Psilocybin Synthesis in 4 Steps & How Magic Mushrooms Rewire Brain Networks (Psychedelic Science)

🍄 Psilocybin is emerging as a promising "therapeutic psychedelic" across various different conditions and diseases. What is the buzz about, and how does psilocybin work?
In this video, we dive into psilocybin's rich history, chemical structure and biochemical mechanism of action. This includes striking effects like dendritogenesis and synaptic rewiring in mice. We will review a large scale synthesis of psilocybin, delivering an impressive 1.2 kg of cGMP material for clinical supply - this works using quite standard chemical reactions that most of you will understand. We then turn to the clinical evidence - where it is strong and where less so - in particular, treatment-resistant depression. This data in published late 2022, has drawn a lot of public attention to psilocybin - but is just one of many interesting reports. Finally, we try to understand psilocybin's effect on brain network modularity/ connectivity which makes it different from traditional anti-depressants.

NOTE:
- This video does not lay out the practical synthesis of psychedelics or drugs
- This video does not suggest that psilocybin is a "wonder drug" for everyone - there are important safety precautions and supervision through qualified medical staff is key

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00:00 Psilocybin - a therapeutic psychedelic?
01:09 Disclaimer and Andrew Huberman psilocybin podcast
01:40 Psilocybin's history might date back 10'000 years
04:20 Albert Hofmann's investigations, including self-experiment
07:23 Hofmann's synthesis and "war on drugs"
08:19 Psilocybin becomes pislocin which can pass the blood-brain barrier
11:22 Psilocybin literally changes the brain of mice
12:36 Organic chemistry and 1.2 kg synthesis by the Usona Institute
16:16 What is the evidence? What is the entourage effect?
17:48 Psilocybin's efficacy in alcohol use disorder
18:28 Psilocybin efficacy in treatment-resistant depression
21:42 How brain networks are "changed and re-shuffled"
25:36 Why do different people experience trips differently?

Disclaimer - This channel does not provide medical advice!
No information on this channel is intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regimen, and never disregard professional medical advice or delay in seeking it because of information on Youtube.

Key references:
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression | NEJM 2022, 387, 1637
- Therapeutic use of psilocybin: Practical considerations for dosing and administration | Front. Psychiatry, 2022, 13, 1040217
- Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics | Front. Psychiatry, 2021, 12, 724606
- Increased global integration in the brain after psilocybin therapy for depression | Nature Medicine 2022, 28, 844
- Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder | JAMA Psychiatry 2022, 79, 953
- DARK Classics in Chemical Neuroscience: Psilocybin; ACS Chem. Neuroscience 2018, 9, 2438
- Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention | NeuroImage 2020, 218, 116980
- Die psychotropen Wirkstoffe der mexikanischen Zauberpilze (Albert Hofmann) | Verhandlungen der Naturforschenden Gesellschaft in Basel 1960, 71, 239
- Research on Acute Toxicity and the Behavioral Effects of Methanolic Extract from Psilocybin Mushrooms and Psilocin in Mice; Toxins 2015, 7, 1018

Some recommended books on organic synthesis:
- Clayden, Greeves, Warren; Organic Chemistry (basic organic chemistry knowledge)
- Wyatt, Warren; Organic Synthesis: The Disconnection Approach (excellent introduction to retrosynthesis)
- Kurti, Czako; Strategic Applications of Named Reactions in Organic Synthesis (extensive toolkit of functional group reactions and applications thereof with common conditions)
- Nicolaou; Classics in Total Synthesis 1-3 (the ultimate total synthesis trilogy)
- Nicolaou; Molecules That Changed the World (the world's most important molecules and their impact on everyday life)
- Carreira, Kvaerno; Classics in Stereoselective Synthesis (compilation of the groundbreaking methods of stereoselective synthesis and application to synthesis of stereochemically complex structures)

[totalsynthesis]

Thanks for watching!
Massive thank you to all channel supporters!
Note: I'm reviewing comments on this video to manage spam from shady IG drug dealers!

[sarlol]

It is anecdotal but, after 6 years of heavy drinking, it took exactly one trip to get completely sober. This was almost 2 years ago, psilocybin completely changed my life for the better.

[patriaciasmith]

Psilocybin saved my life. I was addicted to heroin for 15 years and after Psilocybin treatment I will be 3 years clean in September. I have zero cravings.
This is something that truly needs to be more broadly used in addiction treatment.

[goosecf]

IDK about all the specific details, but I've noticed that mushrooms seem to help a lot with my ADHD. I find it so much easier to just relax and enjoy things now, whereas previously I could barely do anything without getting distracted by some meaningless crap I'd end up wasting all my time on. As a whole I think I just appreciate life more now and it's lovely.

[donaldaustin]

Psilocybin containing mushrooms save my life. The drastically reduced my benzodiazepine withdrawal allowing me to quite illicit pill addiction after three years of heavy daily use before it would had became medically dangerous to quit

[jerryflecther]

Psychedelic is the answer to most severe anxiety and depression. The use of magic mushrooms completely helps one get over depression and makes you feel like yourself.

[Eraserhedd]

I’ve been on Prozac and Wellbutrin for decades. it kept my depression at bay, but I felt numb. I switched to shrooms twice a month and I no longer take those meds. And actually feel things again…being able to feel chills from amazing music even came back.

[Joe-bhpf]

I can honestly say psychedelics experience was probably one of the most profound and beautiful collection of moments I have ever had.

[emilianopereda]

What about a honorable mention to Maria Sabina? the Mexican healer that introduced psilocybin to Albert Hoffman? And Wesson. I mean she is in the pictures! Both with Wasson and Hoffman. As always native indigenous people get snubbed out of history when history is told.

Maria Sabina was the original
Curandera as she conducted “Veladas” a ritual in which the participant and their family took a heavy dose of psilocybin mushrooms while Maria sang and hummed native songs in her indigenous language. She was doing family therapy before it was a “thing” and helped thousands of people with the help of psylocibin and “folk” knowledge of nature.

Source: hallucinogenic fungi etnomicology studies by Italian author Giorgio Samorini.

[MrND]

Was on Sertraline, Fluoxetine, Amitriptyline around 3/4 years ago and I wanted to end my life. Constant chronic pain and depression until I tried DMT. Was the polar opposite of all them horrible meds those Dr’s “trialed” me on, so positive and gave me hope to get out of the mess I was in. I then did Paul Stamets stack on micro dosing and have done that twice this year. So grateful I opened my mind with psychedelics. Love from Liverpool UK

[chanelleblack]

Last year, I took shrooms thinking it was going to hit like an edible or something. Shit was scary at first but amazing once you start getting deeper into your thoughts

[mixskillter]

This is incredibly insightful, instead of repeating how good psilocybin is and it's basic concepts, you digged deep into complex mechanisms of its action, statistics and study based evidence. This is what people interested in psychedelic treatments should know, it brings and makes the knowledge easily accessible. Your research and work is really appreciated <3

[jaspernewcomb]

I was 14 the first time i took psychedelics. Up until that point i had smoked pot a few times with my older brother and his buddy. They'd ask, are you getting a buzz yet? I finally told them I didn't know what a buzz was do you hear it or what? They laughed at that, no you'll know when you get one. A couple weeks later they said give us two dollars and we can get you a hit of acid. Ok i didn't know what acid was but I was willing to find out. The next day they had it. Come on we have some too we can all take it together. It was 9:30 or 10pm when we took it and then they told me come on we're supposed to meet some girls uptown you can hang out with us till they come pick us up. They were supposed to be on their way but close to an hour had went by and they hadn't showed up. Then a cop drove by and they decided to head for the house because of curfew. So we took off running for home full blast and as we came up the back alley the acid kicked in and we all stopped and fell down laughing our ass off. That was just the beginning. Mom must have heard us and started yelling for us to come in. So they told me come on and try not to act like you're high. I hid behind the newspaper reading the comics while mom was watching my brother and his friend like a hawk asking what they were up too. Meanwhile I was cracking up over the cartoons and couldn't stop laughing which made my brother and his buddy start laughing. Then mom grabbed the paper and asked me what was so funny. I said the cartoons but my mom knew better she looked at me and said my God whats wrong with your eyes? That's when she noticed all three of us had dialated pupils so big our eyes looked black. She was pissed and ordered us to go to bed and told my brothers friend, GO HOME. I shot up the stairs to my bedroom and watched out the window as Tommy ran for home. He tried to jump through this swing we had but his foot caught the seat and shot his leg up and laid him out on his back in the yard. Damn i saw tracers coming off of him. It only took him a couple minutes to show back up and I could hear him telling mom his parents had already went to bed and the door was locked. Please he begged her let me stay the night. She was furious now, you get up those stairs and you better not make a noise. I was getting higher by the second our house was on main street and the street light had my curtains lit up and they were billowing out like the wind was moving them but my windows were shut. I tried closing my eyes and i could see a Kaleidescope of vivid intense colors moving in geometric patterns that was beautiful but my eyes seemed spring loaded and I couldnt keep them shut. Everything in my room was moving now i watched tracers coming off my hand when i moved it. Whew, i felt like just a head on my pillow. Then i looked at the clock so many things were happening how long has it been. What only a minute, shit this is crazy i started wondering how long it lasts. Turns out it lasts a really long time. That acid was called Love Saves pure as the driven snow and potent big ol doses. Supposedly Owsley had made it, the best on the planet. I wish i still had some myself i love tripping. I did a quarter ounce of mushrooms once and when they kicked in it was full blast instant. Not only visual but audible as well. There's that buzz you can hear. To me i felt like a big python had me that kept squeezing me. Mushrooms dont last near as long as acid but i only did them that one time. For awhile we were getting what was called purple mesc, supposedly synthetic mescaline. From what I know now i think it was actually a form of speed the king of lsd was making. Whatever it was it was good. Colors were brighter lots of energy feeling good and laughing soaking it all in. Tripping isn't for everybody. When i did it the first time i had no idea what to expect so i had no fear. I loved it. Im 64 now and over the last 50 years i took hundreds and hundreds of hits of acid. The last time i did some has been several years ago and it was good but personally I think the chemistry isnt the same as what it once was. I don't actively seek it now and I'm gonna stop talking and thinking about it because I don't want to call it to me. It does work that way...

[science_and_anonymous]

One of my absolute favorite videos thus far as a tryptamine chemist. This video didn't get to touch on some of the really fascinating heterocyclic building reactions involved in tryptamine synthesis. Fascinating stuff there. Fungi have a tremendously large area of pharmacological interest, and any medicinal chemist will tell you that. Great video, and excited to see more.

[Basidium_King]

Psilocybin is the greatest medicine of our time

[andueskitzoidneversolo]

hey um, so like i have schizophrenia and a history of psychosis. i been micro dosing and it actually helps me stay calm and not be depressed. i been stable for almost 10 years now. i do believe that with more research we might find the best medication for schizophrenia this way. i have found that using hallucinogens actually stop my hallucinations for a while. this is how my friends would test out of they had good stuff or not. they would give me some for free as long as i reported back if my hallucinations went away or not. i found that it is the same with adderal. if you give somone who is already hyper active and you give them adderal it will slow them down. but if you are not hyper active it will speed you up. i found most hallucinates work that way for me. i cannot speak for all people with sz. but hallucinates have the opposite effect on this schizophrenic supposedly because i hallucinate naturally anyways. .

[harkyo]

I quit smoking after 30 years while being on a particularly high dosage of mushrooms one time two years ago. I had stepped down from vaping. Never went back. Had no desire or craving.

[kimcamiliamingang]

Psychedelic are just an amazing discovery. Is quite fascinating how effective they are for depression and stress disorder. Really saved my life.

[matteroftim]

Yeah. More people should try psychedelics. Not only in a medical environment because in some countries they are illegal. But with the right set and setting they can do wonders.

[mr.chrli_]

Fun fact, the brain is always developing, just at slower rates, but changes in the amygdala have been observed in patients over 40.