Proceedings of the National Academy of Sciences
April 13, 2021
Natalie Hesselgrave, Timothy A. Troppoli, Andreas B. Wulff et al.
380 citations
Psilocybin, a psychedelic compound, has fast-acting antidepressant-like effects in mice. Using tests of hedonic behavior and a drug that blocks hallucinogenic 5-HT2A receptors, the results suggest that altered perception may not be required for its therapeutic benefits. Psilocybin also strengthens connections between brain cells in regions involved in reward and emotion processing. These findings indicate it may be possible to retain psilocybin's antidepressant actions while minimizing alterations in consciousness.
The Annual Review of Pharmacology and Toxicology
October 9, 2018
Todd D Gould, Carlos A. Zarate, Scott M. Thompson
132 citations
Depression has long been treated with drugs that target monoamine brain systems, but these take weeks to work. Low doses of ketamine can improve core depressive symptoms—including mood, anhedonia, and suicidal ideation—within hours after a single dose, with effects lasting up to a week. This discovery has shifted thinking about how depression might be treated more effectively. This review covers clinical data on ketamine and other rapid-acting antidepressants and what is known about their mechanisms. It also discusses brain circuits engaged by these drugs and future medication targets such as hydroxynorketamine, metabotropic glutamate receptor 2/3 antagonists, and modulators of NMDA, AMPA, and GABA receptors.
Journal of Neuroscience
January 3, 2023
Panos Zanos, Kyle A Brown, Polymnia Georgiou et al.
109 citations
Ketamine, an NMDA receptor antagonist, produces rapid antidepressant effects, but the role of NMDA receptor activation in these effects is unclear. In male mice, ketamine showed an inverted U-shaped dose-response in antidepressant-sensitive tests, indicating that excessive NMDA receptor inhibition can prevent its antidepressant actions. Pretreatment with other NMDA receptor antagonists blocked ketamine's behavioral effects, upregulation of AMPA receptor subunits, and metaplasticity. The antidepressant-like actions of other rapid-acting compounds were also blocked by NMDA receptor inhibition. Ketamine acted synergistically with an NMDA receptor positive allosteric modulator. The authors conclude that rapid-acting antidepressants share a common downstream NMDA receptor activation-dependent effector mechanism, and promoting NMDA receptor signaling may be an effective antidepressant strategy.
Molecular Psychiatry
December 1, 2024
Chloe E Page, C Neill Epperson, Andrew M Novick et al.
54 citations
Major depressive disorder (MDD) is better understood not as a serotonin deficit but as inflexibility in cognitive and emotional brain circuits that creates a persistent negativity bias. Effective treatments—including conventional antidepressants, ketamine, psychedelics, psychotherapy, and neuromodulation—work by enhancing neuroplasticity, restoring synaptic, network, and behavioral function to enable adaptive cognitive and emotional processing. The article provides accessible language and metaphors for clinicians and researchers to communicate this updated framework to patients and the public, aiming to improve understanding and trust.
Neuropharmacology
March 13, 2023
Andreas B. Wulff, Charles D. Nichols, Scott M. Thompson
30 citations
Psychedelic compounds like psilocybin show promise for treating neuropsychiatric disorders, with clinical trials demonstrating rapid (within days) and persistent (3-12 months) improvement in treatment-resistant depression. This review examines preclinical models and experimental approaches used to study the neurobiological actions of psychedelic drugs, summarizing insights into mechanisms underlying therapeutic effects, including receptor binding and second messenger signaling cascades. It also discusses potential biological processes such as improvements in synaptic structure and function and suppression of inflammation that may produce lasting symptom amelioration. Better mechanistic understanding will advance these medicines.
ACS Pharmacology & Translational Science
August 22, 2025
Devin P. Effinger, Serena S. Schalk, Jillian L. King et al.
3 citations
Microdosing involves taking psychedelics at doses too low to cause hallucinations, and is popular for supposed cognitive and emotional benefits. Psychedelics bind strongly to 5-HT 2B receptors, which can cause heart disease when chronically activated. In mice, researchers gave either serotonin or d-fenfluramine as positive controls, or low doses of LSD. Serotonin caused significant ventricular thickening at 4 and 8 weeks; d-fenfluramine caused aortic valve regurgitation at 4 weeks. No significant heart changes appeared in any LSD group. LSD, psilocybin, and norfenfluramine had similar affinity and potency at mouse and human 5-HT 2B receptors. Low-dose LSD produced substantial but short-lived receptor activation compared to d-fenfluramine. These data provide no evidence that prolonged low-dose LSD causes heart remodeling in mice.
Cell Reports
May 21, 2025
Lace M Riggs, Sage Aronson, Ta-Chung M Mou et al.
2 citations
A single dose of (2R,6R)-hydroxynorketamine (HNK), a metabolite of ketamine, rapidly strengthens weakened synapses in a rat model of treatment-resistant depression. In plasticity-deficient Wistar Kyoto rats, (2R,6R)-HNK boosted glutamatergic transmission, restored long-term potentiation (LTP), and reversed deficits in hippocampal-dependent memory. The drug selectively increased activity of CA1 pyramidal neurons during novelty exploration and restored spatial recognition memory reliant on Schaffer collateral pathways. Prior spatial learning partially blocked LTP in control rats, a pattern mirrored in LTP-impaired rats where spatial learning deficits were reversed by (2R,6R)-HNK. The findings indicate that (2R,6R)-HNK promotes adaptive synaptic changes at impaired synapses, improving cognitive function.
bioRxiv (Cold Spring Harbor Laboratory)
April 14, 2025
Devin P. Effinger, Serena S. Schalk, Jillian L. King et al.
2 citations
preprint
Chronic administration of low-dose LSD in mice does not produce the cardiovascular damage seen with serotonin, a known cardiotoxin. Serotonin caused significant ventricular thickening after 4 and 8 weeks, while LSD at two sub-hallucinogenic doses showed no such changes. Although LSD activates 5-HT 2B receptors—the same receptors linked to heart disease from chronic activation—the activation is substantial but short-lived compared to the cardiotoxin d-fenfluramine. Affinity and potency of LSD, psilocybin, and norfenfluramine at mouse and human 5-HT 2B receptors were similar. These findings indicate no evidence of cardiovascular risk from prolonged low-dose LSD in mice.
Translational Psychiatry
June 13, 2026
Jillian L. King, Devin P. Effinger, Cameron Basquez-Pfeifer et al.
The head-twitch response (HTR) in mice, a standard test for hallucinogenic potential, fails to reliably indicate overall psychoactivity. Lisuride, which did not produce HTR, caused impaired movement, coordination, stress, cognitive disruption, and reduced prefrontal cortex EEG power. LSD, which triggered strong HTR, had minimal effects on these measures. Neither compound's effects beyond HTR depended on 5-HT₂A receptors. The HTR alone is insufficient and should be combined with other assessments.
British Journal of Pharmacology
July 1, 2019
Panos Zanos, Jaclyn N. Highland, Xin Liu et al.
In mice, (R)-ketamine's metabolism to (2R,6R)-hydroxynorketamine (HNK) enhances its antidepressant-relevant actions. A deuterated form of (R)-ketamine that blocks this metabolism had less potency in antidepressant-sensitive behavioral tests, while (2R,6R)-HNK itself produced dose-dependent sustained antidepressant effects. However, (R)-ketamine also caused NMDA receptor-mediated adverse effects—including locomotor stimulation, conditioned-place preference, prepulse inhibition deficits, and motor incoordination—at sub-anaesthetic doses, with about half the potency of racemic ketamine. These findings indicate that while antidepressant-relevant effects occur at lower doses, there is a potential risk for sensory dissociation and abuse liability at higher doses.