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.


“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


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.


MDMA was synthesized in a four-step process with an acceptable yield and excellent chemical purity. The process will facilitate ongoing clinical trials and provide for future therapeutic use.


Interest in the clinical utility of psychedelic compounds has increased dramatically in recent years, provoking regulatory shifts that have further stimulated engagement.

This second wave of psychedelic studies includes compounds like MDMA, which was added to the DEA’s Schedule I in 2004. MDMA has shown promise as a psychotherapeutic aid for patients suffering from PTSD, autism-related social anxiety, and alcoholism.

As the research environment grows more supportive of clinical exploration, the need for pharmaceutically acceptable MDMA continues to expand. A well-controlled manufacturing process is the best-known way to ensure that drugs are of predictably high quality, consistency, and efficacy.

MDMA was first synthesized by Merck, in 1912, as an intermediate to the styptic compound methylhydrastitine. It was not until 1960 that a synthesis identical to Merck’s was published in Poloniae Pharmaceutica, and a variety of synthetic routes from methyl piperonyl ketone were summarized by Shulgin, in 1986.

Clandestine chemists have developed a number of synthetic routes to MDMA, often relying on chemicals readily available to ordinary consumers, in an effort to circumvent controlled substance precursor regulations.

To date, none of the synthetic explorations into MDMA appear to have considered cGMPs. While some clandestine labs reliably produce large quantities of high-quality MDMA, these facilities necessarily operate outside of regulatory frameworks and certainly do not report or document cGMP-compliant procedures.

We report here the first cGMP synthesis of MDMA and its hydrochloride salt (MDMAHCl), which can be used in pharmaceutical formulations. The process was fully validated, four-stage, and achieved an overall yield of 41.854.6% and a minimum purity of 99.4% by HPLC assay.

We developed a cGMP-compliant production process for pharmaceutical-grade MDMA to supply our own Phase III clinical trials and to alleviate existing supply constraints for the broader research community.

We synthesized MDMA from 5-bromo-1,3-benzodioxole, which does not appear on any geopolitical entity’s list of controlled substance precursors. The only significant impurities were 5,6-dibromo-1,3-benzodioxole and succinimide, which were present in very trace amounts.

We used the same aryl Grignard reagent used to synthesize safrole to generate a 2-propanol substituent via ring-opening addition between 1,2-propylene oxide and a nitrous oxide. This reaction was efficient and yielded 1-(3,4-methylenedioxy-phenyl)-2-propanol in excess of 96% chemical purity by HPLC.

The next three steps relied on well-known synthetic transformations, and were accomplished with a biphasic (DCM/H2O) TEMPO/KBr/bleach reagent system, aqueous workup and filtration, and a rotatory evaporator. The crude product was of sufficient purity to proceed to the next process stage, without an additional purification step.

MDMAHCl can form three different anhydrous crystal forms, including Form I, which is the most stable, and Form II, which can be produced from a variety of alcoholic solvents. Both Form I and Form II reversibly convert into the known monohydrate.

To maintain compliance with cGMP regulations, all reagents were visually inspected and tested, prior to use. Reagents that failed to meet all established specifications were not used at any stage of the process.

The presence of residual solvents in cGMP manufacturing must be below solvent-specific concentration thresholds defined in USP 467>. Our process yielded residual solvent concentrations significantly below these limits, over four consecutive validation trials.

MDMAHCl must have impurity profiles less than 0.05% of the total peak area by HPLC. The process we used yielded MDMAHCl with chemical purity in excess of 99.9% of peak area by HPLC, and no single impurity ever exceeded 0.05% of the total peak area.

Heavy metal impurities in finished pharmaceutical products are an area of potential concern. However, the greatest quantifiable amount of any heavy metal impurity was 97% less than the permissible daily intake limit.

To validate this cGMP process, each stage was successfully completed at the 8 kg scale at least four consecutive times. No deviations from the documented procedures or parameters were noted, and the anticipated impact on the final product was characterized.

Reactions were performed using commercially available raw materials and solvents in a 50 L reaction vessel. In-process analysis was conducted by HPLC, and 1H NMR analysis was used to quantify residual solvent content during evaporation steps.

The first step in the synthesis of 1-(3,4-Methylenedioxyphenyl)-2-propanol involves the formation of a Grignard reaction between magnesium turnings and THF at 20 °C. The second step involves the addition of 5-bromo-1,3-benzodioxole to the reaction vessel.

A 50 L reaction vessel was charged with magnesium turnings, 32 L of THF, and 400 mL of the small-batch Grignard solution. The reaction was stirred at a gentle reflux for 40 min.

Addition of copper iodide to propylene oxide results in a dark brown solution and a crystalline suspension. The reaction is completed by HPLC.

The batch was divided into two 20.4 L portions for workup, and the pH was adjusted to 5.0 using acetic acid, followed by 8.2 L of n-heptane, and an additional 8 L of sodium chloride solution. The crude yield was 7442.7 g, and the solvent was removed in a 20 L rotatory evaporator.

The crude product was charged with PEG400 and distilled, yielding 6293.2 g of pale yellow oil (94.2% yield).

Stage 2 consisted of oxidizing crude 1-(3,4-methylenedioxyphenyl)-2-propanol with potassium bromide and TEMPO, cooling the mixture to 0 °C, adding sodium hydrogen carbonate, and removing samples after each addition. HPLC analysis was used to monitor the reaction progress.

The organic layer was cooled to 0 °C, added 4890 mL of 12% aqueous sodium hydrosulfite, warmed to 19.5 °C, stirred for 15 min, and then filtered. The solvent was removed under vacuum, yielding 2442.1 g of a yellow-to-brown oil.

The reaction of 1-(3,4-methylenedioxyphenyl)-propan-2-one with 40% aqueous methylamine, NaOH, and NaBH4 results in a product with a peak area of 81.04%, and the starting material is undetected.

The crude product was returned to the 50 L reaction vessel, stirred with 12 100 mL TBME for 15 min at 18.6 °C, separated into two layers, and the solvent was removed with a 20 L rotatory and evaporator. The product was 2524.0 g (94.57%) peak area by HPLC.

MDMA was returned to the flask and stirred with HCl. The precipitate was captured on a filter and dried under vacuum for 18 h at 57.3 °C.

MDMAHCl Form 1 seed crystals were added to a 50 L reaction vessel, and the mixture was stirred at 67.2 °C for 30 min. The mixture was then cooled to 55.3 °C, over the course of 90 min, and then stirred at 15.2 °C for an additional 10 h.

MDMAHCl was obtained by vacuum filtration from the mother liquor and dried under vacuum for 19 h at 56.6 °C. No single impurity exceeded 0.02% of the peak area by HPLC.


This research was sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS), and the authors declare no competing financial interest.

Study details

Compounds studied

Topics studied
Equity and Ethics

Study characteristics

0 Humans


Institutes associated with this publication

MAPS stands for Multidisciplinary Association for Psychedelic Studies, it's the front runner in making psychedelics a legal way to use (and improve) in therapy.

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