This commentary (2015) examines how inappropriate, non-evidence-based, legislative restrictions of MDMA have failed to mitigate the harms of recreational ecstasy use but have effectively halted clinical research for therapeutic use. They urge the regulatory authorities to re-schedule MDMA and promote research for therapeutic uses within psychiatry.
From its first use 3,4,-methylenedioxymethamphetamine (MDMA) has been recognised as a drug with therapeutic potential. Research on its clinical utility stopped when it entered the recreational drug scene but has slowly resurrected in the past decade. Currently there is enough evidence for MDMA to be removed from its Schedule 1 status of ‘no medical use’ and moved into Schedule 2 (alongside other misused but useful medicines such as heroin and amphetamine). Such a regulatory move would liberate its use as a medicine for patients experiencing severe mental illnesses such as treatment-resistant post-traumatic stress disorder.
Greer and colleagues frame the paper around the tension between MDMA’s historical association with recreational ecstasy and its potential as a clinical therapeutic. They note that media attention on rare harms from recreational use has hindered objective, evidence-based research into MDMA-assisted psychotherapy despite a quarter-century of epidemiological data indicating low morbidity and mortality associated with ecstasy and accumulating clinical data supporting MDMA’s therapeutic effects for conditions such as post-traumatic stress disorder (PTSD). The article aims to summarise the clinical history and emerging trial evidence for MDMA as a treatment adjunct, to outline its putative mechanisms and safety profile, and to argue for a regulatory change in the UK: moving MDMA from Schedule 1 (no recognised medical use) to Schedule 2 to enable and accelerate medically supervised research and clinical use for severe, treatment-resistant psychiatric disorders such as PTSD.
Papers cited by this study that are also in Blossom
Greer, G. R. · Journal of Psychoactive Drugs (1986)
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2010)
Bedi, G., Cecchi, G. A., Slezak, D. F. et al. · Neuropsychopharmacology (2014)
Frye, C. G., Wardle, M. C., Norman, G. J. et al. · Pharmacology Biochemistry and Behavior (2014)
The extracted text is not a primary empirical report and does not present a dedicated Methods section. Instead, the paper functions as a narrative overview/commentary that cites and summarises prior studies, including placebo-controlled clinical trials, neuroimaging investigations and epidemiological work. The extraction does not report a systematic search strategy, eligibility criteria, or formal risk-of-bias assessment; therefore it should be read as a synthesis and policy argument rather than a formal systematic review or meta-analysis. Where trial and neurobiological findings are referenced, the authors draw on published placebo-controlled studies, follow-up cohorts and experimental paradigms (for example social interaction and facial-expression tasks), but the specific study-level methods (sample selection, randomisation procedures, dosing regimens, psychotherapy manuals) are not detailed in the extracted text.
In describing controlled clinical research, the authors report a placebo-controlled study in treatment-resistant PTSD where 85% of participants treated with MDMA-assisted psychotherapy no longer met diagnostic criteria for PTSD after three MDMA sessions, compared with 15% in the placebo group; these improvements were reported to be sustained at 3.5 years of follow-up without further MDMA interventions, with many patients reducing or stopping other psychiatric medications. A subsequent Swiss study is described as demonstrating substantial improvements in a similar population, though the extraction does not provide sample sizes or further numerical details for that trial. The authors summarise mechanistic and experimental findings supporting MDMA’s therapeutic role. Pharmacologically, MDMA acts at multiple receptors (5-HT1A, 5-HT1B, 5-HT2A, dopamine and alpha-2) and promotes oxytocin release, which is linked to increased bonding and empathy. Behavioural and experimental studies cited report that MDMA increases use of friendship/support language, reduces sensitivity to social exclusion, enhances shared empathy and prosocial behaviour compared with placebo, and accelerates detection of happy faces while reducing detection of negative facial expressions. Comparisons with intranasal oxytocin are noted, with one study (Kirkpatrick et al.) finding greater improvements in prosocial communication with MDMA. The authors also state that prosocial effects were consistent across sites (San Francisco, Chicago, Basel). Neuroimaging findings are summarised from recent studies: for example, functional MRI work by Carhart-Harris and colleagues reportedly showed reduced amygdala and hippocampus activity and an attenuation of negative-memory magnitude under MDMA. Regarding safety, the authors distinguish clinical MDMA (pure compound, medically supervised, moderate and infrequent dosing) from recreational ecstasy (often high, frequent dosing with adulterants and poly-drug use). They report that controlled clinical studies have not demonstrated significant neurophysiological impairments or evidence of dependence following clinical MDMA use and state there is no evidence that pure MDMA used in therapy causes lasting physiological or psychological harm. The extracted text cites epidemiological evidence challenging earlier fears of lasting neurophysiological damage associated with ecstasy use, but does not present new adverse-event data or detailed incidence rates.
The authors interpret the assembled clinical, behavioural and neurobiological evidence as indicating that MDMA is a promising adjunct to psychotherapy, particularly for treatment-resistant PTSD, and that the balance of evidence supports continued and expanded clinical research. They place these findings in historical context: MDMA was used therapeutically in the 1970s, research was curtailed after recreational use proliferated in the 1980s, and clinical investigation has slowly resumed in the past decade. A principal policy argument presented is that current Schedule 1 classification in the UK is not evidence-based and impedes medical research; moving MDMA to Schedule 2 would align its regulatory status with other misused but therapeutically used substances (for example heroin and amphetamine) and would facilitate clinical trials and therapeutic development. The authors note practicalities of UK regulation: the Advisory Council on the Misuse of Drugs can recommend rescheduling to the Home Secretary and the UK is not legally bound to follow UN scheduling decisions, citing past national deviations as precedent. The paper outlines the research agenda: further Phase II studies are underway, Phase III trials are planned internationally, and additional mechanistic imaging and experimental studies (including trials in autism-related anxiety) are in progress. The authors argue that rescheduling would not necessarily increase illicit ecstasy use, drawing parallels with the limited diversion of pharmaceutical heroin, and they frame the public-health trade-off by contrasting the relatively low risks associated with supervised therapeutic MDMA against the substantial burden and suicide risk among individuals with untreated, treatment-resistant PTSD. The extracted text does not present a formal limitations subsection, but by its nature as a narrative commentary it does not provide systematic methods or new primary data, which constrains the strength of empirical claims.
The authors conclude that legislative restrictions on MDMA have been applied in ways that are not supported by the available evidence and that these restrictions have impeded valuable clinical research. They call on regulatory authorities to consider reclassifying MDMA from Schedule 1 to Schedule 2 so that its relative harms and therapeutic potential can be more accurately reflected and so that further research into MDMA-assisted treatment for PTSD and other brain disorders can proceed.
First synthesised in 1912 by the German pharmaceutical company Merck as a chemical precursor, MDMA failed to make an impact on the 1960s drug scene. In the 1970s a few psychotherapists were using it legally as a tool in couples therapy, where it was seen to help traumatised clients address repressed emotional memories without being overwhelmed by the negative affect that usually accompanies such memories. It was then banned in the mid-1980s in the wake of growing recreational use. No placebo-controlled studies were conducted with MDMA in the 1980s, but case-control studies showed MDMA could be used without adverse effects to produce qualitative improvements in psychological functioning and resolution of relationship difficulties.
A recent placebo-controlled study of participants with treatmentresistant PTSD showed that 85% of those in the MDMA group (compared with 15% in the placebo group) no longer had a diagnosis of PTSD after three sessions of MDMA-assisted psychotherapy.These results were sustained at 3.5 years longterm follow-up, with no further MDMA interventions required and many patients reducing or stopping their regular psychiatric medications.A subsequent Swiss MDMA study demonstrated substantial improvements for treatment-resistant PTSD.How MDMA may work as an adjunct to psychotherapy MDMA exerts its effects through 5-hydroxytryptamine (5-HT) 1A , 5-HT 1B , 5-HT 2A , dopamine and alpha-2 receptors. It also produces oxytocin release, which improves bonding and raises levels of empathy. Its multiple and varied effects make the drug a good candidate for facilitating psychotherapy -especially for patients with post-traumatic symptoms, in which helping the patient to reach a position of empathic understanding and compassionate regard is part of their resolution and remittance of symptoms.Participants given MDMA are more likely to use words relating to friendship, support and intimacy, in comparison to the drug methamphetamine, which by contrast reduced participants' discussions about compassion.MDMA appears to enhance the quality of social interactions and thereby improve relationships, recently tested using a simulated experimental paradigm of social exclusion by Frye et al, showing how participants taking MDMA exhibited reduced social exclusion phenomena.Similarly, MDMA enhances levels of shared empathy and prosocial behaviour compared with placebo.Furthermore, Wardle et al showed how MDMA can facilitate a faster detection of happy faces, and reduces the detection of negative facial expressions, which leads participants to view their social interaction partner as more caring.A recent study by Kirkpatrick et al comparing MDMA against intranasal oxytocin demonstrated the former produced greater improvements in prosocial communication.And the positive effects of MDMA appear consistent across different environments, with participants examined in San Francisco, Chicago and Basel demonstrating broadly similar prosocial outcomes.Recently, several groups have used neuroimaging to explore the actions of MDMA in the brain. For example, Carhart-Harris et al, using magnetic resonance imaging blood oxygen leveldependent and arterial spin labelling techniques, showed that MDMA reduced amygdala and hippocampus activity and selectively attenuated the magnitude of negative memories.Making a medicine out of MDMA Ben Sessa and David Nutt Summary From its first use 3,4,-methylenedioxymethamphetamine (MDMA) has been recognised as a drug with therapeutic potential. Research on its clinical utility stopped when it entered the recreational drug scene but has slowly resurrected in the past decade. Currently there is enough evidence for MDMA to be removed from its Schedule 1 status of 'no medical use' and moved into Schedule 2 (alongside other misused but useful medicines such as heroin and amphetamine). Such a regulatory move would liberate its use as a medicine for patients experiencing severe mental illnesses such as treatment-resistant post-traumatic stress disorder.
One must distinguish the clinical use of pure MDMA from the recreational use of ecstasy. The former involves moderate, infrequent medically supervised doses whereas the latter often involves high and frequent use, the risk of adulterants and the concomitant use of other drugs -especially cannabis, amphetamine and cocaine. There is no evidence that pure MDMA as proposed for therapy causes any lasting physiological or psychological harm.None of the controlled studies of MDMA-assisted therapy has demonstrated any significant neurophysiological impairments or evidence of dependence following its use clinically, validating the observed low risk of addiction when used recreationally. The fears about lasting neurophysiological damage, popularised in the 1990s, have since been challenged, further validating the epidemiological evidence of low rates of clinical problems associated with ecstasy use, despite its widespread popularity.The concept of risk-benefit analysis is important when considering any medical interventions -pharmacological or otherwise. With dozens of individuals with post-combat treatment-resistant PTSD dying by suicide every day,the massive social, financial and clinical burden of untreated PTSD is a far greater risk to society than the low risks associated with using MDMA in the clinical setting.
Further Phase II MDMA-assisted psychotherapy for PTSD studies are happening, after which Phase III studies are planned across the globe. A planned functional magnetic resonance imaging study at Cardiff University will explore MDMA's mechanism in individuals with post-combat PTSD to add more physiological data to the ongoing therapeutic studies. And an ongoing study underway in the USA is exploring MDMA's ability to boost empathy and for adults with anxiety associated with autism.But for MDMA to become a medicine it needs to be removed from Schedule 1 and put alongside other therapeutic (but also misused) stimulants such as amphetamine and methamphetamine in Schedule 2. If the UK government advisory body on drugs, the Advisory Council on the Misuse of Drugs, recommends this to the Home Secretary, regulations can then be amended within weeks. It is important to note that the UK is not legally obliged to adopt the UN structure for scheduling drugs; and based on medical advice put heroin in Schedule 2 against the UN recommendation. Similarly, in another example the UN placed tetrahydrocanibinol in Schedule 1 in 1971, but in the UK it is available (in the form of the drug sativex) and placed in Schedule 4. Moreover there is no reason to suppose putting MDMA into Schedule 2 would have any impact on illicit use of ecstasy, just as pharmaceutical heroin in Schedule 2 is almost never diverted into criminal hands. We call on the Advisory Council on the Misuse of Drugs to recommend MDMA become a Schedule 2 drug. This will allow medical research to explore the full potential of MDMA as a medicine for treatment-resistant PTSD and other possible brain disorders.
MDMA has been subjected to inappropriate, non-evidence-based, legislative restrictions. These have not effectively reduced the harm or burden of recreational ecstasy use on society but they have effectively held back research on clinical MDMA. We urge the regulatory authorities to consider whether a move from Schedule 1 to Schedule 2 might more accurately reflect MDMA's relative harms and safety, while also facilitating greater research of the substance for possible therapeutic uses within psychiatry.
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´dric, C., Hysek, M., Schmid, Y. et al. · Social Cognitive and Affective Neuroscience (2013)
Wardle, M. C., De Wit, H. · Psychopharmacology (2014)
Kirkpatrick, M. G., Lee, R., Wardle, M. C. et al. · Neuropsychopharmacology (2014)
Carhart-Harris, R. L., Murphy, K., Leech, R. et al. · Biological Psychiatry (2015)
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