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(searched for: doi:10.1038/s41591-021-01336-3)
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Elena Argento, Devon Christie, Lindsay Mackay, Cody Callon, Zach Walsh
Published: 6 September 2021
Frontiers in Psychiatry, Volume 12; https://doi.org/10.3389/fpsyt.2021.716593

Abstract:
The COVID-19 pandemic stands to have impacts on mental health and well-being that will extend beyond its formal resolution. Before COVID-19, mental health disorders were already challenging global healthcare systems, directly accounting for 7.4% of the total burden of disease (1, 2). An estimated 1 billion people worldwide suffer from a mental health disorder, with the two most common disorders—depression and anxiety—costing the global economy US$1 trillion per year (3). Stigma and limited treatment options have amounted to substantial unmet need and violations in human rights for people with mental health disorders (1, 4, 5). Looking ahead, heightened post-pandemic demand for mental healthcare signifies an urgent need to bolster clinical capacity by integrating novel, cost-effective approaches into existing systems (6). Emergent literature globally describes the diverse impacts of COVID-19 on mental health (7, 8). For instance, available data among hospitalized COVID-19 patients in China revealed that approximately 96% suffered post-traumatic stress symptoms (9). Studies among intensive care unit (ICU) patients with previous coronaviruses infer high rates of posttraumatic stress disorder (PTSD), depression and anxiety (30-40%) persisting months after discharge (10), with similar rates observed in patients infected with COVID-19 (11). Highly exposed individuals such as frontline healthcare workers are susceptible to similarly negative outcomes due to prolonged occupational stress, elevating risk of PTSD and suicidality (12–14). Importantly, post-pandemic mental disorders are not limited to individuals directly exposed to COVID-19. Rather, research documents PTSD symptoms among individuals who have been indirectly exposed by witnessing (e.g., via the media) or being confronted with the threat of death or serious illness (e.g., worry/anticipation about the future) (7). COVID-19 has significantly altered lives in ways that exacerbate drivers of mental health problems, with widespread uncertainty, increased experiences of grief and loss, social isolation, economic and housing instability, and decreased access to critical services related to lockdowns (6, 15). Further, available data on the impacts of COVID-19 on substance use patterns indicate increased use of alcohol and other substances in response to stress and negative emotions (8, 16, 17). Social connections are crucial for people struggling with addiction and comorbidities such as depression, and increased social disconnection represents a key risk factor for adverse outcomes (e.g., relapse and overdose) (1, 6, 18). The societal and economic consequences are tremendous, with structurally vulnerable groups at greatest risk of harms. For example, North America has seen dramatic spikes in fatal overdoses attributable to socio-structural conditions worsened by COVID-19 (18, 19), disproportionately impacting racialized groups (20). The legacy of mental health problems that will be left behind by COVID-19 incites innovative solutions to address rising rates of PTSD, depression, anxiety, addictions, and social disconnection. As such, we would be remiss not to consider a novel approach with anti-depressive, anxiolytic, and antiaddictive potential that may also foster a sense of social and environmental connectedness, known as psychedelic-assisted psychotherapy (21–24). A considerable and growing body of evidence speaks to the potential of psychedelic-assisted psychotherapies to enhance treatments for PTSD, depression, end-of-life anxiety, and substance use disorders (23, 24). The ensuing government, industry and social support includes the US Food and Drug Administration (FDA) granting breakthrough therapy designation for psilocybin and 3,4-methylenedioxymethamphetamine (MDMA) for treatment-resistant depression and PTSD, respectively (24). A range of jurisdictions worldwide are expanding access to psychedelic-assisted psychotherapies, including through compassionate use or “right-to-try” pathways. In 2019, the Israeli government approved its first Compassionate Use Program for MDMA-assisted psychotherapy, shortly followed by FDA approval for an Expanded Access program in the US (25). Switzerland has permitted compassionate use of MDMA and lysergic acid diethylamide (LSD) since 2014 (26). The state of Oregon has now legalized psilocybin-assisted psychotherapy and decriminalized all drugs, alongside dozens of similar legislative reforms to legalize or decriminalize psychedelic plants and fungi across the US, including bills to expand “right-to-try” laws for people with serious or life-threatening illnesses (27). In Canada, a growing number of permissions have been granted by the federal government to use psilocybin for existential distress, and for therapist training purposes (28). Health Canada recently announced a notice of intent to restore access to psilocybin and MDMA through the Special Access Programme, which followed a national petition signed by nearly 15,000 Canadians in support of decriminalizing psychedelic plants and fungi (29). Mounting public interest in psychedelic-assisted psychotherapy is reflected in the 2020 Global Drug Survey. Nearly 6% of 110,000 respondents used psychedelics in the past year for self-treatment of mental health conditions, and 90% who had a supervised psychedelic experience in an uncontrolled setting indicated interest in taking psychedelics under a legally regulated and approved treatment system (30). These findings underscore the need for increased public education, training of qualified care providers, and harm reduction approaches as regulatory frameworks evolve. While, the pandemic has illuminated deficiencies and inequalities in our healthcare systems, it also provides a rare opportunity for change. The collective experience of COVID-19 has rearranged priorities by bringing mortality, loss, and mental health to the forefront, and is generating...
, Ryan Hanson, Darryl Wilkinson, Albert Garcia-Romeu
Published: 2 September 2021
Culture, Medicine, and Psychiatry pp 1-14; https://doi.org/10.1007/s11013-021-09749-y

Abstract:
An international ban on psychedelics initiated by the United Nations’ Convention on Psychotropic Substances in 1971 restricted the clinical use of these ancient psychoactive substances. Yet, in an era marked by rising mental health concerns and a growing “Deaths of Despair” epidemic (i.e., excess mortality and morbidity from suicide, drug overdose, and alcoholism), the structured psychedelic use that has long been a part of ritual healing experiences for human societies is slowly regaining credibility in Western medicine for its potential to treat various mental health conditions. We use a historical lens to examine the use of psychedelic therapies over time, translate ancient lessons to contemporary clinical and research practice, and interrogate the practical and ethical questions researchers must grapple with before they can enter mainstream medicine. Given the COVID-19 pandemic and its contributions to the global mental health burden, we also reflect on how psychedelic therapy might serve as a tool for medicine in the aftermath of collective trauma. Ultimately, it is argued that a “psychedelic renaissance” anchored in the lessons of antiquity can potentially help shift healthcare systems—and perhaps the broader society—towards practices that are more humane, attentive to underlying causes of distress, and supportive of human flourishing.
Published: 20 August 2021
The American Journal of Medicine; https://doi.org/10.1016/j.amjmed.2021.07.033

Abstract:
After languishing for decades from legal restrictions and stigma, research into psychedelic drugs is exploding – with the encouragement of the Food and Drug Administration. Recent clinical trial successes suggest some long-banned drugs could soon be authorized as treatments for debilitating illnesses. Yet because of these drugs’ history, FDA approval would be just one important step in a complex process to transform these compounds into therapies. Incorporating psychedelic drugs into clinical practice will require peeling back multiple layers of legal prohibition, clarifying prescribing guidelines, and developing treatment models that work for drug-makers, physicians, and payers.
, Laura G. Moreno,
Published: 13 August 2021
Abstract:
The popular recreational drug MDMA (3,4-methylenedioxy-methamphetamine) has a documented potential as a psychopharmacological clinical and research tool. This is due to its unique ability to promote reprocessing of traumatic memories, empathetic and pro-social states. Although it is established that MDMA exerts its behavioural effects via the serotonin transporter (SERT), the ligand-protein molecular interplay remains elusive. In order to shed light on the binding of MDMA and its primary congeneric entactogens (MDA, MBDB and MDAI), we first combined induced fit with Monte Carlo simulations. The computed interaction energies of the models correlated well with experimental activities (adjR2 = 0.78). Then we carried out ‘ensemble binding space docking' on trajectories generated by interpolation of experimentally derived structures of the hSERT from the outward-open, and the occluded, to the inward-open states. This approach revealed low-energy alternative binding modes, suggesting high occupancy of the central site, yet considerable MDMA mobility within it, favouring the paroxetine-like orientation. Finally, we designed a pharmacophore that may be used to recognise hSERT-mediated serotonin releasers and uptake inhibitors of diverse chemical structure, identifying their active conformations and interacting residues. We conclude that the conserved amine-Asp98 ionic and edge-to-face π-π interactions are crucial to the mode of action of MDMA on the hSERT, underscoring the contributions of Tyr95 and gating residues Phe341, Tyr176 and Phe335. Amenable to experimental testing, our modelling may aid the rational design of novel entactogenic compounds and contribute to the understanding of an action mechanism, common and typical of psychotropic agents.
, Monica Sharma, Aaron S. Wolfgang, ,
Published: 1 August 2021
Biological Psychiatry, Volume 90; https://doi.org/10.1016/j.biopsych.2021.06.001

Abstract:
“This is your brain. This is your brain on drugs. Any questions?” With these 12 words the image of sizzling fried eggs was seared into the brains of millions of Americans. The D.A.R.E. era had begun.
, Benjamin Kelmendi, Ismene L. Petrakis
Published: 1 August 2021
Cell Reports Medicine, Volume 2; https://doi.org/10.1016/j.xcrm.2021.100378

Abstract:
A promising new Phase III study of MDMA plus psychotherapy for PTSD treatment by Mitchell and colleagues that appeared in Nature Medicine raises important new questions about the biology and optimal treatment of this disorder.
Derek K. Tracy, Dan W. Joyce, Dawn N. Albertson, Sukhwinder S. Shergill
The British Journal of Psychiatry, Volume 219, pp 469-470; https://doi.org/10.1192/bjp.2021.91

Published: 28 June 2021
Abstract:
While genetic factors play a critical role in the risk for schizophrenia and other psychotic disorders, increasing evidence points to the role of childhood adversity as one of several environmental factors that can significantly impact the development, manifestations and outcome of these disorders. This paper reviews the epidemiological evidence linking childhood adversity and psychotic disorders and explores various theoretical models that seek to explain the connection. We discuss neurobiological parallels between the impact of childhood trauma and psychosis on the brain and then explore the impact of childhood adversity on different domains of clinical presentation. Finally, implications for prevention and treatment are considered, both on individual and structural levels.
Kate Corrigan, Maeve Haran, Conor McCandliss, Roisin McManus, Shannon Cleary, Rebecca Trant, Yazeed Kelly, Kathryn Ledden, Gavin Rush, Veronica O’Keane, et al.
Irish Journal of Medical Science pp 1-13; https://doi.org/10.1007/s11845-021-02668-2

Abstract:
Introduction Despite the rapid advance of psychedelic science and possible translation of psychedelic therapy into the psychiatric clinic, very little is known about mental health service user attitudes. Objectives To explore mental health service user attitudes to psychedelics and psilocybin therapy. Methods A questionnaire capturing demographics, diagnoses, previous psychedelic and other drug use, and attitudes to psychedelics and psilocybin therapy was distributed to mental health service users. Results Ninety-nine participants completed the survey (52% female, mean age 42 years). The majority (72%) supported further research, with 59% supporting psilocybin as a medical treatment. A total of 27% previously used recreational psilocybin, with a male preponderance (p = 0.01). Younger age groups, those with previous psychedelic experience, and those with non-religious beliefs were more likely to have favourable attitudes towards psilocybin. A total of 55% of the total sample would accept as a treatment if doctor recommended, whereas 20% would not. Fewer people with depression/anxiety had used recreational psychedelics (p = 0.03) but were more likely to support government funded studies (p = 0.02). A minority (5%) of people with conditions (psychosis and bipolar disorder) that could be exacerbated by psilocybin thought it would be useful for them. One fifth of the total sample viewed psychedelics as addictive and unsafe even under medical supervision. Concerns included fear of adverse effects, lack of knowledge, insufficient research, illegality, and relapse if medications were discontinued. Conclusions The majority supported further research into psilocybin therapy. Younger people, those with previous recreational psychedelic experience, and those with non-religious beliefs were more likely to have favourable attitudes towards psilocybin therapy.
, Nadav L. Modlin, James J. H. Rucker
International Review of Psychiatry pp 1-21; https://doi.org/10.1080/09540261.2021.1919062

Abstract:
This review examines the role of trauma in psychiatric morbidity and analogous psychoneurobiological changes. Trauma is a necessary criterion for Post-Traumatic Stress Disorder (PTSD), however, trauma history is highly correlated with a variety of psychiatric conditions. Some evidence suggests that Major Depressive Disorder (MDD) is the most common psychiatric condition that arises following trauma. Approximately 50% of PTSD cases present with co-morbid MDD. Overlapping symptomatology and neurobiology between these conditions underlie the debate over whether these phenomena result from problematic nosology or whether comorbid MDD + PTSD is a distinct phenotype of trauma-related psychopathology. Regardless, similar treatment approaches have been employed historically, with varying success. The drug-assisted psychotherapy treatment model, which combines pharmacological and psychotherapeutic approaches, is currently being trialled as a novel treatment approach in psychiatry. Both psilocybin- and 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have received Food and Drug Administration ‘breakthrough therapy’ designation for the treatment of resistant MDD and PTSD, respectively. This paper reviews the therapeutic rationale of both psilocybin and MDMA for treating both trauma-related MDD and PTSD.
, Harriet de Wit
Published: 24 May 2021
Nature Medicine, Volume 27, pp 950-951; https://doi.org/10.1038/s41591-021-01385-8

Abstract:
A phase 3 study shows that MDMA may be a promising treatment for PTSD, which will require a shift in how this drug is perceived.
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