Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review
Current Treatment Options in Psychiatry April 26, 2024 Noah Chisamore, Erica Kaczmarek, Gia Han Le et al. 8 citations
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Diana Orsini
University Health Network
6 papers in the library · 19 citations · publishing 2024-2026
Papers
Blinding Integrity in Psychedelic Randomized Clinical Trials
JAMA Psychiatry April 15, 2026 Diana Orsini, Sabrina Wong, Sara Di Luch et al. 4 citations
In randomized clinical trials of psychedelic drugs for psychiatric disorders, the drugs' strong subjective effects often reveal which treatment participants or raters think they received, a phenomenon called functional unblinding. A systematic review of 112 trials found that only 29.5% assessed whether blinding was maintained, yet 57.1% cited blinding as a limitation. Blinding failure exceeded 90% in psilocybin, LSD, and ayahuasca studies and 85% in MDMA trials with inert placebos. Ketamine trials rarely assessed blinding but fared better when midazolam was used as an active comparator. No control strategy consistently preserved ideal blinding, raising concerns about the validity of efficacy estimates.
A systematic review of ketamine and esketamine-induced long-term potentiation and synaptic scaling: Do the molecular and synaptic plasticity effects inform dosing intervals?
Journal of affective disorders April 15, 2026 Gia Han Le, Sabrina Wong, Danica E Johnson et al. 4 citations
Ketamine and esketamine rapidly reduce depression in people with treatment-resistant depression and bipolar depression, but the synaptic mechanisms behind dosing and durability are unclear. This review of 61 clinical and 17 preclinical studies found that a single 0.5 mg/kg intravenous infusion produces antidepressant effects peaking at 24 hours and fading over 2-3 days. Early neurophysiological changes appear within 3-8 hours, consolidate by 24 hours, and are rarely detected beyond 3 days. Twice-weekly and thrice-weekly dosing produce comparable four-week outcomes, and weekly maintenance reduces relapse risk. Ketamine may open a plasticity window lasting about 2-3 days, and aligning dosing intervals with this window could optimize durability while minimizing drug exposure.
Biased agonism in psychopharmacology: an opportunity to improve efficacy and safety of treatments.
CNS spectrums August 12, 2025 Gia Han Le, Sabrina Wong, Stavroula Bargiota et al. 3 citations
G protein-coupled receptors (GPCRs) are involved in many bodily processes. Traditional drug classification divides ligands into agonists or antagonists. Biased agonism is a newer concept where a drug selectively activates one intracellular signaling pathway over another, such as G protein versus β-arrestin pathways. This narrative review of literature up to April 2025 describes distinct mechanisms of antagonism and agonism beyond conventional models. Biased agonism has shown potential for greater efficacy, as with the incretin receptor agonist tirzepatide, and improved safety, as with certain serotonergic psychedelics and opioids. Preclinical evidence suggests biased agonism could improve psychiatric and neurological treatments by differentially activating pathways, pending clinical validation.
The Serotonin 2B (5‐ HT2B ) Receptor: A Narrative Review of Preclinical and Clinical Evidence on the Safety Considerations and Therapeutic Potential for the Treatment of Depression
Clinical Pharmacology & Therapeutics May 28, 2026 Gia Han Le, Sabrina Wong, Danica E. Johnson et al.
The serotonin 5-HT2B receptor sits at a crossroads between potential antidepressant effects in the brain and serious heart valve risks when activated peripherally. This narrative review of preclinical and clinical literature finds that peripheral activation of 5-HT2B receptors causes valvular heart disease through cell proliferation and scarring, as seen with older drugs like fenfluramine and some dopamine agonists. In the brain, the receptor's effects are mixed: astrocytic activation may support metabolism and plasticity, while neuronal blockade can normalize dopamine and glutamate activity. Several approved antidepressant adjuncts (aripiprazole, brexpiprazole, cariprazine) antagonize this receptor without observed heart valve problems. The authors propose developing centrally selective, periphery-sparing 5-HT2B antagonists for treatment-resistant depression, with early cardiac monitoring to ensure safety.
Progress, potential and pitfalls of ketamine as a treatment for depression
Expert Opinion on Pharmacotherapy January 22, 2026 Diana Orsini, Sara D Di Luch, Gabrielle F. M. Lovell et al.
A large body of evidence from clinical trials and real-world studies supports the antidepressant effects of intravenous ketamine and intranasal esketamine. Larger studies have provided reassuring safety data, including for long-term treatment. Alternative routes of administration show promise for scalability, but their efficacy relative to intravenous ketamine remains unclear. Preliminary data suggest ketamine may also be effective for bipolar disorders, personality disorders, posttraumatic stress, and obsessive-compulsive disorder. Further research is needed to optimize protocols, such as combining ketamine with other interventions. Challenges include functional unblinding, expectancy-related bias, and treatment costs.