Pharmacological Research
June 26, 2023
Tao Chen, Ling Cheng, Jingwen Ma et al.
48 citations
Major depressive disorder is a chronic relapsing condition. Conventional antidepressants take weeks to work and are ineffective for many patients. The NMDA receptor antagonist ketamine produces rapid antidepressant effects, not only by blocking postsynaptic NMDA receptors or GABA interneurons but also by affecting AMPA receptors, adenosine A1 receptors, and L-type calcium channels. The 5-HT2A receptor agonist psilocybin has also shown potential for rapid antidepressant effects in mouse models and clinical studies. This review examines new pharmacological targets of emerging rapid-acting antidepressants like ketamine and hallucinogens (e.g., psilocybin) and discusses possible strategies for future antidepressant research.
Pharmacological Research
April 1, 2023
Deborah C. Mash
37 citations
Ibogaine is a psychoactive substance that alters perception and mood and can interrupt addictive behaviors. It has a long history of ethnobotanical use in low doses for combating fatigue, hunger, and thirst, and in high doses as a sacrament in African rituals. In the 1960s, self-help groups reported that a single dose alleviated drug craving, opioid withdrawal, and prevented relapse for weeks to years. Ibogaine is rapidly metabolized to noribogaine, and both interact with multiple central nervous system targets, showing predictive validity in animal addiction models. Over ten thousand people have sought unregulated treatment, and open-label pilot studies show positive benefit. Ibogaine has regulatory approval for a Phase 1/2a clinical trial.
Pharmacological Research
March 1, 2024
Sandra Ledesma-Corvi, Jordi Jornet-Plaza, Laura Gálvez-melero et al.
22 citations
Adolescent depression often requires faster-acting treatments than standard selective serotonin reuptake inhibitors, which take weeks to work. This review examines promising fast-acting options for adolescents, including non-pharmacological neuromodulation (electroconvulsive therapy and other brain stimulation) and pharmacological approaches such as ketamine, classical psychedelics, and cannabidiol. Most clinical evidence for these therapies comes from adult studies, but recent preclinical work is beginning to address sex-, age-, and dose-related differences that may affect efficacy and safety in adolescents. The authors call for more clinical studies and for designing novel treatments that are both safe and fast-acting for this age group.
Pharmacological Research
September 1, 2024
Giorgia Caspani, Simon Ruffell, WaiFung Tsang et al.
13 citations
Psychedelics show promise for treating psychiatric disorders, but current explanations focus mainly on their action at serotonin receptors in the brain. This review argues that the gut microbiota, via the gut-brain axis, may also play a role. Evidence suggests psychedelics can alter gut microbiota composition, and microbial metabolism might influence psychedelic effects. The authors call for incorporating microbiome hypotheses into future research, which could lead to personalized psychedelic therapies tailored to individual gut microbiota profiles.
Pharmacological Research
January 1, 2024
David B. Yaden, Andrea P Berghella, Peter S. Hendricks et al.
12 citations
Classic psychedelic-assisted therapies show initial promise for treating substance use disorders (SUDs) and may become legally available options. This article describes how these therapies could fit within current evidence-based SUD treatments, suggesting broad compatibility with most mainstream clinical approaches.
Pharmacological Research
May 1, 2025
Eda Koseli, Belle Buzzi, Torin Honaker et al.
11 citations
Psilocybin and a similar psychedelic, DOI, reduced pain-related behaviors in mice with chronic pain. In a mouse model of chemotherapy-induced nerve damage, both drugs reversed sensitivity to cold and touch in a dose-dependent manner, with different timing of effects. In a model of persistent inflammatory pain, they also reversed sensitivity to heat. These pain-relieving effects depended on activation of the 5-HT2A serotonin receptor. The findings suggest that classical psychedelics may be effective for treating chronic pain through this receptor pathway.
Pharmacological Research
July 31, 2025
C. Pisanu, R. Carvalho Silva, Mattia Meattini et al.
6 citations
Ketamine and esketamine can rapidly relieve depression that does not respond to standard treatments, but how they work at the molecular level is not well understood. A systematic review of 12 studies examined changes in gene activity (RNA expression) after ketamine or esketamine treatment in people with depression or in human cells grown in the lab. The studies found that these drugs alter the activity of genes involved in brain cell communication, immune regulation, and the brain's ability to adapt and change. However, no single consistent marker in the blood was identified across studies. The findings suggest that mapping gene activity patterns could help reveal how these treatments work and identify who might benefit most, though more research is needed.
Pharmacological Research
January 1, 2025
Nicole R Silva, Shokouh Arjmand, Luana B Domingos et al.
6 citations
In a rat model of depression (Flinders Sensitive Line), depressive behavior was negatively correlated with levels of the endocannabinoid 2-AG. A single dose of S-ketamine restored 2-AG levels and increased endocannabinoid signaling in the prefrontal cortex. Although S-ketamine decreased gene expression of the CB1 receptor and the enzyme FAAH, protein levels did not change significantly. S-ketamine increased CB1 receptor binding, and computer modeling suggested it may bind to CB1, CB2, GPR55, and FAAH. However, blocking CB1 receptors with rimonabant did not prevent S-ketamine's behavioral effects, indicating a complex interaction with the endocannabinoid system that requires further study.
Pharmacological Research
November 22, 2025
Zhuo-Ning Zhang, Xin-Yu Hao, Chen Cai et al.
5 citations
A single low dose of esketamine given at the start of cardiac valve surgery reduced rates of depression and anxiety one week after surgery. Among 142 patients, those receiving esketamine had a depression rate of 7.0% compared to 31.0% in the placebo group, and an anxiety rate of 11.3% versus 35.2%. Esketamine also lowered delirium incidence, improved pain, sleep, and recovery quality, and reduced inflammatory markers (IL-6, CRP) and a neuronal injury marker (S100β) while increasing brain-derived neurotrophic factor (BDNF). Side effects did not differ between groups.
Pharmacological Research
July 1, 2024
Ke Wang, Xuan Tan, Kai-Mo Ding et al.
5 citations
Ketamine rapidly alleviates depression-like behaviors by restoring the balance of NR2B phosphorylation both inside and outside synapses in the medial prefrontal cortex. In mice subjected to chronic unpredictable stress, ketamine normalized abnormal levels of phosphorylated NR2B and the phosphatase STEP61 within one hour. The findings indicate that the rapid antidepressant effects of ketamine depend on dynamic regulation of NR2B phosphorylation, offering a new target for developing antidepressant treatments.
Pharmacological Research
May 14, 2025
Rebecca Morris, Janet Treasure, Hubertus Himmerich et al.
4 citations
People with eating disorders often also have anxiety disorders, which can worsen eating disorder symptoms and interfere with treatment. This systematic review examined 51 studies on medications for anxiety in people with eating disorders. Results were mixed: fluoxetine helped anxiety in anorexia and bulimia nervosa but not binge eating disorder; olanzapine showed benefits for anxiety in anorexia nervosa, with preliminary case reports suggesting its use in ARFID. Early evidence for psilocybin and ketamine reported favorable anxiety outcomes in anorexia nervosa patients. More randomized controlled trials are needed to establish efficacy and safety.
Pharmacological Research
December 29, 2025
Martina Colognesi, Daniela Gabbia, Anna Signor et al.
3 citations
Chronic low-dose psilocybin (0.05 mg/kg) reduced body-weight gain, liver steatosis, hyperglycemia, and insulin resistance in mice fed a high-fat/high-fructose diet, without causing central nervous system effects. Multi-omics analyses showed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. The metabolic benefits were independent of the psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver, supporting psilocybin as a potential novel therapeutic for metabolic disorders.
Pharmacological Research
February 1, 2025
Michaela Dvorakova, Ken Mackie, Alex Straiker
2 citations
Coactivating muscarinic acetylcholine receptors and eliciting depolarization-induced suppression of excitation (DSE) in autaptic hippocampal neurons produces a roughly 40% inhibition of excitatory transmission lasting about 10 minutes. This inhibition, termed muscarinic cannabinoid suppression of excitation (MCSE), requires CB1 and muscarinic M3/M5 receptors and is absent in CB1 receptor knockout neurons. Once established, it is reversed by a CB1 antagonist but not a muscarinic antagonist, indicating persistent CB1 receptor activation. MCSE can be mimicked by coapplying muscarinic and cannabinoid agonists and depends on calcium release from internal stores. This represents a novel coincidence detection between cannabinoid and muscarinic signaling systems, potentially modulating hippocampal signaling with implications for learning, memory, epilepsy, and addiction.
Pharmacological Research
July 1, 2026
Yang Zhou, Wanchen Sun, Yuxuan Fu et al.
Among patients undergoing major surgery who had moderate-to-severe depressive symptoms before the operation, a single intraoperative dose of esketamine led to a higher rate of symptom remission three days after surgery compared with a placebo. In a randomized, double-blind trial of 435 patients, 28.3% in the esketamine group achieved remission versus 11.3% in the placebo group. Acute pain rates did not differ between groups. Esketamine treatment requires monitoring for possible dissociative side effects, and its clinical use for depressive symptoms should weigh benefits against risks.
Pharmacological Research
October 1, 2025
Florian Freudenberg, Christine Reif-Leonhard, Gerard R Dawson et al.
Treatment-resistant depression (TRD) affects about 30% of patients with major depressive disorder. While antidepressant development has long focused on monoamine targets, research over the past 35 years has increasingly explored glutamatergic mechanisms. This review discusses developments in glutamatergic drug discovery, emphasizing convergent mechanisms between NMDA and AMPA receptor signaling. Beyond established rapid-acting antidepressants like (es)ketamine and dextromethorphan/bupropion, novel directions include esmethadone, nitrous oxide, and NMDA receptor positive allosteric modulators (rapastinel, zelquistinel, apimostinel), as well as AMPA receptor PAMs (osavampator, tulrampator). The convergent mechanism involves increased AMPA receptor activation, triggering BDNF release and mTOR signaling, promoting synaptic strengthening. Glutamatergic agents represent a transformative path for TRD treatment.
Pharmacological Research
May 1, 2022
C. Carvalho, M. Vieira-Coelho
Genetic variations in dopamine-related genes, particularly COMT rs4680 with the Val allele and AKT1 rs2494732 with the CC genotype, are associated with a higher risk of cannabis-induced psychosis. A genome-wide association study identified signals near the cholinergic receptor muscarinic 3 linked to cannabis-induced hallucinations, without finding dopaminergic targets. Most genetic studies have been guided by pre-existing dopamine theories, highlighting the need for broader genetic research to improve understanding, prevention, and treatment of cannabis-induced psychosis.
Pharmacological Research
December 1, 2021
Tibor Stark, Serena di Martino, Filippo Drago et al.
Adolescent cannabis use, especially of high-THC strains, is linked to long-term social and cognitive deficits in adulthood, as shown by both human and animal studies. Cannabis disrupts the endocannabinoid system, which normally regulates stress circuitry during brain development. Early intervention may prevent these adult deficits. Cannabidiol (CBD), the second most abundant compound in cannabis, is being studied as a potential treatment for neuropsychiatric disorders. This review examines evidence that adolescent THC exposure represents a critical window of vulnerability, possibly contributing to schizophrenia, and also considers adolescence as a window of opportunity for early CBD treatment to reduce risk of neurodevelopmental disorders. The review covers CBD's efficacy for positive, negative, and cognitive symptoms, its safety, and molecular targets.