated that conditions were latent before the use?

Could it also be the case that people with potential mental illnesses is more likely to try drugs? Therefore being a correlational relationship instead of a causal one?

pdkl95• 9 years ago

Most of this effect is survivor bias. The people that don't have a problem - regardless of their past or future mental health - don't attract as much attention.

WalterSear2• 9 years ago

Lifetime prevalence remains the same.

zamalek• 9 years ago

"Reefer Madness" is inconclusive [1] (so far as agitating an underlying psychosis). Many proponents would regard this as a affirmative result, however it does go both ways.

Is there proof that they have a tendency of triggering "latent" conditions, instead of generating the conditions?

Personally, I've had panic attacks (originating from paranoia) bought on by historical heavy use - the correlation isn't subtle at all. Did my paranoia drive me to the initial peace associated with the drug? I'd have a hard time arguing otherwise - it really, really helped at first. My life was altered positively days after the previous dosage. If I take it now the situation becomes unbearable in less than 5 seconds. Anecdote disclaimer, as well as not being the same psychoactive drug (but it is psychoactive).

[1] https://jamanetwork.com/journals/jamapsychiatry/fullarticle/...

nylonstrung• 9 years ago

They definitely can potential prodromal cases that might not otherwise progress to a full blown case of mental illness and do so in a way that exacerbates it. Many cases of schizophrenia in the prodromal phase don't necessarily develop into a clinical case so it isn't simply isn't a matter of psychedelic use being net neutral since they would have gotten it anyways

Psychosis is literally damaging and the earlier and more violently one is subjected to it the worse their lifetime prognosis will be.

anythingnonidin14• 9 years ago

Tendency: "an inclination toward a particular characteristic or type of behavior." "a strong chance that something will happen in a particular way"

“Since the early 1990s, approximately 2000 doses of psilocybin (ranging from low to high doses) have been safely administered to humans in the United States and Europe, in carefully controlled scientific settings, with no reports of any medical or psychiatric serious AEs, including no reported cases of prolonged psychosis or HPPD (Studerus et al., 2011).”1

Then, to address 'controlled environment':

“Lifetime classic psychedelic use was associated with a significantly reduced odds of past month psychological distress (weighted odds ratio (OR)=0.81 (0.72–0.91)), past year suicidal thinking (weighted OR=0.86 (0.78–0.94)), past year suicidal planning (weighted OR=0.71 (0.54–0.94)), and past year suicide attempt (weighted OR=0.64 (0.46–0.89))”13

And

According to US government statistics, magic mushrooms have been used by 22.8 million Americans at least once.12

https://tripsafe.org/shrooms/

While they can lead to this, tendency doesn't seem to be the right word to use.

I'm quite passionate about this topic and I think it's very important that people writing publicly and sharing opinions on these substances are accurately informed, and try to present statics and put references into context.

Does the above change your mind on this? If not, what would change your mind a little bit towards thinking that they don't have a tendency to do this?

celticninja• 9 years ago

That applies to many thing though, cannabis, alcohol an ecstasy can all be triggers but people think that psilocybin or LSD are worse because of their heightened effects.

nugga• 9 years ago

One theory is that combined with shitty set & setting the people who went haywire after using psychedelics had some seriously strong energies/stuff unlocked from their subconscious that they weren't yet prepared to process. There's some indication that great stress can be a trigger for psychiatric illnessess as well.

WhitneyLand• 9 years ago

What your saying is largely horse shit, it’s irresponsible to give misleading impressions, good or bad, of any drugs. Ive seen nothing to prove causation, including what you linked to.

Correlations can be very useful in providing clues about how all these things work together, but determining what “triggers” what takes an incredible amount of carefully teasing out the real meaning of the data.

There are anecdotal reports of problems with these drugs, but that’s true for all drugs. Currently there is no just significant weight of evidence to draw the conclusions your making.

capsulehotel2• 9 years ago

I have suffered from depression all my life and given that hash in combination with a hostile environment brought out some type of paranoid schizophrenia in me (auditory and possibly visual hallucinations), I'm very weary about irreversible mental damage as well and won't try it due to this.

fapjacks• 9 years ago

Or, you know, you had too much.

trgv• 9 years ago

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?

evincarofautumn• 9 years ago

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.

DigitalJack• 9 years ago

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

mabbo• 9 years ago

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.

NegativeLatency• 9 years ago

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

glorifirdious• 9 years ago

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.

Xenograph• 9 years ago

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

anythingnonidin14• 9 years ago

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.

md224• 9 years ago

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...

uoaei2• 9 years ago

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.

WalterSear2• 9 years ago

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

hwillis• 9 years ago

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...

notduncansmith• 9 years ago

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.

drvdevd• 9 years ago

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.

heavenlyblue• 9 years ago

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.

ssijak• 9 years ago

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

anythingnonidin14• 9 years ago

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.'

derefr• 9 years ago

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.

beagle33• 9 years ago

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.

delegate• 9 years ago

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.

CuriouslyC• 9 years ago

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.

gwern• 9 years ago

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.)

amigoingtodie3• 9 years ago

Ketamine is used as a disassociative, though.

bramen• 9 years ago

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.

amigoingtodie3• 9 years ago

The introspection is crucial.

dguaraglia• 9 years ago

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.

jonnycomputer2• 9 years ago

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

adrice727• 9 years ago

  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.

monktastic1• 9 years ago

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.

anythingnonidin14• 9 years ago

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

adammunich• 9 years ago

Anecdotally, I've seen psilocybin to be an excellent assistant, but not treatment per say, for depression. It can temporarily free people from negative thought patterns; but lasting change only comes from persistent self-reflection and actualization.

uoaei2• 9 years ago

Anecdotally, this is precisely my experience. It'll start the engine, but you have to navigate the course.

rubatuga• 9 years ago

I think it would make a trip to a psychologists office much more exciting

debarshri• 9 years ago

My girlfriend has treatment resistant depression. Most of her life doctors prescribed SSRI based drugs which didn't really work. A lot of money was also spent on psychiatrist for CBT. Based on a youtube videos and blogpost, read about 5HTP.

I think 5htp supplements really works in cases where depression is genetic or the depression exists since childhood, where the cause of depression is not known. You can actually see the result and change in personality within few week. I think 5HTP should be the first medication before any other psychoactive medications are consumed.

jonnycomputer2• 9 years ago

Depression is such a broad spectrum disorder (or put another way, a highly variable cluster of symptoms), that its hard to generalize in any way.

pgt• 9 years ago

Beware that 5HTP can cause mitral heart valve damage due to accumulated serotonin in the periphery. Combine with green tea extract (EGCG) to reduce your risk.

beagle33• 9 years ago

Is Psilocybin and/or Ayahuasaca and/or any other DMT source legal anywhere in the world? I would expect at least _some_ places make it legal, possibly have hundreds/thousands of years of experience that might be interesting to read alongside modern studies.

atom-morgan• 9 years ago

I believe Psilocybin is legal enough (decriminalized?) to purchase in Amsterdam right? I remember watching a Vice piece on truffles.

hellofunk• 9 years ago

Mushrooms were made illegal in the netherlands a few years ago, but "magic truffles" are a loophole in the law because they are not mushrooms, so they are still for sale. It's a bid of a shady distinction.

anythingnonidin14• 9 years ago

See also: https://psychedelicsociety.org.uk/experience-weekends (Magic truffle experience retreat in Amsterdam)

noahdesu• 9 years ago

I believe that Psilocybin is legal in Jamaica, see https://www.mycomeditations.com/. Since it would seem that large numbers of people visit South America to attend Ayahuasaca retreats, one may assume it is legal there. And some religious exemptions exist for both Ayahuasaca and Peyote in the U.S., but even this may be a bit fuzzy as this certainly isn't widely advertised. One may also purchase legally, in all but a few U.S. states, Psilocybin spores; they become illegal once grown.

alpine_glass• 9 years ago

I've attended a couple ayahuasca ceremonies in the US. The first was very a peaceful affair. The second was not. There was yelling, screaming, the energy was all over the place. At moments, it felt very chaotic, like the top was going to blow off the whole thing. The facilitators (shamans) did an amazing job of holding things together, but that doesn't mean that I didn't experience some very intense waves of paranoia while all of this was going on. We were in a somewhat secluded place, but maybe not secluded enough to have made the screams inaudible to our closest neighbor. It was a rough evening for everyone.

anythingnonidin14• 9 years ago

It is our understanding that magic truffles are legal in the Netherlands, and in Jamaica magic mushrooms are either outright legal or the laws don’t seem to be enforced.

Magic truffles contain psilocybin, the same as magic mushrooms - they are the part that grows below ground.

https://tripsafe.org/shrooms/#12-psilocybin-is-legal-in-some...

The best seeming retreats are:

https://psychedelicsociety.org.uk/experience-weekends

and

https://www.mycomeditations.com/

sigotirandolas• 9 years ago

Not really, but there are a lot of “research chemicals” (= mostly unregulated drugs) that are serotonin receptor agonists like those. Some like 4-AcO-DMT and 1P-LSD seem to be almost identical to the classics.

avodonosov• 9 years ago

Heroin, BTW, helps from cough.

https://en.wikipedia.org/wiki/Heroin#History

From 1898 through to 1910, diamorphine was marketed under the trademark name Heroin as a non-addictive morphine substitute and cough suppressant.

snvzz• 9 years ago

heroin
non-addictive

I'm confused.

anythingnonidin14• 9 years ago

Somewhat interestingly/surprisingly, heroin is in the same ballpark of addictiveness as alcohol, as measured by the percent of people who use it 1+ times outside of a medical setting who end up becoming dependent.

Alcohol: 15-23%

Heroin: 23%

https://www.ncbi.nlm.nih.gov/pubmed/21145178

askvictor• 9 years ago

marketed as

Anti depressants are addictive in the classical sense. But the pharmaceutical companies don't call it 'withdrawl' but rather 'discontinuation syndrome' when you're coming off them. Looks like not much as changed in 100 odd years of pharmaceutical marketing.

gt_• 9 years ago

I still don't have the words to explain how, but I insist that psilocybin played a major role in the most successful period of my life. I am generally a highly skeptical person and remain a little frustrated that I can't articulate better such an impactful correlation.

anythingnonidin14• 9 years ago

Can you share any more details?

anythingnonidin14• 9 years ago

It is absolutely shocking to me that research into psychedelics isn't swamped with funding. I'd imagine that some wealthy people must find this stuff extremely intriguing - Yuri Milner is spending $100 million on space exploration, and a psilocybin phase 3 research trial needs ~$10 million and finds it really hard to raise money?

Psychedelics have extremely high therapeutic potential, and are also just interesting in a similar same way as space exploration is interesting.

diogenescynic• 9 years ago

It is absolutely shocking to me that research into psychedelics isn't swamped with funding.

I find it more shocking that we as a society put up with it. All the pharmaceutical companies would much rather find synthetic alternatives they can patent/control. Follow the money, as always, and it makes perfect sense.

anythingnonidin14• 9 years ago

I find it more shocking that we as a society put up with it.

Great point.

sannee• 9 years ago

I find it more shocking that we as a society put up with it. All the pharmaceutical companies would much rather find synthetic alternatives they can patent/control. Follow the money, as always, and it makes perfect sense.

Why are not pharmaceutical companies pushing synthetic psychedelics then? The whole {P,T}IHKAL is full of them, it surely isn't a large problem to cook up another variant to patent.

lighttower• 9 years ago

What makes this go into Nature rather than a regular medical journal?

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms [pdf]

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