ORIGINAL ARTICLES Corporate History1, Merck KGaA, Darmstadt; Department of Psychiatry2, University of Ulm, Germany The origin of MDMA (“Ecstasy”) – separating the facts from the myth S. Bernschneider-Reif1, F. xler1, R. W. Freudenmann2 Received February 17, 2006; accepted March 13, 2006 Dr. Sabine Bernschneider-Reif, Merck Corporate History, Merck KGaA, Frankfurter Straße 250, 64293 Darmstadt, Germany [email protected] Pharmazie 61: 966–972 (2006) MDMA (3,4-methylenedioxy-N-methylamphetamine), better known as “Ecstasy”, is a synthetic drug with psychedelic and stimulant effects which has gained great popularity. It is closely tied to the under- ground scene, but has also been used therapeutically as an adjunct to psychotherapy. Both scientific as well as newspaper articles communicate faulty or incomplete information on the origin of MDMA and the role of the German pharmaceutical-chemical company Merck in its development. One of the most common misconceptions is that the substance was synthesized with the goal of creating an anorectic but was not marketed by Merck because of side effects. It was our aim to clarify the circum- stances of MDMA’s discovery at Merck. An interdisciplinary working group conducted a comprehen- sive analysis of the original documents in Merck’s historical archive in Darmstadt, Germany. It could be revealed that MDMA was in fact mentioned for the first time in files from 1912, but not under this name. In the lab journals it was called “Methylsafrylamin”. In a patent certificate it was mentioned only with its chemical structure. Merck applied for this patent to protect an alternative chemical method for synthesizing the styptic hydrastinine, not appetite suppressants. MDMA was not the key substance in this patent, only a precursor. Archive documents revealed that Merck’s scientists did not perform basic pharmacological tests with MDMA (now called “Safrylmethylamin”) before 1927. These tests were halted for economic reasons. In the 1950s, primitive toxicological studies were conducted but MDMA was not tested in humans. 1. Introduction MDMA belongs to the arylalkylamine group like phenyl- ethylamine, ephedrine or norephedrine with the parent 3,4-Methylenedioxy-N-methylamphetamine (MDMA, “Ec- substance amphetamine.2 It is a psychoactive compound stasy”) is a synthetic amphetamine derivative with psyche- with structural similarities to both the stimulant ampheta- delic and stimulant effects (Freudenmann and Spitzer mine and the psychedelic phenethylamine mescaline. 2004). In the “Ecstasy” literature – which covers more Because of the unique combination of stimulant and psy- than 100 years – a large number of synonyms can be chotomimetic properties MDMA has been classified as an found for the substance, which complicates the complete “entactogen” (Nichols 1986). MDMA (and some of its coverage of its history.1 analogs) produced a state of increased energy, reduced an- xiety, lowered defensiveness, and a feeling of “closeness” Table: Synonyms for MDMA to other persons, particularly after intake in music clubs and larger crowds. MDMA’s effects mainly result from an Metyl-safryl-amin increased synaptic availability of serotonin (5-HT) based Safryl-methyl-amin on serotonin re-uptake inhibition and serotonin release b-3,4-Methylendioxy-phenylisopropyl-methylamin from presynaptic storages. The “stimulant” and emotional 3,4-Methylendioxy-N-methylamphetamin effects are mainly produced by the acute release of 5-HT, 1-(2-Methylaminopropyl)-3,4-methylendioxybenzol while the “hallucinogenic” effects of MDMA are mainly 2-Methylamino-1-(3,4-methylendioxyphenyl)-propan evoked by direct interactions with postsynaptic 5-HT re- N-Methyl-a-Methylhomopiperonylamin 2A 3,4-Methylenedioxymethamphetamine ceptors (similar to LSD, mescaline, DOM). In 1986, N-Methyl-3,4-methylenedioxyamphetamine MDMA, methylenedioxymetamfetamine or (1-(1,3-benzo- 3 N,a-Dimethyl-3,4-methylenedioxyphenetyleamine dioxol-5-yl)-propan-2-yl)(methyl)azane, became an illegal N,a-Dimethyl-homopiperonylamine substance according to the “United Nations’ Commission N,a-Dimethyl-b-(3,4-methylenedioxyphenyl)-ethylamine on Narcotic Drug Laws”. In Germany and most other N-Methyl-b-(3,4-methylenedioxyphenyl)-isopropylamine countries it is listed in the most restrictive category of nar- 2-Methylamine-1-(3,4-methylenedioxyphenyl)-propane cotics today.4 N,a-Dimethylbenzodioxole-5-ethylamine It seems necessary to give rise to a scientific debate “Ecstasy”, “Adam”, “XTC”, “MDM, “E.“ ... about the history of MDMA, a substance which has been 966 Pharmazie 61 (2006) 11 ORIGINAL ARTICLES at the centre of a virulent controversy since the early 2. Investigations and results 1980s, a substance which has created its own subculture in the Techno Music and clubbing scene: In 1997, Mat- For this purpose an interdisciplinary working group thew Collin and John Godfrey described that ecstasy sub- searched the historical archives at Merck in Darmstadt, culture offers the “best” entertainment, which is up for Germany, for original information about the discovery of grabs in the market at the moment. It is a combination MDMA. All available documents (including memoirs and of technologies – musical, chemical and computer based personal communications) between 1910 and 1960 were – providing a changed awareness, providing experiences, included in our comprehensive analysis of documents, which change the way of thinking, feeling, acting, living many of which had not been reviewed for decades. These (Collin and Godfrey 1997). “Ecstasy” has gained great works were performed by a pharmacist (SBR), a chemist popularity worldwide as a substance of abuse, but has (F), a physician (RWF) and an international patent law- also been used by experimental psychologists as an ad- yer.7 It was part of the project to make important historical junct to psychotherapy in the 1970s (i.e. before it became material more accessible for the scientific community. Ac- a federally controlled substance). Even today, it pits pro- cordingly, we digitalized all of the relevant certificates and ponents of its use as an adjunctive psychiatric treatment laboratory notes of the chemists who first worked with against those who argue that it poses a grave threat to MDMA. They are available at request at Merck’s histori- public health and safety, e.g. because of MDMA’s toxic cal archive for further studies. effects to central nervous serotonergic neurotransmission In addition to our analysis of files in Merck’s historical and fatal intoxications. It is an illegal drug and cannot be archive, we collected and reviewed many original docu- prescribed. On the other hand, the US-based organisation ments often referred to or mentioned in association with MAPS5 still wants to get MDMA approved by the FDA the discovery of MDMA. Some of them dated back to the as an augmentation to psychotherapy in post-traumatic 1890s. We set out to confront the most common state- stress disorder. Both the scientific community as well as ments about the origin of MDMA point by point with our the public are still grappling with the perception of analysis of the primary document sources. MDMA twenty years after it first became popular in the It was easy to reject statement 3 about the origin of MDMA streets (Johnston et al. 2003; Freudenmann and Spitzer (see above). Fritz Haber’s thesis from 1891 work does not 2004). at all mention MDMA, only a substance close to MBDB, Numerous publications deal with the history and develop- another ring-substituted amphetamine. Similarly, myth ment of this illegal drug, not only scientific articles and number 4 was easily disproved. According to Merck’s his- reviews, but also newspapers and websites. torical personnel files it could be established that Carl Man- But what is said about the first synthesis of MDMA and nich never worked with the company. In a work from 1910, the pioneering pharmacological research on the substance? co-authored by Willy Jacobsohn, he described the “valu- The most often repeated statements about the origin of able pharmacological effects” of “organic phenol-like ba- MDMA in the literature are: sic substances”, in particular those of “hordenin”. He tried 1. MDMA was first synthesized/patented in 1912/4 at the to synthesize related substances and characterized 3,4- German pharmaceutical company Merck in order to create methylendioxyphenyl-isopropylamine as MDA, not MDMA an anorectic or a psychoactive substance but was not mar- (Mannich and Jacobsohn 1910). Apart from the similarity keted because of side effects. 2. MDMA was intended for of the acronyms MDA and MDMA the two substances are use by soldiers in World War I. 3. MDMA was discovered also chemically and pharmacologically closely related by Fritz Haber, a German Nobel Prize winner for chemis- which might explain the mix-up in some publications. try, while working on his doctoral thesis. 4. MDMA was MDA differs from MDMA only by a single CH3 group in discovered by the German chemists Carl Mannich and the side chain of the molecule. It has comparable psycho- Willy Jacobsohn at Merck in Darmstadt.6 tropic effects and is an abused substance, too (called Obviously, these statements are contradictory, and the “Love (Drug)” in the streets). Moreover, MDA is the ac- “Ecstasy” literature appears to communicate faulty or in- tive metabolite of MDMA. complete information about the origin of MDMA. Many The documents in Merck’s historical archive were used to authors apparently repeated “historical facts” from other