Total Synthesis - 2023-03-26
🧠 Did you know that MDMA-assisted therapy was recently proven to be highly effective for people with severe PTSD? In this video, we will break down MDMA's history and discovery, synthetic approaches from the literature - including a kilo-scale process route - and clinical data from a Phase 3 study investigating MDMA's therapeutic benefit. https://www.patreon.com/totalsynthesis 🚀 Thanks to all channel supporters!!! https://www.instagram.com/totalsynthesis_official/ 👉 Follow me on Instagram to follow updates on other random chemistry research and interesting news! https://total-synthesis.com/ https://total-synthesis.com/mdma-synthesis/ https://www.total-synthesis.com * Note, some slides spell safrole as saffrole Please drop a like and comment to support the video's visibility, activate notifications and subscribe to the channel so you do not miss future videos 00:00 MDMA might have valuable therapeutic potential 00:37 Uncontrolled drug use is dangerous!!! 00:53 History and discovery of MDMA 02:26 Organic synthesis and chemical reactions: Safrole, piperonal, GMP synthesis 05:43 PTSD burden of disease and unmet need 07:08 Clinical trial design and results 09:48 Short-term MDMA safety seems acceptable - still, long-term or regular use is discouraged! 10:53 Outlook on potential FDA approval 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: - Fully Validated, Multi-Kilogram cGMP Synthesis of MDMA (ACS Omega 2022, 7, 900−907) - MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study (Nature Medicine 2021, 27, 1025) - The origin of MDMA (‘Ecstasy’) – separating the facts from the myth (Die Pharmazie 2006, 61, 966) 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)
I took MDMA when I was around 18, I suffered childhood trauma and at the time I would say I felt more stunted than anything and MDMA taught me love in a whole other way like I was loved unconditionally and I knew it in every fibre of myself. Big release into life and a massive step towards my authentic self in a way I could never have imagined. One of the best decisions I could have made as it ended up being an integral stage of development for me that I would have just missed out on entirely without this freeing experience.
That is exaclt why MDMA can work in a therapy session. Because of your new point of view (unconditional love for self and others) you can speak about problems openly with a therapist. Extacy is the wrong name it should have been named MPT or Empathy
@@maktiki
I like that a lot, Empathy is the perfect word for it. It’s empathy in its purest and most unobstructed form. What does MPT stand for?
@@Callummullans just like how people say xtc to refer to ecstasy you could say mpt as shorthand for empathy
I was a victim of paroxetine, thanks for mentioning it.
We should never let that be forgotten.
paroxetine ìs just an antidepressant, what are you talking about. It may not be suited for you, of course, but to say you are a victim... pff :-))) :-/
@@Pootie_Tang ssri's can have lasting side effects like sexual dysfunction, idk if he's talking about that but they suck
@@Pootie_Tang of being sold on a medicine that had improper safety testing and reporting which led to a 3billion dollar lawsuit. Its in the video
I remember bck in the late 70s when a paper company started offering 1,3-benzodioxole as a potential feedstock (catechol being a byproduct at that time of paper production). Those of us with dirty minds foresaw a couple synthetic routes utilizing it. However, in those days piperonal, safrole, and even MDP-2-P were readily available, so why bother?
It wouldn't surprise me if the route from 1,3-benzodioxole was already in use by cartel chemists somewhere...
Great video! Was especially interesting as I did a research project investigating psilocybin's viability for treating depression. It's nice to see psychedelics clinical potential getting more attention!
Great stuff!
@@cyro44 well, MDMA is not psilocybin and the idea behind treating depression or things like PTSD with psychedelics is not continuous use, but rather once a year or just once, as the effect it’s supposed to have is based on altering the brains structure and not on manipulation the hormones or blocking receptors like ssri‘s do, which is highly temporary
I really appreciate you stressing the importance of the clinical therapeutic setting. I have had experiences with people on MDMA in a few different social situations and I can say for sure that the wrong setting can be devastating for vulnerable or traumatised people, and the right people in the right place can be extremely valuable. Thanks for this fun & informative video!
The very sad thing is... X is super helpful for drug addicts, 'who are typically suffering from abuse' but,yet is illegal. Sad😢
Stuff like this should be taught in schools in my opinion. This is incredible life changing knowledge, and you are a saint for providing it. It SHOULD be more widely available and talked about, because of the (for lack of a better word) raging drug culture in America that glorifies the use of drugs like these in a terrible manor. BLESS YOUR SOUL
Very Interesting, I wish I had people with similar interests to explore.
I think it could also be helpful for treating disorders such as psychopathy and narcissism as MDMA is also sometimes referred to as the empathy drug. I would like to hear your thoughts on this. Has there been any research on using it for these conditions?
It is unfortunate that when the government bans a drug and places it on a list of scheduled drugs it makes it difficult for researchers to obtain approval and funding to conduct studies which could benefit people.
Incredible video
First synthesis can avoid bromine in first step by reacting catechol with diiodomethane in dmso over a brass powder catalyst... allegedly.
wonderful! may the psychology field get new tools
I wouldn't support psychology as they are not even professionals.
I trust myself and self-medication with time fixes everything.
@@user-ru7im4kz2g Ok. Ok hippie.
Ewe huemans should be aware that loot is abstracted with a tool...
Shulgin published it in PIHKAL, not TIHKAL as you mentioned
I just threw in a random picture, but youre correct! Thanks
In 1998/99 Shulgin came to UK to help Micheal Collins in his 2cb/ DOB trial...
1997 Collins was arrested...
First 2cb / DOB Manufacturing conviction...
He got 7 years...
great video.
Thank you :)
Great video. Hopefully the law enforcement lobby will not derail this kind of research. There are so many groups that exist because of the war on drugs and they will do absolutely anything to continue their funding.
Good video
I remember in about 1986 when I lived in San Antonio we used to go to teen clubs and they sold it in test tubes for like 3 dollars a tube. It had a dye or something in it that made it look sick under the black-light lighting of the club. They also sold nitrous oxide in balloons, but that's not really relevant. MDMA was legal then and was making lots of news treating marital problems. It was really touted as the next big thing in couples counseling, then overnight it until went poof and turned into a schedule whatever drug..
Nitrous oxide is currently in stage II clinical trials as a therapy for treatment-resistant depression. Basically the person would go in and be fed it for a couple of hours, and the therapeutic effect was significant and lasted for several weeks. Another drug that has a similar mechanism of action, Ketamine, is already used for this, (run a search for ' depression ketamine infusion') and so I suppose it shouldn't really be that surprising that it seems to work.
@@davidreed3021 I was reading about that the other day, and I really am glad the attitude is starting to ease on using these methods. I'm 47, and my whole life I have watched these drugs being demonized and banned because of their potential for abuse without being explored for their potential for treatment of mental health. This has also seemed to me a big mistake, to dismiss a drug as illicit and to ban it because some people might experiment with it to get high. Just yesterday I had to talk my son-in-law down "off the ledge" or suicidal urges because of marital problems. I asked him what they are doing to help him, what if any medicines the doctor was using because his thought patterns were obviously not normal. He said he had started Zoloft recently and sirens went off immediately in my head. My brother committed suicide when he was prescribed it, and I asked him didn't the doctor warn you about the side effects? How the shit amplifies suicidal thoughts and tendencies in the early stages of treatment? He said they hadn't mentioned that to him, never. I was fukn shocked that they had sent him out without even a thought of warning him of this so he could be prepared for these extreme mood swings! They were probably afraid he was say no thanks and his doctor might not get his cut for pushing this IMO completely dangerous drug that I feel has already caused more harm than good and had even helped my brother end his life. To conclude my ramble, any drug that has potential to successfully treat depression should be explored regardless of its abuse factor. I am glad the old hardliners are dying off and its refreshing to see the attitudes of my generation finally coming into practice. Maybe it'll bring better options instead of the ones that are helping to kill many people that trusted it because of limited choices.
Where Hamilton at? ehehhe
He just had that chemist on his podcast recently. Would be cool if this channels makes it on there as well
That was the first thing I thought, and then Rick Doblin. I'll make sure they at least get it, if they haven't already.
Alexander Shulgin and his wife Ann . All the way.
Vice has gone down hill.
For some reason I dislike him especially after the frog incident
Wow, excellent video. Very interesting. Thank you for making this video
I like how you sound like Pedro from Napoleon Dynamite... But an intuitive chemist.
From what I've read; if that Saffrole is coming from Sassafras oil, it could be the equivalent of a "blood diamond." Ancient canopy trees being cut down in places like Cambodia and the oil steamed out of the roots on site and smuggled out + a few potential fire fights along the way. Sounds really "cuddly and huggy" doesn't it?
Yeah; starting at 13:00 in this video, seems like there's another, even more potent precursor source than even the Sassafras tree. https://www.youtube.com/watch?v=n0p27YEv7yI
i have that paper on the gmp synthesis
Here we go again 😩
man, i just want there to be more research done on reducing mdma tolerance and the ~loss of magic~. mdma was the first drug i ever tried and my first time was still the most beautiful drug experience i've ever had. unfortunately, i've never even come close to replicating that, even after waiting a year between doses
Did you take the same batch each time? Maybe its your dose.
Not all E is created equal.
@@reedoburrito7456 no, but i don't think the dose was that different. i've tried both higher and lower doses than my first time, and while they felt more or less stimulating than my first time, they never felt as happy
@@cvspvr theres alot of fake molly out there.
@@reedoburrito7456 i always reagent test any drugs that i get
Will there not be a substitute to oil in the synth. It's annoying that we are still bound to it 😢 . Even the MAPS guys confirmed they had to use it
I have doubts, in henri reaction, is a carbanion formed alpha of no2 group and something like aldol reaction?
In reducing No2, why Fe, HCl is used and where oxygen comes from? Can we reduce no2 by h2/pd then use Hno2 to remove 1 degree amine and alcohol so formed can be oxidised by PCC?
Yes to Henri reaction (you can check mechanism). The second one is a Nef reaction (has a more complicated mechanism but you can also find it on google). Oxygen comes from hydrolysis with water which is also added to the reaction (I usually only write key reagents and not all reaction conditions)
Here is another example: http://www.orgsyn.org/demo.aspx?prep=CV4P0573
Was PIHKAL right?
3:19 what is a double Snh2 reaction?? i cant even find a definition of what that is????
Just a SN2 followed by another SN2
Is this the same guy from the book Total synthesis from strike?
- Nicolaou; Classics in Total Synthesis 1-3 is this really a trilogy or just updated editions?? seems like you could just pick 1 if your on a budge??
Thats indeed a trilogy, all different content. But it depends what you are looking for and what your level of chemistry knowledge is. There is nice focus on history and context in the 1st one in particular. Let me know your situation and I can weigh in if it makes sense
im not sure if this has anything on sassafras mda from 70s or not. i really dont think it could.
I'm not sure you understand chemistry.
If a molecule is made in the 70s or the 2020s it's still the exact same molecule, regardless of the synthesis.
If it was a different chemical it would be called such, and if it was the same chemical with an altered structure it would be an analog
Safroil is very temp sense
About the reduction of the nitro compound (4:00), isnt it an oxidation? I mean the carbon has an oxidation state of +I before the reaction to the ketone and +II after it, doesnt it?
I thought a reduction of a nitro compound would yield a primary amine. Explain it please.
Isnt it double bond reduction followed by Nef reaction (nitro->ketone)?
@@totalsynthesis Oh I didnt know the reaction mechanism and assumed its done in one reaction, but you are right. However, eventhough it is first reduced, its later oxidize to the ketone (in the nef reaction) or am I getting it wrong?
Look up uncle fester, hate to say it, but meth manufacturing. That book has a few chapters that cover mda and MDMA. I found them very interesting. Science is very cool. Organic chemistry is even more interesting
What is known about the biological differences for the two enantiomers? And is there a reported asymmetry synthesis?
Unclear in humans - actually there is a first clinical study ongoing: https://clinicaltrials.gov/ct2/show/NCT05277636
Preclinical research indicates that S-MDMA mainly releases dopamine, norepinephrine, serotonin, and oxytocin while R-MDMA may act more directly on 5-HT2A receptors and release prolactin. Animal studies also indicate that the two enantiomers act synergistically to produce the subjective effects of MDMA and that S-MDMA is mainly responsible for psychostimulation while R-MDMA may have fewer adverse effects and have greater prosocial effects. However, acute effects of S- and R-MDMA have never been validly examined in a human study.
shulgin said that the best effects come from a 1:1 mixture of the enantiomers, which is unlike most other phenethylamines where the best effects come from primarily 1 enantiomer
Combination with mild 4-ho-tryptamine dose, it can get even better, as it induces a lot of neuroplasticity.
5-HTP I take daily with .1g mdma.. best anti depressant I've ever had❤
@Michael Boehle you take 5htp amd mdma at the same time?
@@reedoburrito7456 5htp is precursor, so you won't be running on empty.
@@_juraj_ that is a very dangerous combination
@Juro Dobrík but if you take 5htp befor and after mdma then thats okay
I thought the reason MDMA is used in therapeutic trials instead of MDA was due to some kind of confusion regarding what ecstasy is.
In my admittedly experimental and non-scientific experience MDMA is a bit of a roller coaster and I advice against this, in particular if someone already is emotionally unbalanced.
MDA on the other hand is more along the lines of peaceful loving bliss without the bendy roller coaster and therefore seems much more suitable for trials.
(not to mention Vitamin D combined with K2 and Omegas but maybe it is naive to assume basic deficiencies are not addressed in these trials ?)
The "rollercoaster" is only when the dose is above a certain degree. for example very low dose was described by Shulgin as a Martini light/alcohol without calories
I see. Thank you.
Btw, non-coloric alcohol does not exist, it would be like alcohol without alcohol.
Here's to that 🥂 whatever it means
My FBI Agent watching over me rn: 👁️👄👁️
What im interested in seeing is this produceing data in regaurds to neurotoxicity, because so far all we have is rat studys showing that a 4 day cycle of 4 dosages per day results in serotonergic neurotoxicity more severe than would be observed with high dose prolonged methamphetamine use, (most studies on the matter are on users over 500MG a day, however the likely point of toxicity is surely lower.
However low dose prolonged methamphetamine use (dosages of up to 15 MG up to twice a day) for ADHD does not show neurotoxicity and Amphetamine and D amphetamine only show neurotoxicity at dosages in rats at dosages equivalent to 800MG in a 150 pound adult that may have been the result of overheating more than the substance itself. (the rats that did not experience hyperthermia did not exhibit straital dopamine receptor nore serotonin receptor damage)
So Based on other examples in the amphetamine class presumably theres a safe level of use that avoids those risks, but those risks are also proportional to the serotonin affinity of the individual molecule, So im curious to see if brain scans are being done on the trials participants to investigate the matter, Is it that the 80-125 MG in a single sitting simply does not produce toxicity, or is it that the level of toxicity is too low to have an actual perceptible effect to the individual?
If anyones got any data to show on the matter by all means send it because ive been on the hunt and have so far had no luck
Maybe the brain damage caused by mdma is a necessary factor in the clinical efficacy for depression and ptsd. Like chemical shock therapy
he MIGHT be ken carson
Theraputics of MDMA were common knowledge in the '80s.
kilo-scale. now this... this does put a smile on my face
ferb i know what we are doing today!
Oregon🌲 Measure 110
10:27 Ok based
Damn.
If I'd be more intelligent and adventurous I'd attempt making it.
I wish there would be a reliable source for clean MDMA, because honestly I don't see why it's illegal at all.
heres one for the algo
@totalsynthesis - 2023-03-26
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@user-ru7im4kz2g - 2023-03-30
New treatment discovered