Despite the wide prevalence of mood disorders globally, there is a substantial unmet need for effective, mechanistically distinct treatments. Given that approximately 30% of individuals do not display adequate response to standard antidepressant therapies, the past 15 years have seen a shift away from traditional monoaminergic approaches toward glutamatergic and other novel mechanisms....
BACKGROUND: Psychedelics exert widespread effects on brain activity, but their impact on motor function is unclear. This is clinically relevant given the emerging interest in psychedelic-assisted physical therapy for disorders of motor function. This study examined the feasibility and safety of administering movement tasks following low-to-moderate doses of psilocybin in healthy volunteers....
Background and Objective Ketamine and esketamine have emerged as effective and rapid-acting interventions for treatment-resistant depression. Nevertheless, the best-suited candidates for these treatments are not clear. As such, the ability to personalize treatment selection and parameters would likely improve therapeutic response. This systematic review synthesized the literature on clinical...
CNS DrugsJune 15, 2026Edward P. Hackett, Aditi Chaudhri -, Linda Hasman et al.
BACKGROUND AND OBJECTIVE: Dextromethorphan (DXM), widely used as an over-the-counter antitussive in the United States, exhibits psychoactive effects at supratherapeutic levels that overlap with those of classic and dissociative psychedelics. Reported psychoactive effects have generated interest in DXM as a potential therapeutic agent for treatment-resistant psychiatric disorders. Despite this...
Bipolar disorder affects approximately 40 million individuals worldwide, with depression being the most prominent phase of the illness. Owing to limited treatment options, bipolar depression remains a major public health concern, often causing significant functional impairment and increased suicide risk. Current therapies frequently lack rapid effectiveness, highlighting the need for novel...
CNS DrugsJanuary 17, 2026Gaëlle Rached, Anna Campana, Dimitri Fiani et al.1 citation
Monoamine oxidase inhibitors (MAOIs) remain an important option for patients with treatment-resistant depression (TRD) and other psychiatric conditions, despite potentially serious drug-drug interactions and associated dietary tyramine restrictions. However, they are rarely prescribed in patients with comorbid substance use disorders (SUDs) due to concerns about potential drug interactions and...
Eating disorders (EDs) are complex psychiatric conditions characterized by disruptions in eating behaviors, body image concerns, and profound medical and psychosocial consequences. Despite their significant global prevalence, coupled with high morbidity and mortality rates, pharmacological treatment options remain limited. This review synthesizes evidence from clinical drug trials conducted...
CNS DrugsOctober 16, 2025Gisèle Pickering, Véronique Morel, Marion Voute2 citations
Ketamine, an anaesthetic and sedative drug, has emerged as a promising therapeutic option for the management of chronic refractory pain, but is used off-label in this indication and known for its psychomimetic side-effects. The primary objective of this manuscript is to synthesize the current evidence on ketamine efficacy and safety for chronic refractory pain. Furthermore, it aims to identify...
Psychedelics have been studied since the 1950s as a potential treatment for alcohol use disorder (AUD), with over a dozen clinical trials of lysergic acid diethylamide (LSD), and several contemporary trials of psilocybin and ayahuasca for this indication. Herein, we characterize foundational studies from the 1950s to the present, with emphasis on key design factors that varied considerably...
CNS DrugsJune 1, 2025Sijia Zhang, Houtan Afshar, Peter J. Colvonen et al.1 citation
Ketamine and esketamine are increasingly used to manage treatment-resistant depression and have also been shown to reduce symptoms of posttraumatic stress disorder (PTSD). Little is known about how common comorbidities in the veteran population, such as traumatic brain injury (TBI) or obstructive sleep apnea (OSA), may influence ketamine and esketamine treatment outcomes. In this retrospective...
Trauma is prevalent, with lifetime estimates of traumatic exposure ranging from 70% for a single event to 31% for multiple events. While many recover, a subset develop post-traumatic stress disorder (PTSD), a debilitating condition characterized by distressing memories, avoidance behaviors, hyperarousal, and mood disturbances. The National Comorbidity Survey reports a lifetime PTSD prevalence...
CNS DrugsDecember 1, 2024Ruyun Liu, Ning Liu, Lin Ma et al.5 citations
Major depressive disorder (MDD) is a severe mental illness with a complex etiology. Currently, many medications employed in clinical treatment exhibit limitations such as delayed onset of action and a high incidence of adverse reactions. Therefore, there is a pressing need to develop antidepressants that exhibit enhanced efficacy and safety. The N-methyl-D-aspartate receptor (NMDAR), a...
Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2 decades, a promising target emerged to improve patient outcomes in depression treatment:...
Mental health disorders and substance use disorders (SUDs) in particular, contribute greatly to the global burden of disease. Psychedelics, including entactogens and dissociative substances, are currently being explored for the treatment of SUDs, yet with less empirical clinical evidence than for other mental health disorders, such as depression or post-traumatic stress disorder (PTSD). In this...
Scientific and public attention on the therapeutic effects of psychedelics and other psychoactive compounds in headache disorders has recently grown. The use and reported therapeutic effects of such treatments have long been reported, though formal clinical trials are only recently taking place. When considering how these substances might be further studied and eventually applied, it is...
Anhedonia, a complex symptom rooted in deficits across reward processes, is primarily linked to depression and schizophrenia but transcends diagnostic boundaries across various mental disorders. Its presence correlates with poorer clinical outcomes, including an increased risk of suicide and diminished response to treatment. The neurobiological underpinnings of anhedonia remain incompletely...
Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain. Twelve male patients with chronic radicular neuropathic pain participated in...
The renewed interest in psychedelic research provides growing evidence of potentially unique effects on various aspects of reward processing systems. Using the Research Domain Criteria (RDoC) framework, as proposed by the National Institute of Mental Health, we aim to synthesize the existing literature concerning the impact of lysergic acid diethylamide (LSD) on the RDoC's Positive Valence...
A significant proportion of adults with major depressive disorder (MDD) do not respond to treatments which are currently used in clinical practice such as first-generation monoamine-based antidepressants. The objective of this systematic review was to assess the efficacy, safety, and mechanisms of action of AXS-05, a combination of the NMDA-receptor antagonist dextromethorphan with bupropion,...
Anxiety disorders (ADs) represent the sixth leading cause of disability worldwide, resulting in a significant global economic burden. Over 50% of individuals with ADs do not respond to standard therapies, making the identification of more effective anxiolytic drugs an ongoing research priority. In this work, we review the preclinical literature concerning the effects of lysergic acid...
Background: Treatment-resistant depression (TRD) is a chronic illness requiring long-term treatment. Esketamine nasal spray (ESK) has been studied in several long-term trials of patients with TRD, including SUSTAIN-1 (NCT02493868) and SUSTAIN-3 (NCT02782104). This subgroup analysis of SUSTAIN-3 evaluated patients with TRD who received a second induction (IND) and maintenance treatment with ESK...
Anorexia nervosa is a disorder associated with serious adverse health outcomes, for which there is currently considerable treatment ineffectiveness. Characterised by restrictive eating behaviours, distorted body image perceptions and excessive physical activity, there is growing recognition anorexia nervosa is associated with underlying dysfunction in excitatory and inhibitory neurometabolite...
An oral, fixed-dose combination of dextromethorphan hydrobromide [an uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist] and the antidepressant bupropion hydrochloride (an aminoketone and CYP2D6 inhibitor that increases dextromethorphan bioavailability) [AUVELITYTM; dextromethorphan/bupropion], is being developed by Axsome Therapeutics, Inc. for the...
Preliminary results from randomized controlled studies as well as identified molecular, cellular, and circuit targets of select psychedelics (e.g., psilocybin) suggest that their effects are transdiagnostic. In this review, we exploit the Research Domain Criteria (RDoC) transdiagnostic framework, to synthesize extant literature on psilocybin. We aimed to identify RDoC-based effects of...
Intravenous (IV) ketamine is increasingly used off-label at subanesthetic doses for its rapid antidepressant effect, and intranasal (IN) esketamine has been recently approved in several countries for treating depression. The clinical utility of these treatments is limited by a paucity of publicly funded IV ketamine and IN esketamine programs and cost barriers to private treatment programs, as...