The International Journal of Neuropsychopharmacology
July 9, 2019
Maggie Fedgchin, Madhukar Trivedi, Ella J Daly et al.
593 citations
In a phase 3 trial of 346 adults with moderate-to-severe treatment-resistant depression, adding esketamine nasal spray (56 or 84 mg twice weekly) to a new oral antidepressant for 4 weeks did not significantly reduce depression scores compared to adding placebo nasal spray. The 84 mg dose failed to separate from placebo on the primary outcome, and the 56 mg dose could not be formally tested due to the statistical hierarchy. However, the magnitude of improvement with both esketamine doses exceeded what is typically considered clinically meaningful for approved antidepressants. Common side effects included nausea, dissociation, dizziness, vertigo, and headache. The authors conclude the results provide supportive evidence for esketamine's safety and efficacy in treatment-resistant depression.
American Journal of Psychiatry
April 8, 2016
Jaskaran Singh, Maggie Fedgchin, Ella Daly et al.
530 citations
In adults with treatment-resistant depression, intravenous ketamine (0.5 mg/kg) given two or three times per week produced a substantial and similar reduction in depression scores over 15 days compared to placebo. The twice-weekly ketamine group showed an average 18.4-point drop on the Montgomery-Åsberg Depression Rating Scale, versus 5.7 points for placebo; the thrice-weekly group showed a 17.7-point drop, versus 3.1 points for placebo. Headache, anxiety, dissociation, nausea, and dizziness were common side effects, but dissociative symptoms were temporary and lessened with repeated doses.
The Journal of Clinical Psychiatry
May 26, 2020
George I. Papakostas, Naji C. Salloum, Rebecca S. Hock et al.
107 citations
Adjunctive intranasal esketamine is more effective than placebo for treating major depressive disorder. Pooling five randomized, double-blind trials with 774 patients, esketamine outperformed placebo on depression rating scale score change, response, and remission. The effect was statistically significant across different study samples and baseline antidepressant regimens. Esketamine appears to be an effective treatment strategy for patients who are treatment-resistant or acutely suicidal.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
Depression and Anxiety
December 30, 2018
Naji C. Salloum, Maurizio Fava, Marlene P. Freeman et al.
49 citations
In a double-blind trial, 99 people with treatment-resistant depression received either a single intravenous dose of ketamine (0.1, 0.2, 0.5, or 1.0 mg/kg) or midazolam (0.045 mg/kg). Among them, 45 had high baseline anxiety and 54 did not. No significant difference in depression improvement was found between the ketamine and midazolam groups for either anxious or nonanxious participants at 1 or 3 days after infusion. The results suggest that ketamine may work similarly for both anxious and nonanxious treatment-resistant depression, unlike some traditional antidepressants.
Journal of Clinical Psychopharmacology
April 25, 2020
Marlene P. Freeman, Rebecca S. Hock, George I. Papakostas et al.
45 citations
Higher body mass index (BMI) and obesity are linked to a stronger acute antidepressant effect from a single intravenous dose of ketamine in patients with treatment-resistant depression. In a randomized, double-blind, placebo-controlled trial, patients with obesity showed a significantly greater reduction in depression symptoms 24 hours after ketamine infusion compared to those with normal BMI. Overweight patients also showed a trend toward greater improvement. Similar but weaker effects were observed at 72 hours. The findings suggest that obesity may enhance the rapid antidepressant response to ketamine, which could have clinical relevance for the many patients with both major depressive disorder and obesity.
World Psychiatry
June 1, 2024
Matthew D. Sacchet, Maurizio Fava, Eric L. Garland
35 citations
Meditation and psychedelics both appear to alter self-referential processing, potentially leading to experiences of self-transcendence. This review examines whether scientific investigation of self-transcendence through these methods has clinical relevance. The authors suggest that changes in self-referential processing may underlie therapeutic benefits for mental health conditions, though the exact mechanisms remain unclear. The paper argues that understanding how meditation and psychedelics modulate the sense of self could inform new treatments for disorders characterized by maladaptive self-focus, such as depression and anxiety.
JAMA
October 21, 2025
Reid Robison, Robert Barrow, Craig Conant et al.
22 citations
A single dose of MM120 (lysergide D-tartrate) reduces anxiety in a dose-dependent way in adults with moderate to severe generalized anxiety disorder. In a phase 2b randomized, double-blind, placebo-controlled trial with 198 participants, the 100-µg and 200-µg doses produced significantly greater reductions in Hamilton Anxiety Rating Scale scores at 4 weeks than placebo, with differences of -5.0 and -6.0 points, respectively. Lower doses (25 µg and 50 µg) did not differ from placebo. Common side effects included visual perceptual changes and nausea, which increased with dose.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
January 1, 2024
Maurizio Fava
22 citations
New molecular targets and novel treatments for neuropsychiatric diseases, including psychedelics and gene and cell therapies, require more efficient clinical trials. This review examines factors that hinder the detection of therapeutic signals, such as excessive placebo or sham responses and imprecise diagnostic and outcome measures. It also presents methodological approaches to improve trial performance, including the sequential parallel comparison design and independent confirmation of subject enrollment, along with designs that increase the precision of mechanistic trials.
International Journal of Molecular Sciences
August 7, 2023
Alexander Pilozzi, Simmie Foster, David Mischoulon et al.
16 citations
Alzheimer's disease, the most common form of senile dementia, will impose a growing societal and healthcare burden as the population ages. With few treatments for symptomatic relief and unknown causes, more research is urgently needed. Psychedelic drugs target AD-related psychological pathology and symptoms such as depression. Through microdosing, they may help combat the disease by eliciting psychiatric benefits via serotonin and dopamine pathways. This review examines studied benefits of a few psychedelic compounds that may show promise in treating AD and attenuating its depressive symptoms. The putative mechanism of action is that psychedelics act mainly as serotonin receptor agonists and induce potential beneficial effects for treating AD and related depression.
Nature. Mental health
October 1, 2024
Luana Colloca, Maurizio Fava
9 citations
Placebo-controlled trials of MDMA and classical psychedelics like psilocybin, LSD, and DMT for neuropsychiatric disorders have increased, but their success depends on trial design, control conditions, and blinding. Without appropriate controls, placebo and expectation effects are hard to separate from medication effects. This paper explores the neurobiology of placebo and expectation effects and methodological considerations for selecting suitable control conditions, examining advantages and disadvantages of various options and proposing new directions to enhance trial validity and regulatory science.
The Journal of Clinical Psychiatry
November 14, 2022
Anna Feeney, Bettina B. Hoeppner, Marlene P. Freeman et al.
9 citations
Among people with treatment-resistant depression, those taking oral benzodiazepines alongside a single intravenous infusion of ketamine showed less improvement in depression scores 24 hours later if they were on higher benzodiazepine doses. The same pattern was not seen in those who received a midazolam placebo. By day 3 after the infusion, benzodiazepine use no longer affected depression scores. The findings suggest that higher doses of benzodiazepines may temporarily weaken ketamine's rapid antidepressant effect.
Journal of psychopharmacology (Oxford, England)
July 13, 2026
Todd D Gould, Sanjay J Mathew, Maurizio Fava et al.
A new pharmacological model called event-driven pharmacology (EDP) is described, in which a plastogen—a drug that induces lasting neural plasticity—produces sustained effects after only transient binding, unlike traditional drugs that require continuous receptor occupancy. Plastogens such as ketamine and classical psychedelics can trigger metaplasticity, priming synapses to respond to later stimuli long after the drug has left the body. Dosing such drugs to maintain constant target occupancy may paradoxically reduce benefits and increase side effects. The EDP model calls for new drug development, dosing strategies, and biomarkers to harness the therapeutic potential of plastogens for depression and other synaptic disorders.
Molecular psychiatry
June 25, 2026
Clotilde Guidetti, Maurizio Fava, George I. Papakostas
Major depressive disorder and treatment-resistant depression affect many people, and over half of patients do not respond adequately to first-line antidepressants. This review examines promising rapid-acting treatments, including psychedelic compounds like psilocybin, which is in late-stage trials, and neuroplastogen compounds. It also discusses repetitive transcranial magnetic stimulation, including the SAINT protocol, which has shown rapid antidepressant effects and is FDA-cleared for treatment-resistant depression. The ALTO-300 trial is evaluating an adjunctive treatment guided by an EEG biomarker, and a Phase 2 study reports outcomes varying by genotype, suggesting potential for genetically personalized interventions. Challenges include unblinding in psychedelic trials, scalability of neuromodulation, and need for validated biomarkers.
International journal of molecular sciences
October 13, 2022
Stephen M Stahl, Sara De Martin, Andrea Mattarei et al.
Esmethadone (REL-1017) and other uncompetitive NMDAR antagonists may rapidly relieve depression by preferentially blocking hyperactive GluN2D subtypes, restoring physiological neural plasticity. In major depressive disorder, upregulated tonic calcium currents through GluN2D subtypes reduce homeostatic availability of synaptic proteins, contributing to depressive behaviors. Low-potency NMDAR antagonists' selectivity for GluN2D may explain their rapid antidepressant effects without dissociative side effects.