MDMA or ecstasy is not a particularly complex molecule so the chemistry we will discuss will not be too shocking for you. However, did you know that MDMA-assisted therapy was recently proven to be highly effective for people with severe PTSD? Today we will look at MDMA s history and its chemical syntheses.
Aside from many interesting points, like dispelling myths about MDMA s discovery, or laughing at the first kilo-gram scale MDMA synthesis published in a journal, we will also review impressive recent clinical data that suggest ecstasy might help up to millions of people affected by PTSD. This video is educational and not a DIY-tutorial for illegal clandestine synthesis. Also, don t use this information to rationalize your drug use long-term and side effects of MDMA can be severe and regular use is discouraged even by clinical advocates.
The origin of MDMA has quite some tales associated with it. For example, crediting various German scientists with its discovery, even though no documentation or basis for this can be found. MDMA also was not intended for use in World War 1, but interestingly enough, there was quite some military experimentation on stimulants later on in the 1950s.
The first point at least goes in the right direction, but the history is much more intriguing than this. The story actually starts with hydrastine, an anti-hemorrhagic natural product isolated from some random plant. By start of the 20th century, this drug became more and more expensive because the plant was becoming more rare and cultivation attempts had failed.
Therefore, the German company Merck was interested in finding ways to chemically synthesize it. They had some chad chemist reach out to them and offer a new, very cheap synthetic procedure for hydrastine but for some reason, this guy signed the contract with Merck s competitor Bayer quite funny. So the Merck scientists now had to find some new anti-hemorrhagic agents or new syntheses.
You can appreciate that hydrastine is basically a more beefed up version of MDMA so it might not shock you that the Merck scientists produced MDMA as a side product, and were not interested in it at all. So while true that their 1912 patent refers to MDMA s structure for the first time, they did not pursue or test it, so the first MDMA publication and synthesis was published only 50 years later and things gained traction from there on. As a side note, consider becoming a channel member or Patreon if you like this video and want to support the channel!
Let s check out three syntheses of MDMA the first Merck synthesis from 1912, a second one based on late 20th century approaches, and a compliant and regulated kilo-scale synthesis from 2022. There are other clandestine methods, actually mentioned in quite a few papers, but obviously we will not discuss this here. So saffrole is a natural product which was used in the first half of the 20th century as a food flavor due to its nice candy shop aroma.
Human consumption as banned later after people realized it was increasing rates of liver cancer feels like half of pesticides and food ingredients have the same story. Saffrole was the starting material for Merck, but it can also be made synthetically in a few steps. Starting from Catechol, a double SN2 reaction forms 1,3-benzodioxole.
Then, mono-bromination with NBS gives the aryl-bromide, which can be converted into a Grignard reagent and used in a nucleophilic substitution with allyl bromide. From saffrole it s only two steps: first, a normal Markovnikov-selective hydrobromination, and another SN2 with methylamine to get MDMA. Optionally, you can also throw in a Finkelstein halogen exchange to get better yields in the substitution.
The second synthesis from piperonal starts with a Henri condensation reaction, creating a nitro-olefin. This can be reduced in acidic conditions to the ketone and a reductive amination with methylamine gives MDMA. So this synthesis uses a bit less bromines but more redox chemistry.
The final synthesis is pretty sweet. It was published in 2022 by the MAPS PBC, a small biopharmaceutical company and subsidiary of MAPS, a non-profit organization working to raise awareness and understanding of psychedelic substances. They required large amounts of MDMA to supply their two Phase 3 clinical trials, which we will check out shortly.
This is the first-ever document kilogram scale preparation of ecstasy, with product being appropriate for clinical and potential licensed therapeutic use due to the process validation and GMP compliance. Instead of using saffrole or piperonal, both of which are controlled substances and thus highly regulated and difficult to obtain, the chemists used this arylbromide which we saw is an intermediate towards saffrole, and is commercially accessible from different suppliers. This synthesis is very similar to others we saw, but it has a twist.
It starts again with a Grignard reaction but this time, with 1,2-propylene oxide as an electrophile. This epoxide nicely introduces the rest of the aliphatic chain, leaving a secondary alcohol which can, similar to other syntheses, be oxidized to the ketone. This ketone could be used without any purification in the final reductive amination step.
You can check out the paper for more info they go into some more details on validation and impurities. The experimental procedures are quite funny to read, as they ultimately isolate 3. 6kg of MDMA HCl salt with over 99.
4% purity. So they put in a lot of effort in this process but why is it worthwhile to look at PTSD? As crazy as it sounds, 6-7% of people in the US experience PTSD at some point in their lives, with about 1/3 of cases classified as severe.
Often, there are other conditions decreasing chances of successful therapy, so these high-risk patients need more effective treatments. Just as a side note, this did remind me of other shockingly high estimates from the US National Institute of Mental Health for example, they also state that 19% of adults experience what they termed any anxiety disorder per year. This is probably exaggerated, of course anxiety is human but proper clinical disorders are probably not affecting 20% of adults every year.
As a last reason, many patients do not respond to first-line treatment with SSRIs most notably, those are sertraline and paroxetine. The latter was actually part of the massive $3bn fraud settlement due to unlawful promotion and failure to report safety data. You might know that SSRIs are used in various depressive and anxiety disorders, so it would be nice to have a more targeted therapy or intervention.
That s why MAPS has been supporting MDMA clinical trials as early as 1992. All their advocacy and support culminated in two large-scale Phase 3 trials which were recently completed we will dissect one of them. Let s talk about study design before going into results after an initial wash-out of any other psychiatric medications, patients went through four blocks consisting of various therapy sessions.
The important points are the red experimental sessions corresponding to the three occasions where patients in the treatment arm received an 80-120mg dose of MDMA. The individual therapy sessions consisted of supported introspection, experience sharing and probably some other things, and were conducted by trained clinical teams. This was a placebo-controlled Phase 3 study, so the total 90 patients were randomized to two trial arms.
You can see that the patients in each trial had quite comparable characteristics, which obviously is important if you want to compare the effect of a medication for example, the average duration of PTSD was around 13-15 years for both segments, although there was quite a large variation. From a trial endpoint perspective, there are two important measurements to look at. The CAPS-5 score is based on a semi-quantitative questionnaire that sheds some light on how bad the PTSD is a score in the 40s, as present in the trial baseline, means very severe PTSD.
The Beck Depression Inventory score tells you how depressed someone is here a score above 30 is also severe. So, these were quite severely affected patients indeed how did they respond to MDMA-supported therapy? Well, both PTSD severity and depression scores decreased significantly from baseline until end of the last therapy block.
You can see that normal therapy also improves outcomes, so these seemingly fluffy therapy sessions are useful but the effect with MDMA on top is clearly higher, as you can see from illustrative uncertainty ranges as well. At the end of therapy, patients in the treatment arm were much better off, now having only mild to moderate PTSD and much lower depressive symptoms. Please note that guided therapy was still needed, so just taking MDMA wouldn t have the same effect and could make it even worse.
In this other nice visual you can see classification of patients by response while there were quite a few non-responders and only few patients in remission for placebo with therapy, the MDMA group had almost 40% of people completely PTSD-free and only few not responding at all. The nice thing was also that MDMA had an equally positive effect in high-risk people with other disorders, including the especially difficult-to-treat dissociative subtype of PTSD. There s obviously some more statistics which you can nerd out on, we just wanted to look at the visuals but the last thing we should note here is that MDMA had a quite good safety profile.
Several side effects like muscle tightness, appetite loss, nausea were much more frequent in the treatment arm, but most of them are quite OK and harmless. I would guess that you would rather lose appetite and have some tight muscles, than be afflicted with severe PTSD. More severe adverse events, like suicide attempts or self-harm were actually only observed in the placebo control, probably because their intervention was less effective.
So at least in the short-term, there were no concerning safety signals. It is still a mystery how this works physiologically, but the literature speculates MDMA might reopen a window of neuroplasticity that allows for processing and release of fear and other emotions. Doing so, MDMA might support and catalyze therapeutic processing by allowing patients to stay emotionally engaged while revisiting traumatic experiences without becoming overwhelmed.
I could throw some synaptic biochemical pathways at you now but will not go there in this video. The FDA already granted MDMA-assisted therapy a break-through designation in 2017 so with this promising data in hand, MAPS PBC is expecting to file for FDA approval in late 2023. It will be interesting to see how they decide on this.
Let me surprise you with another score which I intentionally left out earlier for simplicity, the Sheehan Disability Scale. This is measures how well an individual functions in key life dimensions, and it seems like MDMA-assisted therapy could also help thousands or millions of people become more functional and independent in their daily lives. Supposedly, US veterans report service-related disabilities that cost the government $73?
billion per year. A sizeable chunk of these costs are probably due to PTSD, which might also encourage the FDA to approve MDMA-assisted therapy, at least for high risk patients. I think this was quite a nice journey, going from almost ancient chemistry to modern clinical outcomes.
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