Psilocybin-assisted therapy may be a promising new treatment for treatment-resistant depression. We examined the feasibility of administering a single 25-mg dose of psilocybin or placebo with psychological support in a randomized controlled trial design with 6 weeks of follow-up. A two-arm, double-blind, randomized, placebo-controlled feasibility trial was conducted at one National Health...
The contribution of patient support to psilocybin's antidepressant effects remains uncertain. Relationships between therapeutic alliance (Scale to Assess Therapeutic Relationship-Patient version; STAR-P), psychedelic experience (Five-Dimensional Altered States of Consciousness Questionnaire and Emotional Breakthrough Inventory; 5D-ASC and EBI) and clinical outcomes (Montgomery-Åsberg Depression...
Esketamine nasal spray (NS) is an established treatment for patients with treatment resistant depression (TRD). To further optimise real-world outcomes, consensus is needed regarding strategies to enhance patient outcomes and decision-making factors for pivotal timepoints in esketamine NS treatment. This modified Delphi panel (3 rounds) established expert consensus (≥80% agreement) from 30...
Mindfulness-based cognitive therapy (MBCT) was developed for relapse prevention in people with remitted depression but is increasingly used for those with difficult-to-treat depression (DTD). A key question regarding this broader application is whether ongoing depressive symptoms constrain therapeutic responsiveness or disrupt MBCT's proposed mechanism, decentering. We explored whether baseline...
INTRODUCTION: Around a third of patients with major depressive disorder experience persistent symptoms despite usual treatments. Identifying scalable, psychological treatment options is critical to reduce the burden associated with difficult-to-treat depression (DTD). We examined the efficacy of mindfulness-based cognitive therapy (MBCT) compared with treatment as usual (TAU) and other active...
Accumulating evidence suggests that the opioid system may modulate ketamine's rapid antidepressant effects. The objective of this study was to test whether opioid system modulation via naltrexone alters ketamine's acute effects on regional cerebral blood flow (rCBF) in major depressive disorder (MDD), and whether these changes relate to symptom measures and map onto receptor density profiles....
Despite renewed investigations into classical psychedelic compounds, their pharmacokinetic profiles remain incompletely understood. This systematic review collated data from healthy adult volunteers on the pharmacokinetic properties of lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), mescaline, and 5-methoxy-N,N-dimethyltryptamine (5-MEO-DMT). We identified 32 eligible...
BACKGROUND: Over the past decade, neuropsychopharmacology has shifted from stagnation to momentum, with first-in-class mechanisms and biomarker-enabled trials spanning psychiatry and neurology. METHODS: We narratively synthesized advances from 2013 to 2026 across central nervous system (CNS) discovery and development, including pivotal trials, regulatory actions, digital/real-world evidence,...
Previous systematic reviews and meta-analyses have reported impressive antidepressant effects of ketamine in treatment-resistant depression (TRD). While ketamine has been compared with electroconvulsive therapy (ECT), the gold standard treatment, the extent and durability of its antidepressant effects over longer periods remain unclear. To our knowledge, this is the first systematic review...
Background: Changes in well-being, personality, and personal values have been documented post-psilocybin; however, evidence from placebo-controlled trials is limited. Aims: To examine the effects of psilocybin versus placebo on psychiatric symptoms, personality, and personal values in healthy participants. Potential mediators were also explored. Methods: This secondary analysis used data from a...
Psychedelics are gaining attention as putative treatments for a range of psychiatric conditions, and evidence suggests that they produce sustained behavioural and clinical change. Enhanced learning is an emerging candidate mechanism mediating these sustained effects. This narrative review synthesises evidence across behavioural, neural and computational levels to examine the current evidence...
It is 60 years since ketamine was first tested in humans as an alternative but safer anaesthetic to PCP (phencyclidine) (Corssen and Domino 1966). It became widely used as the “buddy drug” for combatants in the Vietnam War: because of its great safety margin, it could be injected into wounded personnel by their buddies to relieve pain before the arrival of the medical team. Because of...
1. Classical psychedelics are gaining attention as potential treatments for a range of neuropsychiatric conditions, including depression, anxiety, and addictions [1]. Psychedelics differ from tradi...
We investigated the potential role of the opioid system in modulating glutamatergic effects of ketamine administration in major depressive disorder. Twenty-six adults with major depressive disorder participated in a double-blind crossover study, receiving oral placebo or 50 mg naltrexone before an intravenous infusion of 0.5 mg per kg ketamine. Brain glutamatergic activity in the anterior...
Introduction: Psychedelics are emerging as potential treatments for neuropsychiatric conditions, with evidence suggesting a single administration can lead to enduring behavioural changes. While the underlying putative mechanism(s) remain unclear, there is evidence supporting altered learning as a key candidate. Aim: This systematic review examined studies assessing the effects of psychedelics...
Ketamine has emerged as a putative rapid-acting treatment option for psychiatric disorders, particularly treatment-resistant depression. Chronic recreational ketamine use is associated with ketamine-induced urological toxicity, raising concerns over the safety of repeated ketamine treatments. This systematic review aimed to synthesise urological findings from clinical trials and observational...
Ketamine, a rapid-acting N-methyl-D-aspartate receptor antagonist used as a therapeutic for treatment-resistant depression (TRD), is usually administered intravenously or intranasally. This randomized, double-blind, placebo-controlled, Phase 1 study investigated safety and tolerability (primary endpoint), pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release oral ketamine....
The rates of relapse and suicide risk are higher in treatment-resistant depression (TRD) vs non-treatment-resistant major depressive disorder. Even among patients with TRD who initially respond, the majority (70%) relapse within 6 months. To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD. Phase 3, open-label,...
Non-remission after psychological therapy for major depressive disorder is common, yet there are no established further-line treatments. In the UK National Health Service (NHS) Talking Therapies programme, about 50% of patients with depression who come to the end of the stepped care pathway do not show remission of symptoms. We aimed to investigate whether mindfulness-based cognitive therapy...
Aims: Ketamine is a novel and exciting putative antidepressant medication for patients with treatment-resistant depression. A complication commonly seen in frequent and heavy recreational use of ketamine is ulcerative cystitis, which presents with lower urinary tract symptoms (LUTS) and upper renal tract damage and can be seen in over 25% of regular users. Although ketamine-induced cystitis...
Aims: Ketamine and behavioural activation (BA) reduce levels of anhedonia in major depressive disorder (MDD), though neither resolves anhedonia. Combining these treatments could yield additive or even multiplicative benefits. This poster summarises the development of a PhD fellowship proposal, discussing: (1) the initial patient and public involvement (PPI) interviews, exploring views on...
Treatment-resistant late-life depression (TRLLD) affects nearly half of older adults with major depression. This systematic review evaluates published evidence of effectiveness of both pharmacological and non-pharmacological treatments for TRLLD. A search of MEDLINE, EMBASE, CINAHL, PsycINFO, the Cochrane Library, and online trial registries up to March 2024 was conducted to identify randomized...
To determine the relationships between psilocybin dose, psychedelic experiences, and therapeutic outcome in treatment-resistant depression. For treatment-resistant depression, 233 participants received a single dose of 25, 10, or 1 mg of COMP360 psilocybin (a proprietary, pharmaceutical-grade synthesized psilocybin formulation, developed by the sponsor, Compass Pathfinder Ltd.) with...
In patients with treatment resistant depression (TRD), the ESCAPE-TRD study showed esketamine nasal spray was superior to quetiapine extended release. To determine the robustness of the ESCAPE-TRD results and confirm the superiority of esketamine nasal spray over quetiapine extended release. ESCAPE-TRD was a randomised, open-label, rater-blinded, active-controlled phase IIIb trial. Patients had...
Abstract Background and aims This is the first systematic review of the extant literature on all major psychedelic‐assisted treatment for alcohol use disorder (AUD), tobacco use disorder (TUD) and other substance use disorders (SUD). We aimed to summarise the evidence for efficacy of psychedelic‐assisted treatment for AUD, TUD, and SUD; to evaluate its quality; and to offer recommendations for...