Fully Validated, Multi-Kilogram cGMP Synthesis of MDMA

This paper (2021) outlines a four-step process for synthesizing up to 5kg of MDMA with fully validated cGMP. MDMA is commonly synthesized with safrole, a highly controlled substance. The presented method uses uncontrolled substances achieving results in excess of 99% purity.

Abstract

“MDMA is increasingly used in clinical research, but no cGMP process has yet been reported. We describe here the first fully validated cGMP synthesis of up to 5 kg (≈30 000 patient doses) of MDMA in a four-step process beginning with a noncontrolled starting material. The overall yield was acceptable (41–53%, over four steps), and the chemical purity of the final product was excellent, exceeding 99.9% of the peak area by HPLC in each of the four validation trials. The availability of cGMP-compliant MDMA will facilitate ongoing clinical trials and provide for future therapeutic use if encouraging results lead to FDA approval.”

Authors: Jay B. Nair, Linda Hakes, Berra Yazar-Klosinski & Kathryn Paisner

Notes

Under The Controlled Substance Act MDMA remains a Schedule I substance, the most restrictive category. Substances in this category are thought to be devoid of any medical value but now thanks to the pioneering work of organizations like MAPS and other research groups across the globe, we now have the clinical evidence that supports the use of MDMA for treating mental health disorders like PTSD. Carrying out clinical research with MDMA is no mean feat as its current scheduling makes the substance both difficult and expensive to procure.

Synthesising MDMA can be a costly process given the regulatory standards one must comply with when working with a Schedule I substance. Furthermore, precursor chemicals for the synthesis process, like safrole or piperonal, have become highly regulated given the popularity of MDMA on illicit markets.

The present paper overcomes the inherent issues in the synthesis of pharmaceutical-grade MDMA by presenting a novel four-step process that does not involve the use of a controlled substance like safrole. Importantly, this process is fully validated and compliant with Current Good Manufacturing Practice (cGMP) regulations enforced by the FDA which ensure the identity, strength, quality, and purity of drug products. This proposed method by researchers at MAPS can be considered cost-effective, yielding up to 5kg of MDMA which could be used to treat roughly 30,000 patients, making it highly beneficial to both patients and the research community.

The main findings:

• The synthensis pathway begins with 5-bromo-1,3-benzodioxole which currently does not appear on any controlled substance list across the globe.
• All regaents used in the process were visually inspected and tested prior use. The researchers also tested for the presence of residual solvents and ensured that impurity profiles were of an acceptable level. These factors, amongst others, helped to ensure cGMP compliance.
• The four-step process yielded up to 5 kg of MDMA was reproducibly synthesized, with an overall yield of 41.8−54.6% and a minimum purity of 99.4% (w/w).

The paper at hand presents the first method of synthesizing MDMA at scale in a manner that is cGMP compliant. This method will help improve access to MDMA for clinical research and potential therapeutic use, pending FDA approval. The publication of this process in an open-access format emphasizes the value of taking an Open Science approach to the manufacturing of psychedelics. The Open Science approach increases patients accessibility and the cost-effectiveness of the therapies they need, something which seems to be forgotten by many in an industry which seek to address the global mental health crisis.

Taking a similar Open Science approach, an earlier publication by the team at the Usona Institute details how one could synthesize psilocybin on a large scale. Prior to this publication, psilocybin for research purposes was generally produced on a small scale and faced challenges when scaling up its production. The Usona team addressed these challenges through the second-generation synthesis of up to 100g of high purity psilocybin under cGMPs. Moreover, the methods detailed in the paper could be adjusted to provide over 1kg of psilocybin.

Researchers have reportedly been paying in excess of $7,000 per gram of psilocybin. While it would take a significant amount of dried mushrooms to yield this amount of pure psilocybin, the cost greatly exceeds the current street value of $10 per gram of dried mushrooms. Similarly, the street value of MDMA is roughly $5-$10 per tablet (at least 1 full therapeutic dose) making its current price for research purposes very costly in comparison. However, it must be noted that the purity of black-market MDMA would never come close to the 99.4% achieved by the researchers.

Much of the high costs associated with clinical research and Schedule I substances stems from the paperwork that accompanies working with controlled substances. Not only do the substances themselves have to meet high regulatory standards but so too does the equipment and even the people working with these substances. The rules and regulations surrounding controlled substances leave little commercial incentive for companies to manufacture them and therefore, keeps the prices high.

While regulatory oversight and cGMP procedures are necessary for developing any drug and ensuring it is safe, those that come with Schedule I substances are arguably preventing patients from accessing the therapies they need. While further clinical evidence is undoubtedly needed, the healing potential of these substances to treat disorders like PTSD, depression, and anxiety cannot be overlooked. Thus, a change in drug policy is needed to ensure these substances are easier to manufacture and work with in order to generate the evidence required to transform these substances into viable therapy options.

Overall, the papers presented here emphasize the value of taking an Open Science approach within the psychedelic industry and the accompanying need to reschedule substances like MDMA and psilocybin. Together, these factors will improve patient access, decrease costs and truly help to address the global mental health crisis.