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.
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.
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.