Anhedonia is a core feature of major depressive disorder (MDD) that is frequently resistant to available treatments. Psilocybin's specific efficacy for anhedonia remains unclear. To evaluate psilocybin's efficacy for anhedonia in treatment-resistant MDD. In this randomized, double-blind, placebo-controlled trial, 20 participants with treatment-resistant MDD received psilocybin (25 mg or 1 mg)...
Abstract Oregon (OR) and Colorado (CO) were the first states to enact regulations for provision of psilocybin with support of licensed ‘facilitators.’ As more states and countries adopt similar policies, informed public policy decisions require that client characteristics and rationale for using psilocybin, psilocybin dosing practices, mental health outcomes, and adverse events are understood....
The head-twitch response (HTR) is widely used as a preclinical assay for the hallucinogenic potential of compounds, with its utility based on 5HT 2A R activation. Here, we examine how the polypharmacological agonists lisuride and lysergic acid diethylamide (LSD) influence behavioral and physiological outcomes in mice to test whether the HTR reliably reflects overall psychoactivity. Lisuride...
High Resolution Image Download MS PowerPoint Slide Microdosing, the prolonged ingestion of psychedelics at subhallucinogenic doses, has gained popularity for its perceived cognitive and emotional benefits. Psychedelics have high affinity for 5-HT 2B receptors, a receptor known to cause human heart disease with strong chronic activation. We investigated the effects of microdosed psychedelics on...
Cell ReportsMay 21, 2025Lace M Riggs, Sage Aronson, Ta-Chung M. Mou et al.2 citations
An acute increase in excitatory synaptic transmission contributes to the rapid antidepressant actions of neuroplastogens, including ketamine and its bioactive metabolite, (2R,6R)-hydroxynorketamine (HNK). It is hypothesized that drug-induced metaplastic changes in synaptic strength account for therapeutically relevant behavioral adaptations in vivo. Using the plasticity-deficient Wistar Kyoto...
The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1)...
Psychedelic compounds have shown extraordinary potential in treating a wide range of neuropsychiatric disorders. Psilocybin, for example, has now been shown in several clinical trials to induce a rapid (within days) and persistent (3-12 months) improvement in human treatment-resistant depression and other neuropsychiatric conditions. Here we review the preclinical models and experimental...
Ketamine is a well-characterized NMDA receptor (NMDAR) antagonist, although the relevance of this pharmacology to its rapid (within hours of administration) antidepressant actions, which depend on mechanisms convergent with strengthening of excitatory synapses, is unclear. Activation of synaptic NMDARs is necessary for the induction of canonical long-term potentiation (LTP) leading to a...
Significance Psychedelic compounds, such as psilocybin, have beneficial actions in several psychiatric diseases. They also produce strong alterations of consciousness, which may be a barrier to their widespread use. We found that psilocybin has fast-acting antidepressant-like properties in mice. Using multiple assays of hedonic behavior and an antagonist of prohallucinatory 5-HT2A receptors, we...
(R)-Ketamine (arketamine) may have utility as a rapidly acting antidepressant. While (R)-ketamine has lower potency than (R,S)-ketamine to inhibit NMDA receptors in vitro, the extent to which (R)-ketamine shares the NMDA receptor-mediated adverse effects of (R,S)-ketamine in vivo has not been fully characterised. Furthermore, (R)-ketamine is metabolised to (2R,6R)-hydroxynorketamine (HNK),...
For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal...
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the...
Abstract New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high - frequency correlated activity in mood-relevant regions of...