1) BEST DRUG EPISODE: MAGIC MUSHROOMS
Hey - Wendy here!! We’re busily working away on our next season of Science Vs – which I’m really excited about, I’m excited to share it with you – it’s going to be in your ears pretty soon. And to get you pumped, we wanted to do something a little special. If you remember, a few months back, we did a big survey of you, our listeners. We asked you to pick your all-time favorite episodes of Science Vs.. 16 hundred people responded!! Thank you so much…. and so for the next few weeks we’re going to play those episodes- what we are calling the winners of the inaugural Science VS best episode competition. Yes, bring in the sound effects! Perfect - possibly too many sound effects?? We are kicking off this competition with the very contested: DRUG CATEGORY. So on Science Vs - we've done a lot of drugs… EPISODES about drugs… from CBD… to Magic Mushrooms…. to Adderall. It was a very tight race. And in fact Adderall and Magic Mushrooms were basically neck and neck. But today… we're gonna play Magic Mushrooms.
We made this episode in 2020, and since then, the mushies bandwagon has only gained speed... just this past year, more and more places have legalized access to this drug...
<<Oregon has become the first state to issue a license for a magic mushroom therapy treatment center.>>
<< Psychedelics will soon be used as medicine in Australia
<<In the city of Vancouver, buying magic mushrooms can be as easy as ordering your morning cup of coffee>>
So - should you get your next latte with a side of psilocybin? And what can these shrooms really do for things like depression or anxiety?
A quick warning before we get started, on the show we’ll be discussing depression, so plese take care while you’re listening. And if you’re feeling depressed or you just want to talk to someone, we'll put some numbers that you can call or text in the show notes. Also we'll give you a quick update on the people you hear from in this episode at the end. Alright, let's jump in…
Original Episode:
This is the show that pits facts against pharmaceutical fungi. On today’s show – magic mushrooms… for decades, we’ve kinda seen them as your hippie mum’s psychedelics - but now there's an underground movement… that's reckons they can use this drug to cure things like, depression and anxiety
J I am someone who has suffered from I would say severe anxiety attacks my entire life
We're going to call this guy Joseph. And he can remember having these anxiety attacks as far back as pre-school. And when he says severe… this is what he means.
J Stomach ache, Queasiness, dry heaving or vomiting. A lot of tears. A lot of crying… and just you know like the world is going to end
These anxiety attacks could sometimes go one for days at a time… He grew up learning to deal with them. Fell in love, got married, had two kids .... and then something happened that brought it all back. A couple years ago, he found out his wife was having an affair. She was in love with someone else.
J And that’s when it all hit me. I immediately spiraled into horrible anxiety, the worst of my life. Just the world had collapsed, everything I had spent my entire life working up to and two kids involved, just everything, it was all gone. I would look at my kids and start weeping.
Joseph went to psychiatrists, they put him on antidepressants. But the meds didn’t work. And he was just getting worse and worse -- nothing was helping. One day he sunk down on the couch - in total despair. When he looked up - something on the bookshelf caught his eye. It was “How To Change Your Mind” by Michael Pollan[1] … [2] it came out a few years ago, and helped popularize this idea of.. psychedelic therapy … that drugs like magic mushrooms[3], could cure things like anxiety. It felt like this might be the life raft that could get Joseph out of this
J I'm someone who's literally never up until this point had never taken or had any desire to take a psychedelic but at a certain point reading the book I knew without a doubt that this was going to be what I needed to do.
But, obviously he couldn’t just pop to CVS and grab some mushrooms off the shelf. The Feds still list it as a Schedule I drug[4] - right up there with heroin[5].
WZ what do you do next?
J I just started calling everyone I could think of. I opened up the contact list of my phone and was like will they know someone who knows someone? I'd call people I hadn't talken to in years, weeping.
Finally, Joseph reaches a guy who knows a guy. And this is how he meets someone we’ll Mr Shrooms - he's not a doctor, but he gives people magic mushrooms to help with stuff like their anxiety. So after a few weeks of therapy with his regular therapist -- where he talked about what he wanted to get out of this mushies session, Joseph bought a plane ticket and flew across the country …
J Yknow people were asking you don’t know this guy he could be giving you poison who knows and I was like eh if I die I die I had nothing to lose at this point.
On the big day, Joseph heads to Mr. Shrooms apartment… who had set up the guest bedroom, for this magic mushrooms session. He brings out some capsules with a brown powder in them. And some applesauce. Apparently it helps the magic mushrooms go down better.
J And I said alright so we just open one of these pills into apple sauce? And he was like oh no, we open 20 of them. So we literally sat there opening capsule by capsule and pouring the contents out into a jar of applesauce. And then I just mixed it together with a spoon and just dove right in!
Mr Shrooms has Joseph cover his eyes with a sleep mask, Joseph lays on the bed … lights go out. And some calming music comes on. And soon ... it hits him.
J Oh my god I’m seeing all this stuff this is crazy what is going on… I started seeing metallic particles in the air. like glitter like metallic confetti but very very slowly floating in the air
And Joseph starts talking outloud… Mr Shrooms starts writing down what he's saying… .
J Whoa now it’s everywhere it’s right in front of me but it’s a different plane, it’s getting closer whoa now everything counter clockwise and I’m in the middle of it. it feels like a giant cut out three dimensional not cardboard of an eagle. A bald eagle. The top part of it has the presence of an eagle’s head and the rest of the body this feathery thing there's this line. I don’t want to compare it to ants...
And through all of this, he started thinking about childhood memories - and going through what had gone wrong with his wife …
J It was just me having a conversation with myself and I was crying I mean in such copious amounts and in such an uncontrollable way… and I felt like my eyes were being pushed inside my head and were on fire and so much mucus was coming out it was like just this major yknow shedding of everything at that point. It hit me, there was a moment where I realized that I was done … After the whole experience I knew that the anxiety was gone.
Gone!! It’s been about 2 years since Joseph had that session. And while he's still going to a therapist -- he says he hasn’t had severe anxiety attacks since, no dry heaving… or uncontrollable crying.
J I feel like I am cured. I feel like I am happier than I ever was before
Can this be for real?? How on earth could one trip cure someone's lifelong anxiety and severe depression? And if it really works - should we all spend the 2020s tripping balls?
Today, magic mushrooms ditch their tie dye and get a lab coat.
Because when it comes to magic mushrooms… there’s a lot of
J omg look at i’m seeing all this stuff what is going on
But then… there’s science.
AHHHHH
Science Vs Magic Mushrooms is coming up right after the break.
PREROLL
Welcome back. So there's an underground and illegal movement -- where people are getting dosed up with magic mushrooms -- and saying they're having these amazing, life altering experiences. And all this didn't come out of nowhere.[6] Shrooms have been around for a long time - Aztec shamans were using them thousands[7] of years ago. And scientists back in the 60s and 70s… were experimenting with psychedelics too.[8][9][10][11] Seeing if they would help people with stuff like anxiety and depression[12]. And they were having some luck[13][14][15][16].. but then came the war on drugs.[17]... and this kind of research became virtually impossible in the US.[18][19] Drugs like magic mushrooms were now considered dangerous.[20] Which is the message we got for decades.
AD That drugs are bad and you shouldn't do them and people who do drugs are bad, and you shouldn't hang out with those people.
This is Dr. Alan Davis[21] -- and for years… he was kind of afraid of magic mushrooms.
AD You know I just remember thinking that psychedelics made people go crazy
All this changed after Alan became a clinical psychologist. He helps people with stuff like depression … or tries to. He told us that a bunch of the treatments we have for depression - don’t work for a lot of people[22] – which was really frustrating for him. But then in 2013 he went to a conference... where someone talked about the potential of using the chemical in magic mushrooms that makes people trip – it's called psilocybin. And they said it was really helping some people with depression.[23] And Alan… was so inspired by what he heard that he decided to switch gears and study this full time. And back this – just a few years ago – was very very fringe.[24][25]
AD Yeah, it was a big moment, I had no idea how or if or when it was going to happen, but that's when I set it for a goal for myself, that I wanted to find a way to make this path work for me – it was a big leap of a faith!
And Alan did make it work. Just this year he published a landmark study into depression[26].
WZ The depression trial that you did recently can you tell me like – a typical patient in that trial, what are they like?
AD So the typical types of folks they had been living with depression for a very very long time for decades, some of them two three decades. And had tried a lot of different things. So a lot of them had been through several trials of antidepressants. They had had several different types of psychiatrists or psychotherapists, and they never – for most them they never found a solution.
He set up a clinical trial with 24 people – to give them psilocybin. And before getting the pills – the patients do a bunch of therapy and talk a bit about their intentions. What they want to get out of their trip.
AD And then we administer the psilocybin in a little bit of a ceremonial fashion.
WZ It’s like a really Mari Kondo moment that you’re having
AD Yeah it is a bit like that, it's thinking about what's going to spark joy in their day and trying to help them you know connect with that.
And then it's go time. From here things are actually quite similar to what Joseph did. The patient lies down on a couch [27]… eyes covered[28]… music on…
WZ I'm imagining some Britney and Usher in there... is that the right?
AD Haha there are times where I wish there was some Britney and Usher, I don't think that… there aren't any currently on the playlist… No, a lot of it is orchestral and symphonic music coming from the classical era
And just like with Joseph -- the patients end up taking a massive dose of this stuff. The so-called heroic dose. No applesauce… but the equivalent of around 5 grams of dried magic mushrooms.[29][30]
AD Yes, these are very powerful so I think compared to what people would get in a recreational environment these are probably two to three times higher[31]
WZ Oh wow
Alan says they use these massive doses - because small studies[32][33] have suggested that this might give them the best shot of this treatment working.[34][35][36] And Alan says that when people down this much psilocybin they respond in all kinds of ways.
AD Yknow some people will have very visual, visceral experiences, where they’re completely immersed in a whole different world and landscape. And some people will have not any visual experience, it will all be emotional or it will be physical – We have some people who describe that they spent the entire day kind of feeling like the insides of their body were being re-organised and ground away.
There’s several experiences that I’ve had with folks where they’ll kind of peek outside of the eye shades and look at you and they’ll ask things like yknow, ‘What are you doing?’ haha or ‘What's going on with you?’ Like this is weird. And you know, we just … I just say, you're right this is kind of weird!
Basically, Alan’s team is just there watching to make sure everything goes OK.
WZ Right, so you're not talking to them about their depression in that moment
AD Exactly, and the therapy part of things will happen later.
As Alan worked with more and more patients, he started to realize… that this really might be working.… and he kind of couldn't believe it . He remembers going home one night and...
AD I just started to cry and I think that the tears came because I realized that what was happening was so much more profound than the study, yknow the study is an important piece of this puzzle, but the change that people were having in their lives, the experience of some of them having it been decades before they last felt joy or connection or love in their life. That this wasn't um at that point any longer just an experiment, it wasn’t any longer just this project, it was… it was changing people's lives.
He ran the numbers a month later... and yeah, in these 24 people, it looked pretty great. Not everyone in the trial had a huge transformation – but almost three quarters of the people felt a lot better, and more than half, so 13 people, said that their depression had gone[37]! And remember a lot of these people had tried other – traditional stuff – sometimes for DECADES and nothing else had worked.
AD So even if, even if our effect size was cut in half, we're still two times larger than the next best treatment.
WZ Oh wow.
AD However It’s not a magic bullet[38] there are people who did not improve, or who only improved for a little while and then their depression came back, but our data is suggesting that it's an incredibly powerful treatment.
Other small trials using psilocybin on depression are finding similar results.[39] Like one study that looked at depression in around 50 cancer patients, showed that 65% of them reported no depression around 6 months after the trial ended.[40]
So what could be happening here? Like why is this helping? Well, Alan said that sometimes the wild stuff that happens to people during these trips – actually ends up helping them once they’re out in the world.[41][42][43][44][45] Like one patient in his study – they'd been struggling with suicidal thoughts for years, and had extreme anxiety – particularly about going to work. Deep into the trip – this patient said they transformed into a powerful, mythical creature.
AD They became a dragon. They described flying to their job – very much a source of anxiety for them and fear – and as this dragon, they showed up and immediately started eating all of the people at work, and lighting everything on fire, and destroying everything. And so, flash forward a little bit to after the session day, yknow they’re kind of back at work, they’re starting to engage in their life again… And what was fascinating was they came in and said yknow I went to work the other day and I had zero anxiety,’ and we asked, ‘Well how is this possible? What was work like?’ They said, ‘I went to work, and it occured to me... how can I be afraid or anxious of people that you can eat?’ WZ Haha
But for some people -- what happened in their trip didn't seem at all connected to the problem they were trying to solve. Some people in these studies just have awful, scary experiences… and yet, here's what's weird – sometimes, it still helps them.[46][47][48] One researcher told us about a cancer patient who said they felt like they were in a trash can being kicked over and over again – but afterwards? They still ended up feeling better.[49]
So what on earth is going on here? What is this drug doing inside your mind??
Your brain on drugs. Coming up, just after the break.
BREAK
Welcome back. While magic mushrooms aren't some cure all … it definitely seems the science is on to something here. And the early research we have – is showing some exciting results for some people. Now we want to know – what are these drugs doing inside your brain? So meet Dr. Katrin Preller.[50]
KP Halllooooo
She’s a neuropsychologist from Zurich University in Switzerland. And basically Katrin gets people to take psilocybin and then pops them in an MRI to see what is going on in their brain.
WZ Have you ever been a subject in one of these studies?
KP Uh I have been participating in pilot studies, yes
WZ Was it fun though?
KP Um…. well, hmm I would call it it's certainly interesting yes! umm I think that's the same
WZ haha...
And one of the interesting things that she's found in her studies… helps us explain why being on mushrooms makes you see all of these weird things. Ok so, normally, when you're not high, you see things – like an apple or your friend – because your brain is organising all this information that it's gathering from around you.[51][52]
KP We receive input from our eyes, from our ears, from our skin… but also your emotions
So, Katrin's like, say you look up and see your friend across the park. You’re seeing her because your brain took in all this information, the visual information about her face and her hat – maybe you heard her say something and the brain was like – oh yeah! that's totally Lydia.[53]
KP Usually we don't necessarily question, or actually really notice it…
But sometimes your brain messes up… you wave, you go closer, and realise woopah! That's not Lydia at all. Your brain got some information but interpreted it wrong. So under normal, everyday… circumstances, this kind of thing can happen .. but then when you throw shrooms into the mix – this interpreting pretty much goes haywire.
KP So maybe all of a sudden, y’know, the people are upside down or they have green faces because the way the different parts of the picture are put together is just very different
Your brain isn't just mixing Lydia up for some rando – lots of stuff is getting jumbled in there.[54] Your shroomy brain is now organising information in a totally new way – in fact research has found that the part of the brain responsible for directing traffic kind of relaxes[55]...and that means it becomes a bit of a free for all in there. Parts of the brain that normally don't talk to each other much suddenly start connecting and chatting[56]....and all this higgledy piggledy brain activity can do stuff – like muddle up our emotions with our senses…[57][58]
KP They are highly connected with each other. So if you're feeling sad it can happen that this translates to yknow you see the whole world going dark for example, so that's why the way we perceive the world is very different because the information is just brought together differently.
But none of this explains why tripping might help some people with depression. So what's up with that? Katrin told us about one idea here. It showed up in a small study that she did that came out five years ago.[59] For this, she gave people a placebo or psilocybin, popped them in an MRI ...
WZ Sounds like a recipe for a very bad trip?
KP Most people feel really comfortable in there, so sometimes when yknow the scan is over and we ask them to get out again - they’re like ‘Oh no! I’d really like to stay a little bit longer. It's just so cosy in here!’
While they're cosying up in there... the real experiment begins. Katrin shows.. them pictures – that are designed to get an emotional reaction.
KP let's say a shark, a spider or a gun, they can also be just people who look really sad
And she found that something curious was happening in a particular area of the brain. The amygdala. This part of the brain is linked to fear and sadness. Normally, when you show people pictures of stuff like spiders or guns, their amygdala lights up.[60][61] But when they were on psilocybin - that reaction?
KP it’s just not there anymore, so the amygdala is not as reactive anymore.
It's not clear why some people still have bad, scary trips… but at least in the lab, Katrin is seeing these chilled-out amygdalas[62] … and another paper found the same thing.[63] And she told us that all of this might be a clue why shrooms could help some people with depression.[64] And here's why. Having a hyperactive amygdala is linked to depression …. so maybe psilocybin is sort of calming this area of the brain down a little.[65] So far so good…
But recently… something threw a bit of a wrench into this idea. So, some people in these clinical trials seem to feel better long after they take psilocybin.[66] But just this year, a study came out showing that these changes to the amygdala they don’t last long… they were gone after a month[67].... Which suggests that something else might be going on here, too..
AG Yeah and I think that’s really where the exciting part of this work lies. Yknow you're still seeing changes in the way that the brain works
This is Al Garcia-Romeu,[68] a psychologist at Johns Hopkins University… and he told us that another idea that's brewing about why psychedelics like psilocybin might help people for so long… is because, perhaps, the drug is rewiring people’s brains. And here's the idea…. , if you have depression, maybe your brain is stuck in this unhealthy pattern … then shrooms roll into town … and it just shifts stuff around.
AG Kind of like a snow globe you know you shake the snow globe and you get all this kind of movement and then eventually it settles back down into maybe a new pattern
Studies in rodents have found that mushies might create that new pattern by literally encouraging brain cells to grow. Scientists have seen this in the lab.[69][70][71]
WZ Oh so you get a cell in petri dish and basically bathe it in magic mushrooms and you can see the cells growing?
AG Yes, Basically the cells in the brain you can think of as having roots and branches like a tree and when those neurons are exposed to these psychedelic drugs they can then start to grow new roots and new branches [72]
WZ ooo
AG and what that means is that they form connections and talk to each other in different ways
And scientists also saw this in live mice – when they injected them with a tonne of psychedelics – they grew more cells in a part of their brain.[73] None of this has been shown in humans yet, though.[74] And so the truth is – for now, science doesn't really understand how these drugs are helping some people. It could be getting new brain cells, it could be because their amygdalas are changing - or perhaps it's the things you work through while you're becoming a dragon. And then, there’s another idea we haven't talked about yet: placebo. If some people who took these drugs really believed they're going to work – that can play a role here.[75]… For now… it's a little more magic mushrooms than… science mushrooms. And the best we can say is taking all these shrooms… kinda shakes up your brain – giving it a chance to reset.
So while this is all potentially exciting[76]… shaking up your brain?? Is that safe? Like what if you can't put humpty together again???
WZ You’re giving patients such large doses, at the beginning, aybeyour first patient – were you sort of nervous?
AG Oh no not at all. Actually they're some of the safest drugs that we know of[77]
WZ Really?
AG Yeah. Absolutely. You can eat an enormous dose and it wouldn’t cause your body to shut down or have a fatal response.[78] You can’t say that about alcohol which you can buy on the corner, you certainly can’t say that about opioids which are prescribed quite regularly
A large global survey of drug users taken in 2019 -- found that 0.4%[79] of the people who took mushrooms ended up in the ER – alcohol, by the way, was up to 10 times worse[80].. Psilocybin can cause nausea though[81][82] – in one study, 15% of people puked[83] and it ramps up your heart rate.[84][85]...
But one reason that Al says this drug tends to be safe[86][87] – is because you can't really overdose on magic mushrooms[88]. With something like heroin – you can keep taking it… getting higher, and higher… and higher… until you overdose and die.[89][90] But with psilocybin. That doesn't happen. You can't keep getting high if you keep taking more and more heroic doses. And here's why.
When you take psilocybin – the drug binds to a specific protein in your brain… this is what gets you high. But once psilocybin uses up the proteins... it takes a while for new ones to pop back up – so you won’t be able to feel high again for a few days[91][92]
AG If you took psilocybin the same dose several days in a row you just don’t feel anything anymore. And so there’s nothing there to keep chasing you have to actually stop for a period of time before you use it again
Studies in animal models[93] have also found that shrooms[94][95] – aren't addictive. And you might have heard about people taking psychedelics and getting flashbacks well after the high has faded…
AG Yknow, seeing the walls breathing or the carpet moving...
The science-y term for this is Hallucinogen Persisting Perception Disorder[96]… some people report weird light effects or buzzing in their ears.[97] Scientists don’t really know what causes it… but the good news is that Al says it seems very rare. He’s never seen this in a clinical trial[98][99] And out in the real world, a survey of more than 1300 people who had a bad trip on shrooms … found that only 2 reported having weird visual or auditory hallucinations. That's 2 out of more than 1000 people,[100][101] so yeah, it’s rare.
But still, generally speaking Alan told us that these are powerful drugs – and if you're messing about with them – you do need to be careful.[102]
AD There are people out there who have very significant and serious psychological reactions from taking psychedelics in uncontrolled settings. So I don't want to overstate that because it's few people, however those concerns are real.
And [103]… for now, scientists are being really picky about who is going in their studies[104] -- like, Alan's not giving heroic doses of psilocybin to people with heart problems,[105] or with a history of schizophrenia or bipolar disorder[106] – so that means we don't know how well shrooms might work for those people – or if some folks should actually stay away from this drug.[107]
But still these drugs are getting some serious traction. The science is mushrooming… These days scientists are seeing if psilocybin can treat not just[108] depression and anxiety, but also addiction, OCD, anorexia and migraines.[109][110][111][112][113][114] Recently, the FDA gave two companies the green light to make psilocybin-based drugs for depression[115][116] And in Oregon they legalized psilocybin therapy[117]… And while this is no miracle cure – and it's not working for everyone – Alan says for so long the field of treating depression has been in a bit of a rut – but suddenly, things are looking up.
AD It's one of the things that makes me yknow so hopeful – so much of my clinical training took place in places where there wasn't that sense of hope. Yknow where the treatments were trying to help people in that way, but not inspiring that immense amount of change… and so to see that as a therapist was something that is... I'll be very grateful for for the rest of my life
That's Science Vs.
End of Original Episode
It’s been a few years since this episode first aired… and we have some updates! Both Katrin and Alan have launched a bunch of new clinical trials into magic mushrooms Alan says overall that “the field is rapidly advancing.” As for Joseph? Joseph says he’s been doing good, and that the session he did still impacts his life today.
Also, since our episode came out, we’ve learned that there are concerns around sexual misconduct in the underground and unregulated psychedelic therapy community. Alan says, if you’re thinking of trying this, please wait until there is legal access to this treatment following FDA approval.
This episode had 117 citations, to see them go to our show notes and follow the link to the transcript. You can see our credits there too!
Next week on the show … the winner of our best Wellness and Diet Episode !!
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I’m Wendy Zukerman, fact you next time.
[1] https://www.nytimes.com/2018/06/04/books/review/michael-pollan-how-to-change-your-mind.html
[2] https://www.nytimes.com/books/best-sellers/2018/06/03/combined-print-and-e-book-nonfiction/
[3] Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects.
[4] Psilocybin is a Schedule I substance under the Controlled Substances Act, meaning that it has a high
potential for abuse
[5] Schedule I are: heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), peyote, methaqualone, and 3,4-methylenedioxymethamphetamine ("Ecstasy").
[6] Psilocybin mushrooms were used by the Aztec shaman in healing and in a variety of religious and
divinatory rituals. These mushrooms were known as teonanacatl, meaning “god’s flesh”"; [Alternative translation: ‘god’s mushroom’
[7] The consumption of hallucinogenic mushrooms in ritual ceremonies was widespread among Mesoamerican cultures. Religious practices with sacred mushrooms extended from the Valley of Mexico to the rest of Central America, and they are thought to be at least 3500 years old.
[8] Timothy Leary’s 1965 Concord Prison Experiment, which reported a reduction of recidivism in prisoners who went through psilocybin therapy. This study has since been criticized for its comparison to base rates of recidivism. 1998 Follow up to Timothy Leary’s 1965 Concord Prison Experiment: The 2.3% reduction is not significant and is the same as a finding of no treatment effect.
[9] 1975 paper looks at chemical structures of hallucinogenic drugs: may be of practical relevance if and when hallucinogenic drugs are to be selected as tools to facilitate psychotherapy. These drugs in general and psilocybin in particular are meant to substitute for the charismatic psychotherapist. The drugs heighten considerably the meaning of the therapeutic session
[10] Timothy Leary’s study in 1963 included “graduate students, professional writers and artists, academic psychologists, musicianes, housewives and inmates of a correctional institution…The purpose of the present research was to investigate some of the ways in which consciousness may be altered.”
[11] We consider that the psychedelic experience is neither a replacement for nor an adjuvant to traditional modes of therapy, but rather it adds a new and perhaps neglected dimension to therapy.
[12] e.g. Case I: Marked Improvement. 45-yr.-old engineer with long history of depression… He is no longer depressed.
[13] See Tables 1-3 https://onlinelibrary.wiley.com/doi/full/10.1002/da.23065
[14] The overall results indicate that all treatment-specific effects on psychopathological functioning are in favor of psychedelic therapy - in hospitalized patients with anxiety and depression.
[15] the percentage of patients answering the questionnaire who claimed lasting benefits is high: 83%. ... A list of the most commonly reported benefits would include: increase in ability to love, 78%; to handle hostility, 69%; to communicate, 69%; and to understand self and others, 88%; improved relations, 72%; decreased anxiety, 66%; increased self-esteem, 71%; a new way of looking at the world, 83%
[16] 1959 study of LSD in alcoholics: The conclusion is reached that self-surrender and self-acceptance are more easily achieved in the LSD experience and the thesis is developed that from the psychological point of view the resolution of the problem of the alcoholic lies in this surrender.
[17] the societal backlash in the US and other countries in the 1960s led to a ban on marketing and possession of “hallucinogenic” drugs in the US in 1965
[18] After the passage of the Controlled Substances Act of 1970, LSD and other psychedelics known at the time were placed into the most restrictive category of drugs, Schedule 1. This classification made them virtually impossible to study clinically and effectively ended any significant research into the pharmacology and medical value of psychedelics for more than 3 decades
[19] Stanislav Grof, Realms of the Human Unconscious: Observations from LSD Research, p viii-ix—~1965: Psychedelics had become an issue of general interest. Black-market LSD seemed to be readily available in all parts of the country [US] and for all age groups...The legislative measures undertaken with the intention of suppressing dangerous self-experimentation proved rather ineffective in curbing nonmedical use of LSD but had adverse direct and indirect consequences for scientific research. Only a handful of projects survived under these complicated circumstances. As a result, LSD research was reduced to a minimum and, paradoxically, very little new scientific information was being generated at a time when it was most needed
[20] Psychotropic Substances Act of 1978 The Congress has long recognized the danger involved in the manufacture, distribution, and use of certain psychotropic substances for nonscientific and nonmedical purposes, and has provided strong and effective legislation to control illicit trafficking and to regulate legitimate uses of psychotropic substances in this country.
[22] Although many patients with depression showed reduced or remitted symptoms after treatment with existing pharmacotherapies, approximately 30% to 50% of patients did not respond fully and as many as 10% to 30% of patients were considered treatment-resistant, resulting in average effects that were only modestly larger than the effects of placebo.
[23] Grob et al 2011 As shown in Figure 3B, BDI scores dropped by almost 30% from the first session to 1 month after the second treatment session (t11 = −2.17, P = .05), a difference that was sustained and became significant at the 6-month follow-up point (t7 = 2.71, P = .03).
[24] "We found that all antidepressants included in the meta-analysis were more efficacious than placebo in adults with major depressive disorder and the summary effect sizes were mostly modest." See Figure 3A
[25] In this randomized clinical trial of 24 participants with major depressive disorder, participants who received immediate psilocybin-assisted therapy compared with delayed treatment showed improvement in blinded clinician rater–assessed depression severity and in self-reported secondary outcomes through the 1-month follow-up.
[26] Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen.
[27] The physical environment during hallucinogen sessions is extremely important for ensuring safety for volunteers in two respects. First, an aesthetically pleasing environment may decrease the probability of acute psychological distress. The Johns Hopkins hallucinogen research projects use a living room-like setting (see Figure 1). The furniture is comfortable and is atypical for a research laboratory or medical office setting. An overly “clinical” environment with an “antiseptic” look (e.g., white walls, extraneous medical equipment, personnel in white lab coats) may increase anxious reactions.
[28] For studies that investigate potential therapeutic effects or the phenomenology of introspective hallucinogen experiences, the use of eyeshades and headphones (through which supportive music is played) may contribute to safety by reducing the distractions of environmental stimuli and social pressures to verbally interact with research personnel. (Photo here _
[29] From Forensic Science International: "The psilocin/psilocybin contents in Psilocybe cubensis were in the range of 0.14–0.42%/0.37–1.30% in the whole mushroom
(0.37-1.30% of 1g dried mushroom) = (3.7mg-13mg) per 1 g dried mushroom. For a 70kg/154lb person they would get a dose of 30mg/70kg of psilocybin in clinical trial, so roughly equivalent to (2-8g dried mushrooms[median 5g]) more or less depending on weight of the person.
[30] From a review paper on psilocybin mushrooms: “"The content of psilocybin and psilocin in hallucinogenic mushrooms varies in the range of 0.2 to 1% of dry weight (Table 2.)."
[31] A typical trip on a moderate dose of psilocybin mushrooms (1-2.5g) includes an increased intensity of emotional experiences, increased introspection, and altered psychological functioning in the form of “hypnagogic experiences,” which is the transitory state between wakefulness and sleep.
[32] Dosing for the study is based on studies like this one from 2003, which systematically examined the effects produced by different dosages. Most relevant bit of discussion here: "Analysis of the 5D-ASC scores revealed that only MD and HD PY led to a relevant loosening of ego-boundaries (OB/AED) and to pronounced changes of perception (VR). The loosening of the demarcation between self and environment was generally accompanied by insight and experienced as “touching” or “unifying with a higher reality” (OB).
[33] Dosage was correlated very highly (r = .71) with reported duration of major effects; this correlation may be artificially high due to the fact that some of the very high dosages were taken with long periods interspaced…..Dosage was also correlated with the amount of learning (r = .30); higher dosages were more apt to produce perceptual as opposed to abstract experiences (r = .21).
[34] Madsen 2019 Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores; study was small (8 participants)
[35] Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects.
[36] The proportion of volunteers who met a priori criteria for having had a “complete” mystical-type experience on the States of Consciousness Questionnaire was also an increasing function of dose: 0, 5.6, 11.1, 44.4, and 55.6% at 0, 5, 10, 20, and 30 mg/70kg, respectively Overall, 72.2% of volunteers had “complete” mystical experiences at either or both the 20 and 30 mg/70 kg session.….In addition to not affecting rate of mystical experience, inspection of the data indicated no consistent relationship between psychological struggle and subsequent ratings of the session as having personal meaning and spiritual significance. No volunteer rated the overall experience as having decreased her or his sense of well-being or life satisfaction.
[37] After the psilocybin session, 16 participants (67%) at week 1 and 17 participants (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 met the criteria for remission of depression (≤7 GRID-HAMD score).
[38] 27 participants. 24 completed: 13 got immediate and 11 got delayed (8weeks); First session was 20mg/70kg and Second session was 30mg/70kg; Week 4 [pst - 71% clinically significant response. 54% in remission (13 ppl)
[39] Present study followed-up with 16 patients at 3.2 and 15 patients at 4.5 years. At 4.5 yr follow-up 60-80% of participants met criteria for antidepressant OR anxiolytic responses. 71-100% attributed it to psilocybin therapy
[40] 51 patients comparing high dose psilocybin (22 or 30mg/70kg) to low dose (1 or 3mng/70kg); ‘Rates of clinically significant response and symptom remission for the two primary outcome measures of clinician-rated symptoms of depression (GRID-HAMD-17) and anxiety (HAMA) showed large effects of psilocybin that were sustained at 6 months... Collapsing across the two dose sequence groups, the overall rate of clinical response at 6 months was 78% and 83% for depression and anxiety, respectively, and the overall rate of symptom remission at 6 months for all participants was 65% and 57%, respectively.
[41] Recent work has sought to develop and validate a measure that is sensitive to difficult or challenging psychedelic experiences (Barrett et al., 2016; Carbonaro et al., 2016) and there is some evidence that the intensity of such experiences is predictive of positive long-term outcomes, whereas the duration of struggle is predictive of negative outcomes (Carbonaro et al., 2016). This is presumably because the successful resolution of conflict brings with it, insight and relief, whereas the failure to breakthrough perpetuates suffering.
[42] n=985 Survey. A regression analysis showed that acute effects (i.e., mystical and insightful effects) were significantly associated with decreases in depression/anxiety following a psychedelic experience.
[43] n = 343 Survey. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with a greater reduction in alcohol consumption, controlling for prior alcohol consumption and related distress.
[44] n=444 Survey. Found that: Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with greater reduction in drug consumption.
[45] Given the reliability of these therapeutic effects in recent studies, researchers have begun to elucidate predictors and mechanisms of long-term changes. The degree to which one has a “mystical” experience has emerged as one factor related to a variety of affective changes. … Ross et al. (2016) and Griffiths et al. (2016) concurrently found that the more mystical one’s psilocybin session was rated, the greater the reductions in depression at the 6-month followup. , Carhart-Harris et al. (2016a) noted
that the degree to which one experienced a unitive, spiritual, and blissful (USB) state during the psychedelic session predicted improvements in depression.
[46] In a study on the immediate and persisting effects of psilocybin, (n=18) 39% reported that they had an extreme experience of fear, fear of insanity, or feeling trapped during the session, usually during the highest dosage. There was a positive correlation between dosage and ratings of fear or anxiety, but there was varying onset and duration for each subject. Forty-four percent had delusions or paranoia, again most subjects experiencing this after the highest dose…. In fact, 61% rated the two highest doses to be the single most spiritually significant experiences of their lives, 83% rating it in their top five. Eighty-nine percent indicated those sessions increased well-being or life satisfaction and positively changed their behavior at least moderately
[47] Even in tightly controlled research settings with robust therapeutic support, some experiments have noted up to almost a third of participants reporting acute anxiety or fear at some point during high dose sessions (Griffiths et al., 2006)....Despite these psychological struggles, most of these participants rated the overall experience as having personal meaning and spiritual significance and no volunteer rated the experience as having decreased their sense of well being or life satisfaction.
[48] Garcia-Romeu 2015 - During the study there were a total of 42 psilocybin sessions across the 15 participants [22]. As previously reported, six participants (40%) reported at least one challenging psilocybin experience characterized by feelings of fear, fear of insanity, or feeling trapped. However these acute effects were readily managed by study staff, and had resolved by the end of the sessions.; mean ratings of personal meaning, spiritual significance and mystical experience predicted positive changes in cravings, self-reported abstinence and smoking bio-markers
[49] MH interview w/Mary Cosimano - she also talks about it in this lecture 50:34 “for myself for most of his session Fred and I really didn't know what he was experiencing and in the case of the second part he was going through hell we had no idea it wasn't until the end of the day he said he felt like he was in a trash can and being beaten and battered for hours and he couldn't get out he said he realized it was his cancer he was battling and when he let go of fighting it the beating stopped and the peace came”
[50] https://twitter.com/katrinpreller?lang=en
[51] The 5-HT2AR is one of at least 14 different 5-HT receptor subtypes expressed in the mammalian brain (Glennon, 2000). In the context of neurotransmission, the principal effect of 5-HT binding to the 5-HT2AR is to increase the excitability of the host neuron, and the 5-HT2AR is the main excitatory GPCR of the
serotonin receptor family (Andrade, 2011); The 5-HT2AR is predominantly a cortical receptor; indeed, it is the most abundant 5-HT receptor in the cortex [psilocybin binds to the 5-HT2A receptor]
[52] the brain represents categories in a continuous semantic space that reflects category similarity. These results are consistent with the hypothesis that the brain efficiently represents the diversity of categories in a compact space, and they contradict the common hypothesis that each category is represented in a distinct brain area.
[53] Some fun reading on the science of facial recognition from Smithsonian Magazine: “It turned out that each neuron in the face patches responded in certain proportions to only one feature or "dimension" of what makes faces different. This means that, as far as your neurons are concerned, a face is a sum of separate parts, as opposed to a single structure.” (i.e. your brain is putting together bits and pieces of sensory info!)
[54] Classical psychedelics also induce pervasive changes in network-dynamics that can generally be described as a transition from regularity to increased instability. The coherence of classical resting-state networks was found diminished (disintegrated), while FC of the primary visual cortex expanded—desegregated. In complement to its reduced activity-level, the DMN [default-mode resting -state network] was found to potentially co-activate with the CEN [Central-executive network], a phenomenon which may underlie the reported confusion between internally and externally generated mental contents.
[55] The group level results (Fig. 2) revealed significant CBF decreases in subcortical (bilateral thalamus, putamen, and hypothalamus) and cortical regions [the posterior cingulate cortex (PCC), retrosplenial cortex, precuneus, bilateral angular gyrus, supramarginal gyrus, rostral and dorsal anterior cingulate cortex (ACC), paracingulate gyrus, medial prefrontal cortex (mPFC), frontoinsular cortex, lateral orbitofrontal cortex, frontal operculum, precentral gyrus, and superior, middle and inferior frontal gyrus] (Fig. S1). The decreases were localized to high-level association regions (e.g., the PCC and mPFC) and important connector hubs, such as the thalamus, PCC and ACC/mPFC....results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.
[56] KP Study Psilocybin: Across time, Psi-induced hypo-connectivity was observed across subcortical areas as well as cortical associative networks. Furthermore, hyper-connectivity was induced in sensory areas. Virtually identical to LSD …. These results are consistent with the hypothesis that this pattern of hyperconnectivity in sensory and hypo-connectivity in associative regions is induced by different serotonergic hallucinogens and may therefore underlies the psychedelic state
[57] In summary (see table 2), hallucinations relate more to associative network overactivations in SCZs, while they are linked with primary cortex overactivations under psychedelics. Second, in both cases, the experience is associated with reduced internal integration of functional networks, an enhanced correlation between internally and externally oriented networks as well as an impaired thalamocortical connectivity. This phenomenon may notably blur the differentiation between self-generated and perceived mental contents.
[58] The present study sheds new light on the relationship between changes in spontaneous brain activity and psychedelic-induced visual hallucinations. Strong relationships were observed between increased V1 RSFC and decreased alpha power, as well as ratings of both simple and complex visual hallucinations. The latter result is consistent with previous findings with psilocybin. Importantly, a very strong relationship was also observed between increased V1 RSFC and decreased alpha power in occipital sensors, suggesting that as well as being commonly related to visual hallucinations, these physiological effects are closely interrelated. The increase in V1 RSFC under LSD is a particularly novel and striking finding and suggests that a far greater proportion of the brain contributes to visual processing in the LSD state than under normal conditions. This expansion of V1 RSFC may explain how normally discreet psychological functions (e.g., emotion, cognition, and indeed the other primary senses) can more readily “color”
visual experience in the psychedelic state.
[59] 2015: Twenty-five healthy, right-handed subjects...Using a randomized, double-blind, placebo-controlled, cross-over design, subjects received either placebo or 0.16 mg/kg oral psilocybin in two separate imaging sessions at least 14 days apart.
[60] Correspondence between increased intensity of predominantly left sided amygdala activation and self-rating of sadness was found in 78% of 120 sad trials, in contrast to only 14% of neutral trials. Amygdala activation was reproducible during repeated scanning sessions and displayed the strongest correlation with self-rating among all regions.
[61] All emotional stimuli were associated with higher probability of amygdala activity than neutral stimuli. Comparable effects were observed for most negative and positive emotions, however there was a higher probability of activation for fear and disgust relative to happiness.
[62] Paired t-tests for planned comparisons showed that psilocybin significantly attenuated right
amygdala activation to both negative (24, -4, -22; Z = 4.38; FWE-corrected p = 0.001) and neutral (27,
-7, -19; Z = 4.60; FWE-corrected p < 0.001) pictures (Table S2 and Figure 3). Consistent with these
results, the ROI-based analysis revealed a significant main effect of drug (F1,24 = 19.45; p < 0.001), but
no drug x emotion interaction (F1,24 = 0.29; p = 0.59; Table S3).
[63] 2017: Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms.
[64] KP Nature Review: A negative cognitive and emotional bias is a core symptom of major depression disorder. Hence, the findings above make it conceivable that classic psychedelics enhance positive mood in individuals with major depression disorder by acting as a modulator of the major connectivity hubs of the amygdala, therefore acutely reducing the processing of negative emotions … An important, yet scarcely addressed, question is whether psychedelics produce a sustained beneficial effect on emotional processing. In healthy participants, reduced amygdala reactivity in response to emotional stimuli has been reported 1 week after psilocybin administration, but returned to baseline 1 month after administration (note: talking about cite 66 here)
[65] At a neural level, depression is associated with an increased response in limbic areas of the brain (such as the amygdala, insula, and anterior cingulate) to negative versus positive stimuli, important for the detection and response to emotionally salient stimuli. This limbic overactivity has been coupled with decreased engagement of areas important for regulation and inhibition of such responses, including the dorsolateral and medial prefrontal cortex.Antidepressant treatment reverses this pattern of neural response to affective information in patients with depression, and introduces a similar direction of change in healthy people
[66] Review: an open-label trial of 20 TRD participants reported large group reductions (Cohen’s d=1.4) in Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) scores six months after two psilocybin sessions (Carhart-Harris et al., 2018); In another such study, sustained reductions in HADS and BDI scores 6.5 months after treatment were again mediated by MEQ30 scores (n=29) (Ross et al., 2016)
[67]Feb 2020: One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced.
(However, noting at 1 month, there were other positive increases that sustained) “The observed increase in functional connectivity strength indiscriminately across networks may reflect a domain-general cortical plasticity process supporting the observed changes in affective processing, consistent with preclinical evidence for psychoplastogenic properties of psychedelic drugs”
[68] https://www.hopkinsmedicine.org/profiles/results/directory/profile/10001277/albert-garciaromeu
[69] Ly 2018 serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo … increased synapse number and function, as measured by fluorescence microscopy and electrophysiology. (Study tested, among other compounds, psilocin - the active metabolite of psilocybin..
[70] The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.
[71] [PREPRINT] One day post psilocybin injection, we observed 4.4% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in hippocampus (+9.24%) and PFC (+6.1%) whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin’s antidepressive actions are linked to increased persistent synaptogenesis and possibly also to an acute decrease in 5-HT2AR density.
[72] Depression, post-traumatic stress disorder (PTSD), and addiction share common neural circuitry…and have high comorbidity …. A preponderance of evidence from a combination of human imaging, postmortem studies, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders and is precipitated and/or exacerbated by stress …These structural changes, such as the retraction of neurites, loss of dendritic spines, and elimination of synapses, can potentially be counteracted by compounds capable of promoting structural and functional neural plasticity in the PFC …, providing a general solution to treating all of these related diseases.
[73] (Behavioral neurogenesis) Psychedelics were able to help mice get over “fear conditioning”; researchers observed dose-dependent effects of pilocybin on neurogenesis -- low doses tended to increase formation of new neurons, large doses _decreased_ neurogenesis.
[74] Evidence from animal models of depression and increasing, but indirect evidence from human studies suggest that neuroplasticity is impaired in MDD. Both in humans and in animal models, treatment with brain stimulation (ketamine, DBS, or other methods) induces regional increases in grey matter volume that are associated with antidepressant response. These brain volume changes involve structural neuroplasticity mechanisms, such as dendritic spinogenesis, synaptic reorganization, or axonal sprouting or regrowth.
[75] Placebo arms of these trials were often surprisingly effective too. "The first of these questions has to do with the expectancy effects associated with the extensive psychotherapeutic support and education provided to participants before, during, and after their exposure to psilocybin" this editorial points out that it's a LOT of facetime with a therapist which probably explains part of why it helps: https://sci-hub.se/10.1001/jamapsychiatry.2020.2901
[76] Given both psilocybin and placebo groups received equivalent behavioral interventions, the additive ben- efit of psilocybin may be substantial. However, this effect was not robust to publication bias, highlighting the need for further placebo controlled studies. As supportive behavioral interventions were included in all studies, results cannot be interpreted to indicate general benefits associated with the use of psilocybin in the absence of support.
[77] Although there is a general public perception that psychedelic drugs are dangerous, from a physiologic standpoint they are in fact one of the safest known classes of CNS drugs. They do not cause addiction, and no overdose deaths have occurred after ingestion of typical doses of LSD, psilocybin, or mescaline.
[78] Its [psilocybin] lethal dose in humans has been theoretically estimated at approximately 1000 times an effective dose (Gable, 2004), which is an amount that is likely not possible for an individual to consume when in the form of psilocybin-containing mushrooms
[79] The 2019 iteration of the largest study of recreational drug use shows ( pg 94 here) since GDS 2017 magic mushrooms have been the drug least likely to result in people seeking emergency medical treatment.
[80] Incidence varies by country but as many as 4.1% of alcohol users require medical treatment Page 28 https://issuu.com/globaldrugsurvey/docs/gds2019_key_findings_report_may_16_
[81] In this study on dosage: Systolic blood pressure, Diastolic blood pressure, Heart Rate, anxiety/fearfulness, unresponsiveness to questions all increase as dosage increases (0, 5, 10, 20, 30mg/70g). Nausea does not increase with progression of dose, but is present compared to 0mg (no dose).
[82] Its binding to and agonist effects at 5-HT2A serotonin receptors are associated with dilation of the pupils (mydriasis), reduced threshold for knee reflex, and commonly increased heart rate and blood pressure, and feelings of nausea (Isbell, 1959a; b).
[83] Nausea or vomiting occurred in 15% of participants in the high-dose session and none in the low-dose session. An episode of physical discomfort (any type) occurred in 21% of participants in the high-dose session and 8% in the low-dose session. https://journals.sagepub.com/doi/10.1177/0269881116675513
[84] In this study on dosage: Systolic blood pressure, Diastolic blood pressure, Heart Rate, anxiety/fearfulness, unresponsiveness to questions all increase as dosage increases (0, 5, 10, 20, 30mg/70g).
[85] See Table 1 Systolic blood pressure, Diastolic blood pressure, Heart Rate, anxiety/fearfulness, unresponsiveness to questions all increase as dosage increases (0, 5, 10, 20, 30mg/70g). Nausea does not increase with progression based on dose, but is present compared to 0mg (no dose).
[86] Carbonaro et al. (2016) reported on an online survey of psilocybin users about their single most psychologically difficult or challenging experience after consuming mushrooms. Eleven percent reported putting her/himself or others at risk of physical harm. Greater estimated dose, duration and difficulty of the experience, and lack of physical comfort and social support, were all related to increased risk. Approximately three percent reported behaving in a physically aggressive or violent manner, and the approximately three percent reported receiving medical help.
[87] Psychedelics are not regarded to elicit violence [14] and dangerous behavior leading to suicide or accidental death under the influence of psychedelics is regarded as extremely rare.
[88] Unlike prototypic opioids and sedatives of abuse, psilocybin carries a low risk of overdose toxicity by respiratory depression or cardiovascular events or other causes of death associated with substances of abuse. The LD50 of intravenous psilocybin has been determined to be above 250 mg/kg (with 200 mg/kg killing no animals, and 250 mg/kg killing a small portion of animals (Cerletti, 1958).
[89] Heroin has strong dose-dependent effects, but too much depresses heart rate and breathing.
https://www.drugabuse.gov/sites/default/files/heroinrrs_11_14.pdf
[90] https://www.cdc.gov/nchs/products/databriefs/db356.htm
[91] Further, while the 5-HT2A receptor is known to internalize rapidly with both agonism and antagonism, it is thought to be re-expressed roughly 24–48 hours after internalization (in the absence of chronic engagement)59, and thus any transient changes in receptor dynamics related to psilocybin administration would be resolved by the 1 week time point.
[92] Tolerance begins to develop after the administration of a single dose. The mechanism behind this rapid desensitization is the physiologic response to 5-HT2A receptor overstimulation by quickly downregulating receptor sites.In general, it is thought that these receptor sites return to fifty percent of their baseline within three to seven days of the initial dose and return to baseline within one to four weeks, depending on dose and duration of repeated use.
[93] There are no literature reports of successful attempts to train animals to self-administer classical hallucinogens, an animal model predictive of abuse liability, indicating that these substances do not possess the necessary pharmacology to either initiate or maintain dependence. (Section mostly on LSD, so assumptions are being made about the entire class of drugs)
[94] No apparent physiological dependence as evidenced by withdrawal symptoms has been documented in humans (clinical observations) or animals (laboratory studies), although tolerance has been observed (Abramson et al., 1960; Appel and Freedman, 1968; Isbell et al., 1961). For example, no withdrawal was reported following chronic psilocybin use in humans in ARC studies including a study by Isbell et al. (1961)
[95] Study of rhesus monkeys showed weak reinforcing results; some individuals had aversive effects.
[96] Review of Long-term Effects of Psychedelics. Case reports of HPPD resulting from recreational use have appeared in the literature (e.g., Hermle et al., 2012) but are rare. In our search, few subjects reported lasting negative side effects. Ross and colleagues (2016) commented that no long-term adverse effects had been reported across over 2000 participants that had been run through contemporary psychedelic trials as of 2016.
[97] There is considerable variability in symptoms experienced by those with HPPD, but the most common effects include afterimages of color, “floaters” in field of vision, difficulty concentrating, and tinnitus, persisting after using a psychoactive drug. Type I HPPD involves transient flashbacks, whereas Type II is more chronic and invasive. … Finally, Type II HPPD seems to be relatively rare, with an estimated 1/50,000 psychedelic users meeting criteria (Halpern et al., 2016).
[98] There were no serious AEs, either medical or psychiatric, in the trial that were attributed to psilocybin. 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)
[99] Study of Acute, subacute and long-term subjective effects of psilocybin in [N=110] healthy humans (2010): Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairment of functioning in any of our subjects.
[100] See: “Enduring negative psychological and emotional experiences”(n=1338) Inspection of data and review of open-ended comments documented three cases in which the challenging experience with psilocybin was reported to be associated with the onset of enduring and impairing psychotic symptoms.
The first individual described auditory hallucinations (hearing voices) and paranoia. The second described severe depersonalization, very disturbing visual hallucinations, and extreme confusion. This individual subsequently started taking unspecified antipsychotic drugs and later received a diagnosis of schizophrenia.
[101] Krebs and Johansen in 2013, based on data from the national survey on drug use and Health from 2001 to 2004, (n=21,967) which found no association between the use of psychedelics and any increased rate of mental illness (psychosis, schizophrenia, HPPD, etc.).
[102] Web-based questionnaire (of real-world recreational use): Out of 503 respondents who reported using psilocybins 3% (15 individuals) reported that psilocybin had had a negative (2.4%) or a very negative (0.2%) effect on their wellbeing. Fifty-nine subjects commented on the health risks of psilocybin use … Eight subjects reported increased anxiety, including panic attacks (four subjects); eight subjects reported persistent psychotic symptoms including paranoia (three subjects), confusion (two subjects), derealization (two subjects), disconnection from reality (one subject), and mania (one subject). Five subjects reported worsened depression, five subjects reported gastrointestinal problems associated with the ingestion of mushrooms, four subjects reported symptoms of HPPD, and five subjects reported having been generally negatively affected by a difficult drug experience.
[103] Furthermore, a Structured Clinical Interview for DSM-IV-TR (First et al., 2012) was performed at screening to exclude individuals with personal or family history of psychotic or bipolar disorders, and/ or drug dependence (including alcohol; excluding nicotine) within the past 5 years.
[104] Participants were excluded if screening showed them to have exclusionary medical or psychiatric conditions; family history of schizophrenia, bipolar disorder, or suicide; cocaine, psychostimulant, or opioid dependence; or history of using hallucinogens more than 10 times (or any use in the past 30 days
[105] Use of high doses of psychedelics can lead to vascular problems because the 5-HT2A receptor is associated with vascular smooth muscle contraction, platelet aggregation, thrombus formation, and coronary artery spasms
[106] Additional eligibility requirements included being medically stable with no uncontrolled cardiovascular conditions; having no personal or family history (first or second degree) of psychotic or bipolar disorders; and, for women, being nonpregnant, being non-nursing, and agreeing to use contraception.
[107] Screening procedures which commonly exclude those with cardiovascular conditions as well as those with personal or family histories of schizophrenia, Psychotic Disorder, or Bipolar Disorder also limit the generalizability of findings.
[108] https://www.clinicaltrials.gov/ct2/results?cond=&term=psilocybin&cntry=&state=&city=&dist=
[109] Alcoholism - proof of concept study (10 individuals, no control group): Psilocybin was administered in context of therapy. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5–8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5.
Prior literature on LSD/alcoholism: meta-analysis by Krebs and Johansen (2012) a single dose of LSD was associated with a decrease in alcohol misuse.
[110] Albert’s study: (N=15) In controlled studies, the most effective smoking cessation medications typically demonstrate less than 31% abstinence at 12 months post-treatment... whereas the present study found 60% abstinence more than a year after psilocybin administration.; Secondary publication: Nine of 15 participants (60%) met criteria for “complete” mystical experience. Smoking cessation outcomes were significantly correlated with measures of mystical experience
[111] OCD (Moreno et al, 2006) (n=9) double blind study - found associated with acute reductions in OCD symptoms
[112] The primary aim of this study is to assess the acceptability and efficacy of treating anorexia nervosa with psilocybin.
[113] This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin.
[115] October 2018 FDA granted “breakthrough therapy” status to COMPASS pathways for psilocybin therapy for treatment-resistant depression.
[116] November 2019 Usona Institute has received Breakthrough Therapy Designation from the US Food and Drug Administration (FDA) for psilocybin in the treatment of major depressive disorder (MDD)
[117] Nov 3, 2020: Oregon becomes the first state in the nation to allow the use of psilocybin, the psychoactive ingredient of hallucinogenic mushrooms, in therapy.