Over One Hundred Years of MDMA Research

Written by Libby Furminger



3,4-Methylenedioxymethamphetamine (MDMA), also known as Mandy, Molly, Ecstasy or ‘E’, is a class A drug known for inducing feelings of happiness, chattiness, liveliness, and overall feelings of ecstasy, making it a common adjacent to enhancing raves, clubs and parties. Lesser known, MDMA has historically also been used in research to aid in therapy until it became illegal. More recently, there has been a shift back to focusing on the use of MDMA in medical research.

In 1912, MDMA was first synthesised by a German pharmaceutical company, Merck, who aimed to create a medication to regulate bleeding. A by-product of this formulation was the first synthesis of MDMA. Soon after, Merck patented the compound as they believed that it had potential medicinal value. For the next few decades, there wasn’t much development in MDMA until 1978 when researchers investigating phenethylamines, Alexander Shulgin and David Nichols, first reported its psychological effects. It wasn’t long until the drug began piquing the interest of psychiatrists and scientists who had been studying various psychedelic drugs and their potential in treatment for various mental health conditions. Shulgin shared his findings with a psychotherapist, Leo Zeff and soon after MDMA started being used to assist in psychotherapy. In about 12 years Zeff administered approximately 4000 people MDMA; Zeff even provided training for Shulgin’s wife (Ann Shulgin), who had been using MDMA at the time to help her friends. Ann began running her own MDMA sessions with various patients and became hugely influential for other psychotherapists in the field.

George Greer additionally took advantage of the legal grey area this drug was in during the early 80s and with assistance from Shulgin, gained his own batch of clinically pure MDMA. Greer was a psychiatrist who had initially administered both himself and his wife with the drug. It wasn’t long until he acknowledged the many useful applications, namely enhanced communication, experienced as a result of taking MDMA. Greer went on to carry out one of the first MDMA studies: he administered 75-150mg of the drug to 29 participants who would then undergo an MDMA session either individually or alongside a therapist. All 29 participants reported a positive change in their attitudes or feelings – many of whom also described experiencing deepened perspective and higher levels of self-acceptance. All 9 participants with prior mental health diagnoses (Primarily either depression or phobias) described the experience as having provided them with relief – two of whom reported full remission. Many also reported having found a deeper insight into their lives. These results persisted during the follow-up period which varied between two months and two years after the study. However, experiments such as Greer’s soon came to a halt when the drug was made illegal in the US in 1985.

The initial research prior to the ban allowed for insight into the workings of MDMA in the brain. At a chemical level, MDMA works by affecting the nervous communication within the brain. Nerves communicate using neurons, which pass signals from one to another via microscopic gaps called synapses. To pass a signal, chemicals called neurotransmitters are released from the first neuron, entering the synapse before binding to receptors on the neighbouring neuron. MDMA works primarily on neurotransmitters such as serotonin (associated with numerous functions including regulating mood, specifically related to happiness) and dopamine (associated with motivation and motor function amongst other things). MDMA causes the release of both serotonin and dopamine as well as blocking the reuptake (removal) of serotonin in the synapse – this creates an abundance of both neurotransmitters in the synapse and causes strong neuronal signals, which result in the extreme heightened emotional effects caused by the drug.

Despite research having been halted due to prohibition, in recent years MDMA has begun to re-emerge as a useful therapeutic option in treating various mental health conditions. Its applications in treating Post Traumatic Stress Disorder (PTSD) and addictions, as well as other conditions, are currently under investigation. Various sections of this research shall be overviewed herein.



Firstly, and most famously, MDMA has been prominently researched for the treatment of PTSD. PTSD is an anxiety disorder caused by a traumatic experience or event of some form; it can cause flashbacks, nightmares, emotional numbing and hyperarousal as well as being highly comorbid with other disorders such as depression or substance abuse.  A double-blind placebo-controlled study of MDMA-Assisted Psychotherapy for PTSD found that at the primary study endpoint (18 weeks after baseline), 28 of 42 (67%) of participants in the MDMA group no longer met the diagnostic criteria for PTSD compared to 12 of 37 (32%) of those in the placebo group. This indicates that MDMA-assisted psychotherapy significantly enhances the effects of PTSD supportive therapy.

In the brain, MDMA releases the neurotransmitter, serotonin, which results in a reciprocal increase of a hormone called oxytocin. The heightened levels of oxytocin have been shown to have effects on the fear and stress centre of the brain – the Amygdala – leading to decreased activity here and thus reducing the brain’s ability to process and experience anxiety and trauma. This decrease in the fear response can reduce the fear around engaging with traumatic memories and allow participants to discuss their trauma more openly. Many also found that even after treatment these repressed memories caused less distress than before and they were able to address them in the long term.

Further applications for MDMA in treating PTSD can be seen in relationship counselling. Relationships in which one partner suffers with PTSD can often be strained due to trauma-related interpersonal struggles. These can manifest as symptoms such as detachment, numbness and avoidance. MDMA has been seen to have a positive effect on communication which was described by Greer as feeling like a previously unknown barrier being lifted. MDMA allowed himself and his wife to talk and communicate issues freely – they noticed suddenly it was easier to open up and listen.

Dr Candice Monson carried out a trial of MDMA-facilitated cognitive-behavioural conjoint therapy (CBCT) for patients with post-traumatic stress disorder. Participant couples, of which one partner had a PTSD diagnosis, underwent 15 sessions of CBCT over 7 weeks with 2 sessions involving both partners receiving a dosage of MDMA. The study found significant improvements in the diagnosed patients’ PTSD symptoms but also an increase in relationship satisfaction, relational support, and social intimacy, when compared to non-MDMA facilitated CBCT controls. This study was the first of its kind and there are intentions to begin a larger phase II, randomised controlled trial to investigate this further.

Research into MDMA-Assisted Psychotherapy for PTSD has passed the pivotal Phase III trials making it closer to becoming authorised as a licensed medical treatment. These initial studies into PTSD effectively provide a foundation for future research to investigate MDMA’s applications to a wider range of disorders such as addiction.

Dr. Ben Sessa is a consultant child and adolescent psychiatrist who has also carried out work in adult addiction services. He expanded on these treatments for PTSD with his preliminary study investigating the potential of MDMA-assisted psychotherapy for alcohol use disorder. Sessa acknowledged the correlation between experiencing psychological trauma (often in childhood) and addiction in adulthood whereby alcohol was used as a coping mechanism for the trauma; he hypothesised that there was potential for MDMA assisted psychotherapy to address and treat these past traumas resulting in the adjacent treatment of alcoholism. The results of the initial four participants were analysed in his 2019 proof of concept paper. Participants attended eight sessions over eight weeks; in two of these sessions, participants were administered a dosage of MDMA (these two sessions lasted approximately 7 hours). Participants were followed up for a further 9 months after the therapy to assess the long-term and side effect profile of this treatment. None of the participants suffered any negative physiological effects as a result of this study. At the follow-up, none of the participants had returned to harmful drinking – half of the participants remained fully abstinent following the study; the other participants have reported having a low dosage of alcohol on a single occasion since the study. In 2021, the results of an additional 14 participants who had received 10 psychotherapy sessions for alcohol use disorder – 2 of which involved an open-label dosage of MDMA – were published. This study found that at 9 months post-detox, the average participants’ alcohol consumption was 18.7 units per week compared to 130.6 units per week prior to undergoing MDMA-Assisted Psychotherapy.

In a separate observational study, Sessa analysed standard treatment being offered for alcohol detox in Bristol, England; finding 75% of people revert to drinking in excess of 14 units a week at 9 months post-detox. This was compared to his MDMA sample in which only 21% of participants were drinking over 14 units of alcohol a week at 9 months. Whilst direct comparisons can’t be made between these outcomes due to the non-randomised, open-label design of this study, there are plans to expand on these findings further with a randomised double-blind placebo-controlled study.


Harms of MDMA

MDMA is currently a Class A drug in the UK which makes this research area controversial, expensive and slow. There is significant debate in the fields of science and politics around MDMA and various other substances which have revealed therapeutic values.

Professor David Nutt, a psychiatrist and neuropsychopharmacologist specialising in psychopharmacological drugs and their effects on the brain has spent the last few decades studying psychedelics. Nutt famously published an article evidencing drugs such as MDMA and LSD to be less harmful than the commonly acceptable and attainable, alcohol. Nutt has gained significant appraisal for breaking down stigmas associated with these substances and producing an evidence-based foundation, free from political or commercial influence, from which objective discussions on their clinical applications can be had. Following the publishing of a paper in the Lancet demonstrating evidence that MDMA consumption is less harmful than horse-riding, Nutt was fired from his position of chair of the Advisory Council on the Misuse of Drugs; following this, he founded our charitable organisation – Drug Science.

Nutt has illustrated the bias formed by the general public due to the newsworthiness of MDMA-related harms. Every single ecstasy-related death has been reported; however, this media trend is not seen in deaths caused by common legal drugs such as paracetamol with only 1 in every 250 deaths making the news. This leads to the widely held belief that MDMA-related fatality is common when in fact it is highly uncommon with only 1 in 1000 suffering from any adverse effects as a result of its consumption. A toxicology report of MDMA related deaths found that when an overdose occurs, MDMA is often not the only drug in their system – this could be either the result of combining different drugs for a stronger high or a lack of testing recreational drugs prior to consumption. Only one-seventh of MDMA-related deaths reported within the toxicology were caused by MDMA alone. It is suggested that whilst MDMA itself is relatively safe, pairing it with other substances can increase its risks; this is additionally evidenced by the presence of alcohol being in 75% of all MDMA-related admissions to the emergency department in Australia between 2008-2010.

Additionally, MDMA can pose a risk through its effect on increasing body temperature and blood pressure – this could potentially cause strain on the heart of an individual with a cardiovascular disorder. These risks are controlled in clinical research by carefully monitoring patients during their sessions to ensure they do not enter into unsafe conditions as well as excluding participants with conditions such as hypertension, cardiac disease, and pregnancy in the screening prior to the study. Additionally, the MDMA used in clinical trials is produced to a far higher standard than what is used recreationally on the streets – further increasing the safety and ethics of the research

MDMA is a drug showing an increasingly substantial application in the field of medicine. Despite various laws having halted research for a significant period, its usefulness is becoming more apparent, aiding in the treatment of many mental health conditions. Additionally, recent public awareness of the mental health “crisis” faced by many developed nations provides further incentive to investigate novel therapeutic options for mental health disorders and has garnered support for MDMA use in treating PTSD and addiction disorders. MDMA is likely to be the first scheduled drug to be licensed as a medicine, yet the drug still remains highly stigmatised and has a long journey of discovery ahead of it to further investigate its possible therapeutic armamentarium.



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