This commentary article (2016) by Mithoefer, Grob, and Brewerton gives an overview of recent research into psilocybin and MDMA.
4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.
Grob and colleagues frame their Personal View against a longstanding clinical problem: conventional psychopharmacology and psychotherapy, while beneficial for many patients, often fail to cure underlying psychiatric disorders and can be limited by modest efficacy, non-response, and adverse effects from long-term dosing. The authors note growing interest in improving psychological treatments, especially for conditions such as post-traumatic stress disorder (PTSD), existential distress at the end of life, and treatment-resistant disorders, and they highlight patient preference for psychotherapy over medication as a further impetus for novel approaches. This paper outlines and evaluates a model in which classic psychedelics (psilocybin) and the entactogen MDMA are administered on one or a few occasions to catalyse or augment psychotherapy. Rather than presenting these compounds as daily pharmacotherapies, Grob and colleagues describe them as adjuncts that can facilitate intense therapeutic experiences thought to produce rapid and potentially durable clinical benefits. The authors state their aim as reviewing evidence from early and recent clinical studies of psilocybin- and MDMA-assisted psychotherapy, discussing mechanisms, safety considerations, challenges (for example masking), and directions for future research.
Papers cited by this study that are also in Blossom
Grof, S., Goodman, L. E., Richards, W. A. · Pharmacopsychiatry (1973)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
This article is a narrative Personal View rather than a systematic review or meta-analysis. The authors drew on literature known to them from prior investigational new drug work and symposium preparation, supplemented by targeted searches using PubMed and Google Scholar when specific questions arose. They state that these additional searches were not planned prospectively and that reference selection was therefore not systematic. When describing specific clinical trials and pilot studies, the paper relies on published reports, earlier research from the 1950s–1970s, and information provided to the authors via personal communication from investigators running more recent trials. The authors also reference safety guidelines developed by the Johns Hopkins psilocybin research group and report on phase 1 and phase 2 clinical trials of MDMA and psilocybin; details of individual trial designs (for example double-blind, placebo-controlled designs) are summarised in the text where available. Where fMRI or other mechanistic substudies are mentioned, the paper notes that some results are pending or that protocols are planned.
Psilocybin-assisted psychotherapy: Early mid-20th-century investigations suggested therapeutic potential for classic hallucinogens in treatment-refractory conditions, but research largely halted for political reasons. More recently, small clinical studies have reopened investigation. A double-blind, placebo-controlled crossover study at Harbor-UCLA (12 patients serving as their own controls) administered a moderate dose of psilocybin (0.2 mg/kg) and reported safe physiological and psychological responses, no clinically significant adverse events during sessions, and significant reductions in anxiety measured by the State-Trait Anxiety Inventory at 1 and 3 months after treatment. Mood improvement measured by the Beck Depression Inventory reached significance at 6 months. The authors note that higher-dose trials at Johns Hopkins and New York University have regulatory approval and that publication of those results was expected (personal communication). Additional findings summarised include a Swiss LSD study that showed a strong effect size for reduction in state and trait anxiety, and a pilot study by Bogenschutz and colleagues in which a single dose of psilocybin reduced drinking behaviour and craving in ten individuals with alcohol use disorder. Mechanistically, psilocybin's neuropharmacology is linked primarily to agonism of serotonergic 5-HT2A receptors, with downstream second-messenger and gene-expression effects likely contributing. Safety guidance and careful screening are emphasised as essential to minimise risks. MDMA-assisted psychotherapy: MDMA was used clinically in the late 1970s and early 1980s and has been studied more formally in recent decades. The authors report that more than 1100 individuals have received MDMA in Phase I or Phase II trials without unexpected drug-related serious adverse events; the sole reported drug-related serious adverse event was transient ventricular ectopy requiring overnight observation. Two completed double-blind, placebo-controlled Phase II trials for treatment-resistant PTSD are described. In the first completed Phase II trial of 20 chronic, treatment-resistant PTSD patients, those randomised to MDMA with psychotherapy experienced significantly greater reductions in PTSD symptoms than those given inactive placebo with psychotherapy; 83% of the MDMA group no longer met criteria for PTSD versus 25% of placebo participants. When the placebo group later received open-label MDMA-assisted psychotherapy, they achieved similar improvement. A long-term follow-up (mean 45.4 months after treatment) found that at least 74% had durable remission of PTSD symptoms. A Swiss study with 12 patients did not reach statistical significance on Clinician-Administered PTSD Scale reductions but reported an effect size greater than 1 and significant reductions on the Posttraumatic Diagnostic Scale. Mechanistic and ancillary findings: The paper summarises putative mechanisms for MDMA's facilitative effects on psychotherapy, including monoamine release (serotonin primarily, with dopamine and norepinephrine), oxytocin and prolactin release, and functional brain changes such as decreased amygdala and hippocampal activity and altered resting-state functional connectivity. Small neuroimaging substudies are underway or planned; for example, a substudy of MP-8 examining fMRI before and after MDMA-assisted psychotherapy is noted as having results pending. The authors also highlight practical challenges such as difficulty maintaining masking (blinding) because of the prominent subjective effects of these drugs, and they report that some psilocybin studies have used active placebos or open-label designs.
Grob and colleagues interpret the accumulated evidence as suggestive that psilocybin and MDMA, when used in carefully controlled settings alongside structured psychotherapy, have therapeutic promise for populations that are often refractory to existing treatments, including patients with end-of-life anxiety, alcohol use disorder, and chronic PTSD. They emphasise that the treatment model differs from standard daily pharmacotherapy: these compounds are administered on one or a few occasions to catalyse a therapeutic process, with substantial preparatory and integration psychotherapy before and after drug sessions. The authors point out differences in session structure between the two approaches: MDMA sessions typically alternate talking with periods of inner focus, whereas psilocybin sessions concentrate inner focus during the drug effect with more talking before and after. The paper acknowledges important limitations and uncertainties. Sample sizes in many clinical studies have been small, some trials were open-label or used imperfect active placebos, and research was historically impeded by regulatory and political barriers. Debates persist about the neurotoxic risks observed in some retrospective studies of recreational MDMA users; the authors note methodological confounders in that literature and stress the need for rigorous prospective safety data. Masking remains a methodological challenge because the drugs' subjective effects are conspicuous, although blinded independent raters are feasible and could be further protected in larger trials. In terms of implications, the authors call for expeditious, rigorous clinical trials to establish efficacy and safety, identification of suitable patient populations, elucidation of neuropsychopharmacological mechanisms, and development of standardised safety and treatment manuals. They also encourage qualitative analyses of the extensive video archives from recent studies to study phenomenology and recommend that research and funding decisions be driven by scientific evidence and patient needs rather than political or financial pressures. The authors underscore the importance of maintaining strict screening and monitoring procedures to reduce risk in clinical research settings.
Advances in psychopharmacology during the past 60 years have benefi ted millions of patients with debilitating but common psychiatric disorders. However, approved psychopharmacological drugs have fallen short of defi nitively correcting underlying pathology and curing psychiatric illness. Antipsychotics, antidepressants, anxiolytics, and mood stabilisers can help to decrease symptoms, and can even be life-saving for some patients; however, for many, the benefi ts are disappointing, and the side-eff ects of long-term daily use can be problematic. Advances in evidence-based psychotherapy have yielded improved treatments for several disorders, including post-traumatic stress disorder (PTSD) and anxiety associated with lifethreatening illness. Psychological treatments seem to be more eff ective than medications for PTSD; 1 however, a large percentage of patients do not respond adequately to psychotherapy, with or without concomitant medications.Interest is also growing in development of more eff ective psychotherapy for existential suff ering at the end of life.Research into methods to improve psychological treatments is especially important in view of a 2013 meta-analysisreporting that patients' preference for psychotherapy is three times greater than for medication. In our experience, most clinicians who treat psychiatric patients are all too familiar with the suff ering and frustration endured by those who try successive medications, often with several drugs, but do not fi nd relief or cannot tolerate the side-eff ects. Likewise, patients frequently do not make adequate progress in psychotherapy, or drop out because they are not able to tolerate emotionally challenging aspects of treatment such as prolonged exposure. The need for new approaches to psychological treatments is clear. The limitations of existing pharmacotherapy and psychotherapy and the paucity of resources for psychotherapy research and treatment leave millions of patients suff ering, and psychiatrists are faced with what has been called psychiatry's identity crisis.A promising new model of treatment is under investigation in a resurgence of research into use of psychedelic drugs to augment psychotherapy. In this model, the drug is used on one or a few occasions during psychotherapy sessions to overcome obstacles to successful psycho therapy and to catalyse a therapeutic experience. It is theorised that the experience itself, rather than simply the pharmacological eff ects of the drug, might lead to cure or sustained remission of severe, treatment-refractory psychiatric disorders. Results of both early and recent studies of 4-phosphorloxy-N,N-dimethyl tryptamine (psilocybin) or methylene dioxymetham fetamine (MDMA) in conjunction with psycho therapy off er the possibility of rapid, comprehensive, and lasting psychological healing and growth, and raise many intriguing questions about the mechanisms and clinical applicability of this model of treatment. Therapeutic approaches used in psilocybin and MDMA studies overlap substantially, but the two drugs have been studied for diff erent indications in most cases. Both approaches include inner focus and talking with therapists; however, in MDMA-assisted sessions, periods of talking generally alternate with periods of inner focus, whereas in psilocybin-assisted sessions, most of the talking occurs before and after the period of drug eff ect. We discuss psilocybin and MDMA separately.
The classic hallucinogen psilocybin exists in nature as an active alkaloid in more than 100 species of mushrooms. Although used for healing and divination in many indigenous cultures in South and Central America, psilocybin was not discovered by Western cultures until the 1950s.During the 1950s to early 1970s, together with the better known lysergic acid diethylamide (LSD), psilocybin was used in investigations in human beings. In addition to their range of eff ects on CNS function, psilocybin and LSD had promising therapeutic potential in preliminary studies, most interestingly in patients with various treatment-refractory disorders. Unfortunately, these studies were brought to an abrupt halt, as a result of the notorious so-called culture wars of that era.
One population in which this novel psychedelic treatment model is showing promising results, and for whom conventional treatments have long been known to be inadequate, are patients with advanced-stage cancer with severe reactive anxiety. Results of a series of studies done several decades ago showed subtantive and sustained reductions in anxiety, improved mood, and enhanced quality of life in patients with terminal cancer after one closely monitored dose of LSD or di-propyltryptamine (DPT), a compound chemically related to psilocybin.More recent investigations have corroborated these early fi ndings, with moderate-dose psilocybin as the active agent for a one-session treatment model (table).The fi rst study in more than 30 years to investigate the potential of a classic hallucinogen treatment model in patients with advanced cancer and anxiety, at Harbor-UCLA Medical Center (Torrance, CA, USA) and the Los Angeles BioMedical Research Institute (Torrance, CA, USA) and supported by the Heff ter Research Institute (Santa Fe, NM, USA), used a double-blind, placebocontrolled research model.12 patients functioning as their own controls were given two separate experimental treatment sessions 1 month apart, receiving the active drug, psilocybin, on one occasion and placebo on the other, in a random order. All patients were screened and prepared through several meetings with treatment staff to establish rapport and acquire understanding of the range of altered states of consciousness that they might encounter during their treatment sessions. Follow-up data were collected for 6 months after the second treatment session. Results included safe physiological and psychological responses during treatment sessions. No clinically signifi cant adverse events were noted. Signifi cant reductions in anxiety at 1 month and 3 months after treatment were measured with the State-Trait Anxiety Inventory trait anxiety subscale, and an improvement of mood was measured with the Beck Depression Inventory, which reached signifi cance at 6 months. For this fi rst investigation of use of a classic hallucinogen treatment in several decades, a moderate dose of 0•2 mg/kg bodyweight was used. Subsequently, two other research groups, at Johns Hopkins University (Baltimore, MD, USA) and New York University (New York, NY, USA), have received approval from the US Food and Drug Administration (FDA) to use a higher dose in a similar population of patients. Publication of the results of these larger-scale studies is expected to be forthcoming (Roland Griffi ths [Johns Hopkins University School of Medicine, Baltimore, MD, USA] and Stephen Ross [New York University, New York, NY, USA], personal communication). A similar study in Switzerland with LSD rather than psilocybin showed a strong eff ect size in reduction of state and trait anxiety.One line of inquiry that has emerged from research done in the 1960shas been the study of the range of profound psychospiritual experiences that might be induced by psychedelic drugs when administered under optimal conditions (set and setting), and their role in achieving therapeutic outcomes.The capacity to activate innate mechanisms for psychospiritual healing, especially in individuals with life-threatening medical illness and severe existential anxiety, depression, and demoralisation, might be an important advance for the healing arts and medicine. This shift is taking place in the context of major developments in neurotheology, which are elucidating the biological or brain basis of religious or spiritual experiences.Results of carefully undertaken studies at Johns Hopkins University showed that screened healthy volunteers treated under optimal conditions with high-dose psilocybin reliably experienced profound mystical experiences (defi ned as encountering a profound sense of unity, transcendence of time and space, deeply felt positive mood, noetic quality, ineff ability, transiency, and paradoxicality) infused with a renewed sense of purpose and meaning, that even more than a year later retained their personal value.The association between psychedelic-induced mystical experience and therapeutic outcome when psychedelic drugs are given under optimal conditions provides a potentially valuable therapeutic intervention for disorders that are otherwise diffi cult to treat, including end-of-life anxiety and alcoholism-a very dangerous disorder with high rates of resistance to existing treatments, and the focus of several promising research studies starting in the 1950s and continuing until the early 1970s.This strategy has also been studied as part of a potential treatment model at the University of New Mexico (Albuquerque, NM, USA) and New York University. For example, Bogenschutz and colleaguesshowed that a single dose of psilocybin resulted in reductions in drinking behaviour and craving in ten individuals with alcohol use disorder. In a pilot The neuropsychopharmacological mechanisms of action of psilocybin and other similar psychedelic drugs are thought to be mediated via fairly specifi c binding to serotonergic 5-HT 2 receptors, primarily 5-HT 2A receptors, although non-5-HT 2 receptors are probably also involved.Downregulation of 5-HT 2A receptors mediates antidepressant and antianxiety eff ects of antidepressants and atypical antipsychotics.Because of the high binding affi nity of psilocybin and other psychedelic drugs to the 5-HT 2A receptor, it might produce its eff ects in human beings mostly, but not wholly, through modulation of 5-HT 2A receptors, in addition to complex downstream second messenger signalling and gene-expression eff ects.In view of the long-standing Western cultural reputation of psychedelic drugs as dangerous drugs of abuse, when taken recreationally by vulnerable individuals under uncontrolled and high-risk conditions, to establish and maintain strong safety parameters is essential when undertaking modern, approved research into the therapeutic potential of psychedelic drugs. Careful investigation of the extensive psychiatric research record with psychedelic drugs from the 1950s to early 1970s identifi ed an extremely small number of adverse outcomes in formal research studies.An important contribution by the Johns Hopkins psilocybin research group is a set of safety guidelines for clinical research with hallucinogens,which should be used as standard in this rapidly changing fi eld. Careful screening and monitoring, specifi cally for underlying psychological and cardiovascular vulnerabilities, substantially reduce risks incurred by unwitting recreational users.
MDMA has become infamous for its use as the purported ingredient in recreational ecstasy, although results of surveys have shown that drugs other than MDMA were present in a high proportion of collected samples.Less well known is that in the late 1970s and early 1980s, before MDMA became an illegal Schedule 1 compound, it was used in conjunction with psychotherapy by an estimated 4000 psychiatrists and psychologists.MDMA has been called an entactogen, meaning literally "to produce touching within", referring to its tendency to enhance inner awareness and distinguishing it from classic psychedelic drugs such as psilocybin.Case reports of successful clinical use were published, but no controlled research was done at that time.Descriptions of the therapeutic process catalysed by MDMA suggested that it might be especially useful for treatment of PTSD. For example, Greer and Tolbert 39 stated that, "clients found it comfortable to be aware of, to communicate, and to remember thoughts and feelings that are usually accompanied by fear and anxiety". Because of the urgent public health need for a wider range of eff ective PTSD treatments, these promising reports should have quickly led to formal investigations of the potential risks and benefi ts of MDMA as a therapeutic agent. Unfortunately, a hostile regulatory and funding climate inhibited research of MDMA treatment for nearly 20 years. Meanwhile, a large amount of money has been spent worldwide on preclinical research, retrospective studies in recreational ecstasy users, and a few phase 1 trials in healthy volunteers assessing the risks of MDMA without investigation of the possible benefi ts. From the mid-1980s to early 2000s, substantial US National Institutes of Health (NIH) investment was made to investigate serotonin and dopamine neurotoxicity induced by MDMA, in animals and human beings, although careful inspection of many of these studies identifi ed fl aws in the methods.Fortunately, now that the benefi ts as well as the risks are being studied with rigorous research designs, existing preclinical and retrospective data are available to the non-profi t research sponsors who have taken up the eff ort. As a result, far more is known about the range of eff ects and the risks of MDMA, which has been taken by millions of people worldwide, than about usual investigational new drugs. A comprehensive discussion of MDMA toxicity is beyond the scope of this Personal View, and possible neurotoxic eff ects in recreational users are still under debate. When used in high-risk contexts, MDMA can be dangerous, and rarely recreational users have died, usually of heat stroke and dehydration during raves or of brain oedema from over-hydration in an ill-informed attempt to avoid dehydration. A specifi c area of concern regarding possible MDMA toxicity comes from studies of recreational users, some of whom performed more poorly on memory tests than did controls who did not use drugs.Almost all studies in this population have been retrospective, and are fraught with problems with methods, such as polydrug use and uncertainty about the composition of drugs taken.The study best designed to minimise these confounders identifi ed "little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic self-regulation… [that] might have refl ected a pre-morbid attribute of ecstasy users".This subject has been debated at length in the medical literature, and the most evidence supports continued investigation of the therapeutic benefi ts of MDMA (reviewed by Doblin and colleagues).Many approved and clinically useful psychiatric medications are well known to have dose-dependent and frequencydependent neurotoxic eff ects. The risks of these drugs are
often judged to be acceptable compared with the untreated disease state in question. MDMA and psilocybin have the advantage of being given only once or a few times rather than daily for months or years. What is most relevant to risk/benefi t calculations for clinical research and possible clinical use is evidence that pure MDMA in moderate doses can be given safely to individuals participating in clinical trials in controlled medical settings. More than 1100 individuals have received MDMA in phase 1 or phase 2 clinical trials so far without any unexpected drug-related serious adverse events. The only drug-related serious adverse event reported was a transient increase in pre-existing ventricular ectopy requiring overnight observation; there was no associated cardiac disease identifi ed on further cardiac work-up. A phase 2 study in patients with PTSD that included neuropsychological testing before and after two doses of MDMA or inactive placebo reported no evidence of impairment.So far, two phase 2 clinical trialstesting MDMAassisted psychotherapy for treatment-resistant PTSD have been completed. In view of their encouraging results, these double-blind, placebo-controlled trials support the hypothesis that MDMA, used as a catalyst to psychotherapy, can be eff ective in treatment of PTSD in patients who did not respond to previous psychotherapy or medications. Similar additional trials are underway in the USA, (ClinicalTrials.gov, numbers NCT01458327, NCT01211405, and NCT01793610), Canada (ClinicalTrials.gov, number NCT01958593), and Israel (ClinicalTrials.gov, number NCT01689740). An earlier phase 2 dose-escalation trial started in Spain in 2000, but was terminated because pressure from the Madrid Anti-Drug Authority led to permission to use the study site being revoked. No medical or scientifi c reasons existed for termination of the study.In the fi rst completed phase 2 trial, in 20 patients who had not responded to both psychotherapy and pharmacotherapy (with average duration of PTSD of >20 years), participants randomly assigned to MDMA with psychotherapy had signifi cantly greater decreases in PTSD symptoms than did participants assigned to receive inactive placebo with the same psychotherapy, and 83% no longer met criteria for PTSD, compared with 25% of placebo participants.When seven of the eight patients in the placebo group subsequently received MDMA-assisted psychotherapy in an openlabel crossover group, they all achieved roughly the same level of improvement as the original MDMA group. A long-term follow-up study a mean of 45•4 months (range 17-74, SD 17•3) later reported that at least 74% had durable remission of PTSD symptoms.A similar study in Switzerland with 12 patients did not reach statistical signifi cance in Clinician Administered PTSD Scale score reductions, but nevertheless did have a strong eff ect size of more than 1, and showed signifi cant reductions in the Posttraumatic Diagnostic Scale.The success of MDMA-assisted psychotherapy in these studies was not simply due to replacing one form of psychotherapy with another, or one drug with a more eff ective drug; rather it is an altogether diff erent approach that could apply to various psychoactive compounds. This approach involves use of a drug to support and catalyse a more eff ective therapeutic process by stimulating access to an individual's innate ability to engage in his or her own unique course of healing. Participants in these clinical trials, in addition to showing improvements in validated measures of PTSD symptoms, often report deeply meaningful therapeutic experiences and ensuing improvements in various areas of their lives. On long-term follow-up questionnaires, most participants endorsed benefi ts such as "increased self-awareness and understanding" and "enhanced spiritual life".These responses suggest a subjectively authentic process of psychological and spiritual exploration and growth that could logically be expected to enable trauma processing and symptom reduction, and to promote healthy psychological development. These results are based not on daily medication doses, but on two or three doses of MDMA, spaced several weeks apart, during 8-h psychotherapy sessions in which periods of inner focus are as important as periods of interaction with the therapists. Furthermore, the therapeutic process is not limited to the period of drug eff ect (MDMA has a half-life of about 8 h),but continues over time.Accordingly, MDMA research protocols include follow-up non-drug psychotherapy sessions to support the ongoing lessons and challenges of integrating the resulting psychological changes into daily life. The mechanism of action of MDMA as a catalyst to psychotherapy is the subject of ongoing research, so our observations about it are speculative. During MDMAassisted psychotherapy sessions, we observe a decrease in avoidance and defensiveness accompanied by clearer memory of past events, and willingness and ability to process them. Additionally, MDMA research participants often show a new awareness of their own counterproductive patterns of emotional and cognitive response to trauma, and a capacity for fearless and compassionate reappraisalin many ways the ideal eff ects to augment psychotherapy. MDMA does not make revisiting traumatic memories easy, and certainly not ecstatic, but it can make it possible for individuals who had not been able to process trauma eff ectively during months or years of psychotherapy. This eff ect can be conceptualised in various ways: that the prosocial eff ects of MDMA might improve the therapeutic alliance with patients who have diffi culty trusting; that MDMA in a therapeutic set and setting provides several hours in the optimal arousal zone, during which therapeutic change is possible; 55 that MDMA enables memory retrieval and reconsolidation with new associations to safety; or that MDMA causes a shift from constrained styles of thinking to less rigid, unrestrained thinking.Each of these concepts is consistent with what is known about the physiological Personal View eff ects of MDMA, which include: release and reuptake inhibition of serotonin, and to a lesser extent dopamine and norepinephrine; release of oxytocin and prolactin; decreased activity in amygdala and hippocampus,and perhaps increased activity in medial prefrontal cortex;increase in resting state functional connectivity (RSFC) between amygdala and hippocampus; and decreased RSFC between ventromedial prefrontal cortex and posterior cingulate cortex.Additionally, healthy volunteers given MDMA have reported a less negative response to worst autobiographical memories, and fMRI data showed attenuated activation to worst memories in the left anterior temporal cortex.Several studies are underway to further elucidate MDMA's therapeutic mechanisms. A substudy of MP-8 (table) has examined fMRI with trauma script exposure before and after MDMA-assisted psychotherapy (results pending; ClinicalTrials.gov, number NCT02102802), and another study of individuals with PTSD examining fMRI with trauma script exposure during peak MDMA eff ects is planned at Cardiff University (Ben Sessa, Imperial College London, London, UK, and Cardiff University, Cardiff , Wales, UK, personal communication). An additional group of patients in whom an MDMA treatment model is being investigated are adults on the autistic spectrum with social anxiety. An ongoing FDA-approved double-blind, placebo-controlled study (ClinicalTrials.gov, number NCT02008396) is using two closely monitored sessions of moderate-dose MDMA in a screened population naive to the drug.Although outcome data are masked until the conclusion of the study, physiological and psychological safety have thus far been carefully monitored and maintained. In addition to clinical outcomes, primarily social anxiety, the study is also assessing the roles of the neurohormones oxytocin and vasopressin, which have been reported to be sensitive to MDMA and have a role in interpersonal connections and bonding.
MDMA-assisted psychotherapy and psilocybin-assisted psychotherapy clearly diff er in many ways from most established methods of psychotherapy. The structure, including 8-h psychotherapy sessions, is unusual, and therapists take a fairly non-directive approach. However, to think that what happens in MDMA-assisted sessions would be unfamiliar to therapists experienced in other methods, or that MDMA might be incompatible with various existing therapies, would be a mistake. MDMAassisted sessions often include imaginal exposure, correction of cognitive distortions, insights about psychodynamics and transference, and other recognisable therapeutic elements. In MDMA-assisted sessions, these elements often occur spontaneously with little or no direction from therapists. The therapeutic method used in MDMA studies is described in detail in our Treatment Manual,and overlap with other therapies has previously been discussed.
The prominent subjective and objective eff ects of MDMA and psilocybin make masking of investigators and research participants more diffi cult than it is in studies of many other classes of drugs. Attempts to address this problem by use of low doses of MDMA as an active placebo have had little success (ClinicalTrials. gov, numbers NCT01211405, NCT01793610). Use of other active placebos has been an important aspect of research methods in most recent psilocybin studies. Some of the psilocybin pilot treatment studies were open label,whereas others have used various active placebos.Eff ective masking of independent raters has been much easier to accomplish, and could be strengthened further in phase 3 trials by randomly assigning each assessment to a blinded rater from a centralised pool.
In order for medical interventions to be based on valid science, clinical trials should be rigorously designed and undertaken. It is also essential that pursuit of research into promising potential treatments is neither neglected nor blocked by outside forces. In our view, psychedelic research should be pursued as expeditiously as possible. When people are suff ering and medicine does not have an adequate response, many will seek alternative treatments. Ideally, patients should be able to go to their physicians for scientifi cally based guidance and access to the most eff ective treatments; however, many patients
will prove unwilling to wait indefi nitely for this. If we as a profession are not suffi ciently proactive in studying and discovering a range of new treatments, patients will look elsewhere, and will be vulnerable to unproven treatments from unregulated practitioners. Choices about which potential treatments receive research approval and funding should be driven by evidence and patients' needs. Many people do not trust mainstream medicine to advocate their best interests.Sadly, in view of the political and fi nancial forces that have aff ected medical research in the past few decades, their fears are not wholly unfounded. We should acknowledge this reality, and keenly strive for the academic freedom and funding necessary to investigate potential benefi ts of psychedelicassisted psychological treatments. Future studies should expand eff orts to establish effi cacy and safety in patient populations, to identify which patient populations might be most appropriate to treat, which of these compounds should be used, and to elucidate the neuropsychopharmacological mecha nisms of action of MDMA, psilocybin, and other psychedelic drugs (panel). Because recent studies have yielded thousands of hours of video recordings, there is also a rich opportunity to study the phenomenology of MDMA and psilocybin-assisted therapeutic experiences through qualitative research.
Most of the references cited were known to the authors either because they were included in the Investigators Brochure for the author's Investigational New Drug research, were written by the authors, or were read in preparation for the American Psychiatric Association Symposium on which this manuscript is based. Any additional searches were done with PubMed or Google Scholar. These searches were not planned and were done when necessary to answer a specifi c question.
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