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The emerging role of psilocybin and MDMA in the treatment of mental illness


Introduction: Mental illness has a chronic course of illness with a number of clinical manifestations. Affected individuals experience significant functional, emotional, cognitive, and/or behavioral impairments. The growing prevalence of mental illness has been associated with significant social and economic costs. Indeed, the economic burden of mental illness is estimated to exceed $1.8 trillion USD over the next 30 years. A significant number of individuals affected by mental illness fail to respond to first-line treatment options. Therefore, there remains an unmet need for rapidly attenuating therapeutic options for mental health disorders with minimal social and economic burden.

Areas covered: The paucity of novel treatment options warrants a renewed investigation of psychedelic-based psychotherapy. Herein, the authors will evaluate the therapeutic potential of traditional psychedelics, psilocybin, and MDMA, in the treatment of mental illness with a narrative review of available literature.

Expert opinion: Psychedelics, such as psilocybin and MDMA, offer an alternative avenue of therapy for many mental health disorders. Available evidence indicates that psychedelics may offer a single-dose, rapid effect model that have robust effects with treatment-resistant mental disorders and a unique advantage as a possible monotherapy for mental illness. Novel clinical trials that evaluate the safety, tolerability, and efficacy in clinically representative populations are warranted.

Gill, H., Gill, B., Chen-Li, D., El-Halabi, S., Rodrigues, N. B., Cha, D. S., Lipsitz, O., Lee, Y., Rosenblat, J. D., Majeed, A., Mansur, R. B., Nasri, F., Ho, R., & McIntyre, R. S. (2020). The emerging role of psilocybin and MDMA in the treatment of mental illness. Expert review of neurotherapeutics, 20(12), 1263–1273.

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What is the future of legal MDMA?

There has been a renaissance in the research of psychedelics, and much of it has been led by promising studies over the past two or three decades. Aside from the discussion of whether MDMA is a true ‘psychedelic’, it is clear that recent studies have created momentum to reconsider these substances as medication for severe mental health problems such as depression, anxiety or addiction.
MDMA’s application to trauma therapy has become one of the central priorities of psychedelic researchers. So what is the current state of knowledge and where do we stand in the regulatory process? According to MAPS-founder Rick Doblin, MDMA will be legal soon if the hard work continues. “I keep saying it’s going to be 2035”.
MDMA Treatment
Victims of war or sexual assault are prone to develop anxiety and avoidance behaviors as a result of these tragic experiences. Some of them may be diagnosed with Post-Traumatic Stress Disorder (PTSD), a condition characterized by severe feelings of fear and distress in response to trauma-related details. The increasing prevalence of PTSD is aggravated by the lack of treatment options.
Current trauma-focused psychotherapies, such as exposure and cognitive-behavioral therapy, have important problems of access for certain high-risk populations, as well as high dropout rates. In regard to efficacy, some reviews have found that up to 70% of patients retain their PTSD diagnosis after treatment.
The only two pharmaceuticals with FDA approval also seem to be inefficient for many. One third of all PTSD patients are estimated to be treatment-resistant. This diagnosis is given when several different treatments fail to improve symptoms.

MDMA trials have focused on this specific population because of strategic reasons. It is easier to get permission to test a new drug on patients for whom everything else has failed. Psilocybin trials have taken a similar approach by focusing on treatment-resistant depression or anxiety related to the end of life.
Current clinical research employs a hybrid treatment model that combines the administration of 75 to 125mg of MDMA with therapeutic support provided in preparation and integration sessions. During the drug sessions, therapists monitor the patient and adopt a non-directive approach that allows the person under the effects of MDMA to dive into the experience with minimal interruptions. This model of psychedelic-assisted psychotherapy entails a groundbreaking paradigm in psychiatry that goes beyond mere medications and talk therapy.
A long path
It has taken a while before these modern trials were set up. MDMA is an amphetamine derivative first synthesized by Merck Laboratories in 1912 and later rediscovered by chemist Sasha Shulgin in the 1970s. At the time, psycholytic therapy was being developed with LSD and psychiatrists saw a new potential tool for psychotherapy in MDMA and its empathogenic properties.
Unfortunately, the increasing popularity of “Ecstasy” in recreational contexts and the ensuing anti-drug propaganda soon led to the classification of MDMA as a Schedule 1 substance in 1986, which introduced immense obstacles to scientists investigating its medicinal application.
Ever since, the Multidisciplinary Association for Psychedelic Studies has been working for the approval of MDMA as a therapeutic treatment in mental health and to remove the immense barriers that were thrown up for the potential medication.
Although preliminary investigations by Charles Grob had successfully proved the safety of administration of MDMA to healthy subjects in the 1990s, the first MAPS-sponsored trial for PTSD conducted in Spain by José Carlos Bouso was shut down because of political pressure from the Spanish authorities.
Placebo challenges
So far, six phase-2 clinical trials have been completed, and despite the small samples and the methodological limitations, the results are very promising. The first randomized controlled trials with PTSD patients began to take place in the late 2000s, and resulted in a landmark paper from 2011 by Michael Mithoefer, Mark Wagner, Ann Mithoefer, Lisa Jerome, and Rick Doblin. It concluded that ‘the rate of clinical response was 10/12 (83%) in the active treatment group versus 2/8 (25%) in the placebo group’.
One year later, most of these patients for whom all other treatments had failed still showed a persistent and significant improvement. More importantly, the lack of serious adverse effects pointed at the safety of MDMA in a clinical context and paved the way for more trials.

Skeptics pointed at the methodological weaknesses of this first trial. They criticized the use of lactose as placebo and the difficulties to blind the effects of MDMA to patients and investigators, a common problem in psychedelic therapy trials. An attempt of replication in Switzerland by Peter Oehen which circumvented the blinding problem with an active placebo group (25mg MDMA) showed good results, but were not statistically significant.
Researchers suspected that differences in the work and style of the Swiss therapists might have been behind these suboptimal results, which raised the question of how to standardize the psychotherapeutic part of the treatment. In subsequent trials, MAPS developed an adherence rating system in order to ensure that therapists stick to the standard guidelines of their therapeutic model.
In 2018, Michael Mithoefer published the first dose-response study, which compared the efficacy of three different doses of MDMA: 30mg, 75mg and 125mg. The groups with middle and high doses showed significant remission of PTSD with respectively 86% and 58% of each group’s sample not meeting the diagnostic criteria anymore after treatment, improvements which persisted in the one year follow-up. Shortly after, a similar study by Marcela Ot’alora replicated the results with 76% of patients not meeting the diagnostic criteria for PTSD one year after the treatment.
A Path Towards Regulation
Given these promising results, the FDA accelerated the approval process of MDMA with the Breakthrough Therapy designation in 2017 and allowed the early compassionate use of MDMA-assisted psychotherapy for treatment-resistant patients in 2020.
Two ongoing multi-site phase-3 trials sponsored by MAPS are currently assessing the efficacy of MDMA in around 200 participants from the US, Canada and Israel. Recently, MAPS’ interim analysis of the first phase-3 trial suggested that their results will probably reach statistical significance, and if nothing goes wrong, MDMA could be approved for the treatment of PTSD by mid-2022.
In the meantime, more phase-2 trials are starting to take place in Europe for PTSD and other conditions such as alcoholism. With the first psychedelic substance on the verge of approval, many questions remain in the air:

All these questions will require years of additional research, which needs to be done by current and future doctors, researchers and policy makers. But the direction and ambition of all this research is clear: to turn the hard facts of well-researched trials into a regulatory model, so that MDMA will be a legal future medication to help many.

Compassionate use of psychedelics


In the present paper, we discuss the ethics of compassionate psychedelic psychotherapy and argue that it can be morally permissible. When talking about psychedelics, we mean specifically two substances: psilocybin and MDMA. When administered under supportive conditions and in conjunction with psychotherapy, therapies assisted by these substances show promising results. However, given the publicly controversial nature of psychedelics, compassionate psychedelic psychotherapy calls for ethical justification. We thus review the safety and efficacy of psilocybin- and MDMA-assisted therapies and claim that it can be rational for some patients to try psychedelic therapy. We think it can be rational despite the uncertainty of outcomes associated with compassionate use as an unproven treatment regime, as the expected value of psychedelic psychotherapy can be assessed and can outweigh the expected value of routine care, palliative care, or no care at all. Furthermore, we respond to the objection that psychedelic psychotherapy is morally impermissible because it is epistemically harmful. We argue that given the current level of understanding of psychedelics, this objection is unsubstantiated for a number of reasons, but mainly because there is no experimental evidence to suggest that epistemic harm actually takes place.
Greif, A., & Šurkala, M. (2020). Compassionate use of psychedelics. Medicine, Health Care, and Philosophy.,
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Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin


The aim of this systematic review was to examine the efficacy of MDMA, ketamine, LSD, and psilocybin for the treatment of posttraumatic stress disorder (PTSD). A search of four databases for English language, peer-reviewed literature published from inception to 18th October 2019 yielded 2,959 records, 34 of which were screened on full-text. Observational studies and RCTs which tested the efficacy of MDMA, ketamine, LSD, or psilocybin for reducing PTSD symptoms in adults, and reported changes to PTSD diagnosis or symptomatology, were included. Nine trials (five ketamine and four MDMA) met inclusion criteria. Trials were rated on a quality and bias checklist and GRADE was used to rank the evidence. The evidence for ketamine as a stand-alone treatment for comorbid PTSD and depression was ranked “very low”, and the evidence for ketamine in combination with psychotherapy as a PTSD treatment was ranked “low”. The evidence for MDMA in combination with psychotherapy as a PTSD treatment was ranked “moderate”.

Varker, T., Watson, L., Gibson, K., Forbes, D., & O’Donnell, M. L. (2021). Efficacy of Psychoactive Drugs for the Treatment of Posttraumatic Stress Disorder: A Systematic Review of MDMA, Ketamine, LSD and Psilocybin. Journal of psychoactive drugs, 53(1), 85–95.

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Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy


The last two decades have seen a revival of interest in the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA) as an adjunct to psychotherapy, particularly for the treatment of post-traumatic stress disorder. While clinical results are highly promising, and MDMA is expected to be approved as a treatment in the near future, it is currently the only compound in its class of action that is being actively investigated as a medicine. This lack of alternatives to MDMA may prove detrimental to patients who do not respond well to the particular mechanism of action of MDMA or whose treatment calls for a modification of MDMA’s effects. For instance, patients with existing cardiovascular conditions or with a prolonged history of stimulant drug use may not fit into the current model of MDMA-assisted psychotherapy, and could benefit from alternative drugs. This review examines the existing literature on a host of entactogenic drugs, which may prove to be useful alternatives in the future, paying particularly close attention to any neurotoxic risks, neuropharmacological mechanism of action and entactogenic commonalities with MDMA. The substances examined derive from the 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole and amphetamine classes. Several compounds from these classes are identified as potential alternatives to MDMA.

Oeri H. E. (2021). Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy. Journal of psychopharmacology (Oxford, England), 35(5), 512–536.

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The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats


Rationale: The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called “benzofury” compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.

Methods: Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats.

Results: All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection.

Conclusions: Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain.

Brandt, S. D., Walters, H. M., Partilla, J. S., Blough, B. E., Kavanagh, P. V., & Baumann, M. H. (2020). The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3, 4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats. Psychopharmacology237(12), 3703-3714; 10.1007/s00213-020-05648-z

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Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies


Introduction: Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders.

Objective: To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients’ accounts, and elucidating how these affect the treatment process.

Methods: We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP).

Results: Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses.

Conclusions: This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.

Breeksema, J. J., Niemeijer, A. R., Krediet, E., Vermetten, E., & Schoevers, R. A. (2020). Psychedelic treatments for psychiatric disorders: a systematic review and thematic synthesis of patient experiences in qualitative studies. CNS drugs, 1-22; 10.1007/s40263-020-00748-y

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[Psychedelics for existential distress in terminally ill patients]


Existential distress in patients with a terminal illness is often associated with (symptoms of) anxiety and depression. Psychotherapeutic interventions seem effective but effects are short-lived. There are no proven effective pharmacological interventions.<br/> AIM: To present an overview of literature on psychedelic treatment of existential distress in patients with terminal illness.<br/> METHOD: Literature research in PubMed/Medline databases, supplemented with cross-references.<br/> RESULTS: 14 clinical studies have been conducted: 6 with classic psychedelics between 1960 and 1980, and 8 with classic psychedelics and ketamine after 2000. Results of early pre-post studies are promising but have serious methodological limitations. Recent clinical research with LSD, psilocybin and ketamine are also promising although limited in terms of research design and generalizability. Overall, studies show a positive effect on existential and spiritual well-being, quality of life, acceptance and (symptoms of) anxiety and depression. Mystical experiences are correlated with positive outcomes. Few adverse effects are reported.<br/> CONCLUSION: Treatment of existential distress using classical psychedelics or ketamine in patients with terminal illness seems auspicious. Larger clinical studies in a more diverse patient population with fewer methodological limitations are needed to draw conclusions about efficacy and generalizability.
Schimmel, N., Breeksema, J. J., Veraart, J. K. E., van den Brink, W., & Schoevers, R. A. (2020). Psychedelics for existential distress in terminally ill patients. Tijdschrift Voor Psychiatrie62(8), 659-668.,
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[Psychedelics in the treatment of PTSD]


Posttraumatic stress disorder (PTSD) is often a chronic condition, despite the availability of various evidence-based treatment options. Psychedelics offer new treatment opportunities.<br/> AIM: An overview of the current evidence, therapeutic context, and possible mechanisms of action of different types of psychedelics in the treatment of PTSD.<br/> METHOD: A scoping review of the available literature.<br/> RESULTS: MDMA-assisted psychotherapy has shown to produce lasting reductions in PTSD symptoms in multiple RCTs. Based on a small number of studies, ketamine administration appears to lead to temporary symptom relief. Current studies are investigating whether the use of ketamine in combination with psychotherapy can lead to lasting reductions in PTSD symptoms. Classical psychedelics (such as psilocybin and LSD) induce psychoactive effects (on behavior or experience) that could contribute to the psychotherapeutic treatment of PTSD but have not yet been investigated in controlled studies. Reported positive effects extend beyond PTSD symptoms only.<br/> CONCLUSION: Psychedelics may have potential to serve as a catalyst for the psychotherapeutic treatment of PTSD. Most evidence exists for MDMA-supported psychotherapy; relatively little research is available on ketamine and classical psychedelics. Future research needs to show whether the use of psychedelics can be integrated into available treatment options for PTSD.
Vermetten, E., Krediet, E., Bostoen, T., Breeksema, J. J., Schoevers, R. A., & van den Brink, W. (2020). Psychedelics in the treatment of PTSD. Tijdschrift Voor Psychiatrie62(8), 640-649.,

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3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for victims of sexual abuse with severe post-traumatic stress disorder: an open label pilot study in Brazil


Objective: To conduct Brazil’s first clinical trial employing 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder (PTSD), given its high prevalence resulting from epidemic violence.

Methods: Of 60 volunteers, four matched the inclusion & exclusion criteria. Three patients with PTSD secondary to sexual abuse (diagnosed by the Structured Clinical Interview for DSM-IV and the Clinician Administered PTSD Scale for DSMV-4 [CAPS 4]) completed enrollment and treatment, following a standardized Multidisciplinary Association for Psychedelic Studies protocol consisting of 15 weekly therapy sessions: three with orally administered MDMA with concurrent psychotherapy and music, spaced approximately 1 month apart. CAPS-4 scores two months after the final MDMA session were the primary outcome.

Results: No serious adverse events occurred. The most frequent adverse events were somatic pains and anguish. CAPS-4 reductions were always greater than 25 points. The final scores were 61, 27, and 8, down from baseline scores of 90, 78, and 72, respectively. All reductions were greater than 30%, which is indicative of clinically significant improvement. Secondary outcomes included lower Beck Depressive Inventory scores and higher Post-Traumatic Growth Inventory and Global Assessment of Functioning scores.

Conclusions: Considering the current limitations in safe and efficacious treatments for PTSD and recent studies abroad with larger patient samples, MDMA-assisted psychotherapy could become a viable treatment in Brazil.

Jardim, A. V., Jardim, D. V., Chaves, B. R., Steglich, M., Ot’alora G, M., Mithoefer, M. C., … & Doblin, R. (2020). 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for victims of sexual abuse with severe post-traumatic stress disorder: an open label pilot study in Brazil. Brazilian Journal of Psychiatry, (AHEAD); 10.1590/1516-4446-2020-0980
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