Pharmacological Reports
April 16, 2020
J. Kryst, P. Kawalec, Alicja Mikrut Mitoraj et al.
157 citations
A meta-analysis of 20 randomized controlled trials found that a single dose of ketamine produces a rapid and robust antidepressant effect in patients with major depression, with the largest reduction in depressive symptoms observed at 24 hours and effects lasting up to 7 days. The effect was significant in treatment-resistant patients and when ketamine was added to ongoing antidepressant treatment, but not when used as monotherapy at 7 days. Repeated ketamine administration sustained the initial antidepressant effects over 2–3 weeks, with significant reductions in depression severity scores compared to placebo.
Expert Opinion on Drug Discovery
August 8, 2022
Andrzej Pilc, Agata Machaczka, Paweł Kawalec et al.
20 citations
A new generation of antidepressant drugs is emerging that works faster and helps patients who do not respond to current treatments. Unlike standard antidepressants that take weeks to work, these compounds—including ketamine, psilocybin, and scopolamine—can produce rapid effects, often after a single dose, and their benefits outlast the drug's presence in the brain. Their mechanism involves enhancing AMPA receptor function and antagonizing mGlu2/3 receptors, pointing to a strong glutamatergic component. Based on accumulating preclinical and clinical data, new drug approvals are expected soon.
Expert Opinion on Emerging Drugs
October 2, 2023
Katarzyna Śladowska, Paweł Kawalec, Tomasz Brzostek et al.
4 citations
Psilocybin shows promise in early clinical trials for treating major depressive disorder and treatment-resistant depression, with effects appearing relatively quickly after administration. However, large phase III trials are still needed to confirm its efficacy and safety before it can be approved and accepted by physicians and patients.
Pharmacological reports : PR
December 1, 2023
Barbara Chruścicka-Smaga, Agata Machaczka, Bernadeta Szewczyk et al.
2 citations
Developing a universal pharmacotherapy for depression is challenging due to symptom complexity. Understanding of depression's pathophysiology has shifted from the monoaminergic theory after ketamine's discovery, focusing on glutamatergic transmission as a new target. Glutamate plays a key role in rapid-acting antidepressants (RAAs) like ketamine, scopolamine, and psilocybin. These hallucinogens provide fast, robust, and sustained antidepressant action but have significant undesired effects that limit clinical use. This review explores combining lower doses of RAAs with mGlu2/3 receptor antagonists to reduce adverse effects and improve outcomes, examining behavioral, synaptic, and molecular actions.
The International Journal of Neuropsychopharmacology
August 1, 2025
Yana Babii, C. Barbara, Dorota Bederska‐łojewska et al.
Hallucinogens from different classes, such as scopolamine and psilocybin, show rapid antidepressant effects that are enhanced by blocking group II metabotropic glutamate (mGlu2/3) receptors. In mice, scopolamine reversed depressive-like behaviors induced by chronic mild stress, and a selective M1 muscarinic antagonist produced dose-dependent antidepressant effects potentiated by an mGlu2 receptor negative allosteric modulator. Scopolamine increased extracellular dopamine, serotonin, and glutamate in the frontal cortex, while the mGlu2 modulator had opposite effects on glutamate. A low dose of the mGlu2/3 antagonist LY341495 boosted the antidepressant effect of low-dose psilocybin in the tail suspension test, with rapid onset and long duration, while also reducing hallucinogenic-like head twitch responses. Combined targeting of these systems may allow lower doses and fewer side effects while maintaining antidepressant efficacy.