Hallucinogens, such as lysergic acid diethylamide, act primarily through the 5-hydroxytryptamine 2A (5-HT2A) receptor, but their regulatory mechanisms remain unclear. G protein-coupled receptor 143 (GPR143), an L-3,4-dihydroxyphenylalanine (L-DOPA) receptor, modulates specific GPCRs. We examined the role of GPR143 in the action of 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)....
Dextromethorphan (DM) is an FDA-approved treatment for major depressive disorder when combined with bupropion. DM functions as an inhibitor for 5-HT membrane transporters and antagonist for sigma-1 receptors (S1Rs) and NMDA receptors, which are pharmacological actions potentially therapeutically relevant for obsessive-compulsive disorder (OCD). The present study examined DM and compounds...
Psilocybin has emerged as a transformative, rapid-acting, and long-lasting therapeutic for treatment-resistant depression, with its efficacy rooted in the induction of sustained structural and functional remodeling of mood-regulating neural circuits 1 , 2 . However, the field faces a fundamental mechanistic paradox that defies linear signaling models: psilocin, the bioactive metabolite of...
Despite renewed investigations into classical psychedelic compounds, their pharmacokinetic profiles remain incompletely understood. This systematic review collated data from healthy adult volunteers on the pharmacokinetic properties of lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), mescaline, and 5-methoxy-N,N-dimethyltryptamine (5-MEO-DMT). We identified 32 eligible...
Major depressive disorder (MDD) and treatment-resistant depression (TRD) remain leading causes of disability, providing the impetus for receptor-level treatment strategies beyond monoamine reuptake. The serotonin 5-HT2B receptor (5-HT2BR) is uniquely positioned at the interface of central-antidepressant mechanisms and peripheral cardiac risks. Herein, we reviewed preclinical, translational and...
High Resolution Image Download MS PowerPoint Slide Tryptamine psychedelics induce psychoactive effects via agonist actions at serotonin 2A receptors (5-HT 2A ), but the compounds are generally nonselective. 4-Methoxy- N -methyl- N -isopropyltryptamine (4-MeO-MiPT) is a 5-HT 2A agonist which also blocks the 5-HT transporter (SERT) and has blunted visual and other psychedelic effects in humans....
Background and objective: Anxiety disorders are among the most prevalent psychiatric disorders worldwide and affect all age groups. Current pharmacological treatments, such as selective serotonergic reuptake inhibitors (SSRI’s) and benzodiazepines, have limitations in terms of adverse effects and efficacy, which highlights the need for alternative therapies. Serotonergic psychedelics have...
High Resolution Image Download MS PowerPoint Slide Serotonin 5-HT 2 receptor ligands have attracted the attention of medicinal chemists for the last half-century, first as hallucinogens and later for their antipsychotic, appetite suppressant, antiaddictive and antidepressant potential. Unlike the very potent N -benzylphenethylamine derivatives that include the abundantly studied NBOMe drugs, N...
Aging is associated with chronic, low-grade inflammation ("inflammaging"), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer's disease, and Parkinson's disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug-drug interactions. Psilocybin, a serotonergic...
Abstract Background and Purpose New synthetic cannabinoid receptor agonists (SCRAs) are associated with severe adverse effects, including unexpected psychiatric symptoms. These compounds are mainly active through their potent agonism on the cannabinoid receptors CB 1 and CB 2 . Recently, evidence of the direct interaction of some SCRAs with the serotonergic 5‐HT receptors has emerged....
Serotonergic psychedelics are being investigated in the treatment of various disorders and in the improvement of well-being. Evidence suggests that their subjective effects may play a role in long-term behavioral outcomes. The subjective effects are mediated by 5-HT2A receptor agonism, but the 5-HT1A receptor may also play a role in the subjective effects. This study elucidates the effects of...
Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau pathology, synaptic dysfunction, and neuroinflammation, which collectively drive progressive memory loss, cognitive decline, and behavioral changes. Increasing evidence implicates epigenetic dysregulation as a key contributor to these pathological processes by altering gene...
Abstract Introduction Ayahuasca is a psychoactive brew used in Amazonian ceremonies, containing monoamine oxidase inhibitors (MAOIs) from Banisteriopsis caapi and N,N-dimethyltryptamine (DMT) from Psychotria viridis or Diplopterys cabrerana. Its global use has expanded for perceived antidepressant and anti-addictive effects. However, its MAOI content predisposes users to serotonergic toxicity...
Recent studies highlight the promising use of psychedelic therapies for psychiatric disorders, including depression. The persisting clinical effects of psychedelics such as psilocybin are commonly attributed to activation of the serotonin 2A receptor (5-HT2AR) based on its role in the acute hallucinatory effects. However, the active metabolite of psilocybin binds to many serotonin receptor...
Aim This study aims to compare two treatment procedures (standard selective serotonin reuptake inhibitors and rapid-acting therapies/specifically ketamine) for patients suffering from treatment-resistant depression along with evaluating the effectiveness of these approaches in alleviating symptoms and improving patient outcomes. Materials and Methods This study examined 80 patients suffering...
Provided herein are novel indoline derivatives serotonergic psychedelic agents as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating psychosis, mental illness and central nervous system (CNS) disorders and processes for preparing such compounds.
Hallucinations are perceptual disturbances occurring without external stimuli, commonly observed in psychiatric disorders such as schizophrenia and substance-induced psychosis. Dysregulation of monoaminergic neurotransmitters, particularly dopamine and serotonin, plays a central role in their pathophysiology. Dopaminergic hyperactivity in the mesolimbic pathway leads to aberrant salience...
Serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) and 4-phosphoryloxy-N,N-dimethyltryptamine (psilocybin) show therapeutic promise for psychiatric and neurodegenerative disorders but may be limited by liabilities from serotonin (5-HT)-2A mediated psychoactive effects and potential cardiotoxicity via 5-HT2B activation. To address these limitations, we designed and synthesized...
Serotonergic psychedelics primarily exert their effects through activation of the serotonin (5-HT) 2A receptor (5-HT 2A R). However, the full pharmacological profiles of these substances involve multiple serotonin receptor subtypes and intracellular signaling pathways. This study characterized the signaling behavior of a panel of serotonergic psychedelics using stable cell lines and a series of...