Equasy revisited.

3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, was developed by Merck over a century ago and was used by clinicians in the 1970s to augment psychotherapy. MDMA was also widely used recreationally and this led to legal prohibitions in many countries. In the United Kingdom, MDMA was made illegal in 1977 by a modification order to the existing Misuse of Drugs Act (1971). In the USA the decision to make MDMA as a Schedule 1 drug was controversial, and some argued that the therapeutic uses of MDMA had not been sufficiently considered. As we have seen in the COVID-19 pandemic, politics can trump science and perhaps one of the more egregious examples of this was the reaction to an editorial in this Journal by Professor Nutt (2009) in which he tried to set the potential harms of MDMA in context and was then subsequently dismissed by the UK Home Secretary from his position as the chairman of the Advisory Council on the Misuse of Drugs. Following this, recognition of potential therapeutic benefits led eventually to the Food and Drug Administration granting breakthrough therapy designation for MDMA use with psychotherapy for post-traumatic stress disorder (PTSD) in 2017, thus providing some retrospective vindication for Nutt. The story of ecstasy has clearly been agonising at times over recent decades and often coloured by politics, but the question remains, what does the science show and has the balance of benefits and risks changed? We have five papers in this edition of the Journal which add to this literature. Firstly, the systematic review by Illingworth et al. (2021) reports therapeutic benefit with minimal physical and neurocognitive from the use of MDMA-assisted psychotherapy in treatment with resistant PTSD. Although bigger trials are called for, one can only speculate as to the number of persons in treatment with resistant PTSD who might have been helped if such research on MDMA’s putative benefits had been permitted sooner. Oeri (2021) reviews the existing literature of benefits and harms for several entactogenic drugs, with a few compounds from these classes identified as potential alternatives to MDMA. Van Amsterdam et al. report the results of a multi-decision, multicriterion decision analysis and how this might contribute to MDMA policy. They conclude that their results provide a feasible and realistic set of policy instrument options to revise the legislation towards a rational MDMA policy, that is likely to reduce both adverse (public) health risks and MDMA-related criminal burden (van Amsterdam et al., 2021). Borissova et al. (2021) conducted a double-blind, placebocontrolled experiment examining the effects of MDMA on trust, co-operative behaviour and empathy and interestingly report no increase in prosocial behaviour in a laboratory setting. The last MDMA paper in this edition of the Journal is by Studerus et al. (2021) who examined the prediction of MDMA response in healthy humans in a pooled analysis of placebo-controlled studies and concluded that both pharmacological and nonpharmacological (notably personality traits) variables influence the response to MDMA. What might we conclude from these papers over a decade after the original ‘Equasy’ editorial? A few points might be agreed by all, namely MDMA remains a medicine with therapeutic potential, the evaluation of benefits and harms of this drug for various illnesses is a legitimate exercise and finally science should guide our efforts, rather than politics, wherever possible. This edition of the Journal has more than MDMA papers however, with fascinating papers on the association of the OPRM1 A118G polymorphism and Pavlovian-to-instrumental transfer and the clinical relevance for alcohol dependence (Sebold et al., 2021); a profile of a short-acting kappa-antagonist, LY2795050, on self-grooming behaviours, forced swim test and locomotor activity (Butelman et al., 2021); a report that projection-specific dopamine neurons in the ventral tegmental area participated in morphine-induced hyperalgesia and antinociceptive tolerance in male mice (Sun et al., 2021); a [11C] carfentanil molecular imaging study (Ashok et al., 2021) and a finding that cocaine-specific speed-accuracy trade-off during anti-saccade testing differentiates patients with cocaine use disorder who achieve initial abstinence during treatment (de Dios et al., 2021). Of course, many of the drugs studied in these scientific papers are, like MDMA, agents which have important legal, social and political connotations. Such is the nature of Psychopharmacology. Lastly, we note with great regret the recent passing of two seminal figures in Psychopharmacology, Richard Green and Malcolm Lader. They will be much missed figures and we commend to all the full obituaries which are available and which detail the outstanding scientific contributions and fully lived Equasy revisited