New and emerging treatments for major depressive disorder.

Major depressive disorder (MDD) affects a substantial portion of the population; however, much is still unknown about the pathophysiology of this disorder. Treatment resistance highlights the heterogeneous nature of MDD and the need for treatments to target more than monoamine neurotransmission. This review summarizes research into the new and emerging targets of MDD. These include drugs such as psychedelics, antibiotics, opioid modulators, neuropeptides, and onabotulinumtoxin. Neuromodulatory treatments such as light based therapies and neuromodulation involving either magnetic or electrical stimulation are also discussed. Almost all interventions, pharmacological and neuromodulation, were trialed as adjunctive treatments to an antidepressant. Most research has been conducted on psychedelics, with trials suggesting rapid antidepressant and anti-suicidal effects. Trial findings, tolerability, study design limitations and quality of research have been considered throughout this review. There remains challenges in forming recommendations with the current research at present. With there being considerable interest into the research of new and emerging treatments-in particular, psychedelics-there may be scope in the future to form more robust recommendations.

Investigating the impact of psychedelic drugs on social cognition defects: A scoping review protocol.

BACKGROUND: Impairments in social cognition are known to be a key factor in several psychiatric and neurodevelopmental disorders. Interest in psychedelic drugs has increased in recent years, with significant research identifying psychedelic and hallucinogenic drugs as modulators of social cognition. However, more research is necessary before psychedelics are implemented in clinical settings as treatments for social cognition defects. Therefore, this study describes a scoping review protocol which will be used to analyze the body of literature on psychedelic drugs as modulators of social cognition in patients with psychiatric and neurodevelopmental disorders. METHODS: This scoping review protocol was developed using the JBI Scoping Review Methodology Group's description of how to conduct a scoping review. The guidelines identified by this group as well as a search strategy developed with the assistance of a research librarian will be applied to a search of several peer-reviewed journals, including MEDLINE (Ovid), PsycINFO, EMBASE (Elsevier), and Scopus (Elsevier). Each study extracted will be screened in a two-step screening process, including a title and abstract screen, and a full-text screen. One independent individual will complete both steps of the screening, and a second independent individual will review the completed screening. DISCUSSION: An understanding of the current literature on psychedelic drugs as modulators of social cognition will provide insight into what is presently known on the subject, and any gaps in the literature that can be addressed in future studies. The knowledge gained from this scoping review could lead to a new treatment for social cognition defects in clinical populations.

Tratamiento con microdosis de hongos con psilocibina en trastorno depresivo mayor: reporte de un caso.

La depresión mayor es una enfermedad de gran prevalencia e impacto mundial. Los tratamientos actuales presentan una tasa de no respuesta del 15 al 30 %, mientras que en casos de eficacia se suelen observar efectos adversos como el síndrome de apatía y la falta de respuesta emocional. Se postula que el tratamiento con hongos psilocibios genera la posibilidad de reducción de dosis y suspensión de psicofármacos clásicos y ocasiona cambios a nivel emocional y comportamental benéficos en pacientes con trastorno depresivo mayor. Este es un caso de un paciente no binario de 19 años de edad con diagnóstico de trastorno depresivo mayor. Se realizó unacompañamiento y asesoramiento del paciente apelando al derecho de autonomía, en el proceso de autoadministración de microdosis de psilocibina, para disminución de riesgos en salud y potenciar efectos benéficos probables, con evaluación semanal, durante un periodo de 7 meses; utilizando la anamnesis clínica, análisis de laboratorio y la escala validada de depresión de Hamilton. Como resultado de esta intervención se evidenció una remisión completa sintomática, la suspensión del tratamiento farmacológico convencional, sin síntomas de discontinuación y mejorías a nivel comunicacional, de interacción social y bienestar general. Estos hallazgos apoyan la idea de que los tratamientos con microdosis de psilocibina son una herramienta prometedora en los tratamientos de depresión. Se necesitan más estudios que aporten evidencia científica para comprobar dichos hallazgos.

Interrupting the Psychedelic Experience Through Contextual Manipulation to Study Experience Efficacy.

This quality improvement study investigates the association of interruptions during psychedelic therapy with ratings of intensity of experience.

Longitudinal experiences of Canadians receiving compassionate access to psilocybin-assisted psychotherapy.

Recent clinical trials have found that the serotonergic psychedelic psilocybin effectively alleviates anxiodepressive symptoms in patients with life-threatening illnesses when given in a supportive environment. These outcomes prompted Canada to establish legal pathways for therapeutic access to psilocybin, coupled with psychological support. Despite over one-hundred Canadians receiving compassionate access since 2020, there has been little examination of these 'real-world' patients. We conducted a prospective longitudinal survey which focused on Canadians who were granted Section 56 exemptions for legal psilocybin-assisted psychotherapy. Surveys assessing various symptom dimensions were conducted at baseline, two weeks following the session (endpoint), and optionally one day post-session. Participant characteristics were examined using descriptive statistics, and paired sample t-tests were used to quantify changes from baseline to the two-week post-treatment endpoint. Eight participants with Section 56 exemptions (four females, Mage = 52.3 years), all with cancer diagnoses, fully completed baseline and endpoint surveys. Significant improvements in anxiety and depression symptoms, pain, fear of COVID-19, quality of life, and spiritual well-being were observed. Attitudes towards death, medical assistance in dying, and desire for hastened death remained unchanged. While most participants found the psilocybin sessions highly meaningful, if challenging, one reported a substantial decrease in well-being due to the experience. These preliminary data are amongst the first to suggest that psilocybin-assisted psychotherapy can produce psychiatric benefits in real-world patients akin to those observed in clinical trials. Limited enrollment and individual reports of negative experiences indicate the need for formal real-world evaluation programs to surveil the ongoing expansion of legal access to psychedelics.

Developing an Ethics and Policy Framework for Psychedelic Clinical Care: A Consensus Statement.

Importance: As government agencies around the globe contemplate approval of the first psychedelic medicines, many questions remain about their ethical integration into mainstream medical practice. Objective: To identify key ethics and policy issues related to the eventual integration of psychedelic therapies into clinical practice. Evidence Review: From June 9 to 12, 2023, 27 individuals representing the perspectives of clinicians, researchers, Indigenous groups, industry, philanthropy, veterans, retreat facilitators, training programs, and bioethicists convened at the Banbury Center at Cold Spring Harbor Laboratory. Prior to the meeting, attendees submitted key ethics and policy issues for psychedelic medicine. Responses were categorized into 6 broad topics: research ethics issues; managing expectations and informed consent; therapeutic ethics; training, education, and licensure of practitioners; equity and access; and appropriate role of gatekeeping. Attendees with relevant expertise presented on each topic, followed by group discussion. Meeting organizers (A.L.M., I.G.C., D.S.) drafted a summary of the discussion and recommendations, noting points of consensus and disagreement, which were discussed and revised as a group. Findings: This consensus statement reports 20 points of consensus across 5 ethical issues (reparations and reciprocity, equity, and respect; informed consent; professional boundaries and physical touch; personal experience; and gatekeeping), with corresponding relevant actors who will be responsible for implementation. Areas for further research and deliberation are also identified. Conclusions and Relevance: This consensus statement focuses on the future of government-approved medical use of psychedelic medicines in the US and abroad. This is an incredibly exciting and hopeful moment, but it is critical that policymakers take seriously the challenges ahead.

[Up-to-Date on clinical and preclinical studies of psilocybin therapy].

Major Depressive Disorder (MDD) poses a significant global health burden, with 30-40% patients developing resistance to standard clinical antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants. In 2016, Carhart-Harris and colleagues reported that psilocybin, the hallucinogenic compound derived from magic mushrooms, exhibits rapid and enduring antidepressant effects in patients with treatment-resistant depression. Subsequent clinical studies have found the therapeutic potential of psilocybin in MDD, depressive episode in bipolar disorder, anorexia, and drug addiction. In 2018 and 2019, the U.S. Food and Drug Administration designated psilocybin as a "breakthrough medicine" for treatment-resistant depression and MDD, respectively. Notably, the side effects of psilocybin are limited to transient and mild issues, such as headache and fatigue, suggesting its safety. In 2023, we published a review on the role of serotonin 5-HT2A receptors in the antidepressant effects of serotonergic psychedelics (Nihon Yakurigaku Zasshi, Volume 158, Issue 3, Page 229-232). Here, we present our study alongside the latest clinical and preclinical research on the antidepressant effects of psilocybin and provide an overview of the potential and issues related to psilocybin therapy.

Therapeutic modulation of the kynurenine pathway in severe mental illness and comorbidities: A potential role for serotonergic psychedelics.

Mounting evidence points towards a crucial role of the kynurenine pathway (KP) in the altered gut-brain axis (GBA) balance in severe mental illness (SMI, namely depression, bipolar disorder, and schizophrenia) and cardiometabolic comorbidities. Preliminary evidence shows that serotonergic psychedelics and their analogues may hold therapeutic potential in addressing the altered KP in the dysregulated GBA in SMI and comorbidities. In fact, aside from their effects on mood, psychedelics elicit therapeutic improvement in preclinical models of obesity, metabolic syndrome, and vascular inflammation, which are highly comorbid with SMI. Here, we review the literature on the therapeutic modulation of the KP in the dysregulated GBA in SMI and comorbidities, and the potential application of psychedelics to address the altered KP in the brain and systemic dysfunction underlying SMI and comorbidities. Psychedelics might therapeutically modulate the KP in the altered GBA in SMI and comorbidities either directly, via altering the metabolic pathway by influencing the rate-limiting enzymes of the KP and affecting the levels of available tryptophan, or indirectly, by affecting the gut microbiome, gut metabolome, metabolism, and the immune system. Despite promising preliminary evidence, the mechanisms and outcomes of the KP modulation with psychedelics in SMI and systemic comorbidities remain largely unknown and require further investigation. Several concerns are discussed surrounding the potential side effects of this approach in specific cohorts of individuals with SMI and systemic comorbidities.

The cyclical revival of psychedelics in psychiatric treatment.

There is an increasing demand for effective treatments for depression, particularly for individuals grappling with treatment-resistant depression. Over recent years, a surge of interest has focused on exploring the safety and efficacy of psilocybin as a potential treatment for depression. However, preliminary findings from phase 2 studies have been inconclusive, prompting critical examination of issues such as maintaining blinding and the role of adjunctive psychotherapy. The maintenance of double-blinding and the role of adjunctive psychotherapy introduce biases that complicate the attainment of conclusive results in clinical research. Examining historical data reveals a recurrent pattern linked to the use of psychoactive substances, which starts with an excess of optimism and ends with general addictive behaviors and a heightened risk of serious public health problems. Considering these findings, a cautious and measured approach is imperative, given that the efficacy and safety of psilocybin treatment have yet to be unequivocally established. The potential for excessive optimism among researchers is a notable concern, as unwarranted enthusiasm may inadvertently facilitate the widespread adoption of this treatment without sufficient empirical support. In navigating the complexities of depression treatment, it is necessary to strike a balance between innovation and prudence to ensure evidence-based advancement of therapeutic approaches.

Psychedelic 25H-NBOMe attenuates post-sepsis depression in rats.

Sepsis-associated encephalopathy, which manifests in severe cognitive and depressive symptoms, is directly linked to neuroinflammation. Our study investigates the efficacy of 25H-NBOMe, a phenethylamine, in alleviating these symptoms, potentially offering an innovative treatment for post-sepsis depression. Wistar rats, weighing between 250-300 g, were subjected to cecal ligation and puncture (CLP) surgery to induce sepsis. Depressive-like behaviors were assessed using the forced swim test (FST) on either day 7 or 14 post-surgery, to establish the presence of depressive symptoms. The impact of 25H-NBOMe treatment was then evaluated, focusing on the head-twitch response (HTR), performance in the FST, and GFAP expression in the prefrontal cortex. Treatment with 25H-NBOMe resulted in significant behavioral changes, demonstrated by decreased immobility and increased swimming times in the FST, along with a rise in the HTR. These outcomes indicate a reduction in depressive-like symptoms post-sepsis and the psychoactive effects of the compound. Furthermore, a notable decrease in GFAP expression in the study highlights the compound's impact on mitigating sepsis-induced astrogliosis. This study demonstrates the effectiveness of 25H-NBOMe, a psychedelic in the phenethylamine class, in treating post-sepsis depression and reducing astrogliosis. However, the psychedelic nature of 25H-NBOMe calls for further investigation into similar compounds with less psychoactive impact, crucial for advancing treatment options for neuropsychiatric symptoms following sepsis.

At the Forefront: Social Workers' Role in Psilocybin Treatment for Depression and Substance Misuse.

This article underscores the critical role of social workers in harnessing the potential therapeutic benefits of psilocybin for treating major depressive disorder (MDD) and substance use disorder (SUD). Contemporary treatments for MDD often have side effects, and the success rate for SUD treatments remains low. The pervasiveness of MDD, combined with the challenges in treating SUD, highlights a need for innovative treatments. This article provides an overview of the resurgence of literature over the past two decades that illuminates the therapeutic promise of psilocybin for mental health treatment; clinical trials elucidate the efficacy of psilocybin-assisted therapy in mitigating MDD and demonstrate great promise in reducing SUD symptoms. The long-lasting posttreatment effect emphasizes its potential as a novel treatment modality. Furthermore, psilocybin's recognition as a "breakthrough therapy" by the U.S. Food and Drug Administration (FDA) and the accelerating pace of psychedelic reform bills indicate growing acceptance and interest in its therapeutic capacities. Psilocybin-assisted therapy emerges as a potent treatment option, showcasing remarkable effectiveness even after a single dose. Recommendations and pathways for social workers to be involved in psilocybin-assisted therapy investigation, advocacy, and implementation are provided.

Psychedelics and Evidence-based Psychotherapy: A Systematic Review with Recommendations for Advancing Psychedelic Therapy Research.

Administration of psychedelics for mental health treatment, typically referred to as "psychedelic-assisted therapy," is a broad term with a very heterogeneous implementation. Despite increasing interest in the clinical application of psychedelic compounds for psychiatric disorders, there is no consensus on how to best integrate the psychedelic experience with evidence-based psychotherapeutic treatment. This systematic review provides a timely appraisal of existing approaches to combining psychotherapy with psychedelics and provides clear recommendations to best develop, optimize, and integrate evidence-based psychotherapy with psychedelic administration for straightforward scientific inference and maximal therapeutic benefit.

Effect of MDMA-assisted therapy on mood and anxiety symptoms in advanced-stage cancer (EMMAC): study protocol for a double-blind, randomised controlled trial.

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.