Expert opinion on therapeutic targets
June 1, 2025
Naomi Xiao, Liyang Yin, Kayla M Teopiz et al.
5 citations
Sigma-1 receptors (S1Rs) may be a target and mediator of antidepressant activity. They regulate neurotransmitter release (including monoamines and glutamate), influence intracellular calcium levels, and affect immune inflammatory responses. In August 2022, the FDA approved dextromethorphan-bupropion, the first antidepressant whose hypothesized mechanism includes activity at S1Rs. The review synthesizes preclinical and clinical data on S1R physiology, pathophysiology, and function. Modulating sigma-1 systems is relevant to current FDA-approved treatments for major depressive disorder and may inform future therapeutic development. Whether sigma-1 modulation uniquely targets difficult-to-treat symptoms like anhedonia remains unknown.
Pharmacopsychiatry
February 5, 2026
Tianyi Xu, Sabrina Wong, Gia Han Le et al.
Lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine activate the 5-hydroxytryptamine 2B receptor, a pathway known to cause drug-induced valvular heart disease. This systematic review of 17 studies found no research on psilocybin, dimethyltryptamine, or mescaline. Both lysergic acid diethylamide and 3,4-methylenedioxymethamphetamine show high or moderate affinity for this receptor and promote signaling linked to fibrotic changes in heart valve tissue. In vivo studies confirm serotonin-induced valvulopathy, and chronic 3,4-methylenedioxymethamphetamine use has been associated with valve abnormalities in humans. No clinical cases of lysergic acid diethylamide-induced valvulopathy have been reported, but preclinical data suggest potential for fibrotic signaling under sustained exposure. Preliminary evidence supports the need for cardiac safety monitoring in psychedelic research.
Journal of affective disorders
February 1, 2026
Kayla M Teopiz, Sabrina Wong, Gia Han Le et al.
Reward processing disruptions in major depressive disorder (MDD) may relate to altered frontostriatal brain activity. Glutamatergic modulators might improve reward function. This systematic review examined 11 fMRI studies testing glutamatergic agents—ketamine (9 studies), nitrous oxide (1), and memantine (1)—on frontostriatal activity in people with MDD or healthy controls. Preliminary evidence suggests intravenous ketamine may alter functional connectivity in striatal regions, potentially relevant to improved reward function in treatment-resistant depression. More research is needed on how these modulators affect reward-related brain structures, the timing of effects, and baseline characteristics predicting antidepressant response.