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The Journal of Headache and Pain Jun 2020Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to... (Review)
Review
Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT receptors. The discovery that the serotonin 1F (5-HT) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT receptors, the activation of 5-HT receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.
Topics: Animals; Benzamides; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Neurons; Piperidines; Pyridines; Receptors, Serotonin; Serotonin Receptor Agonists; Trigeminal Ganglion; Tryptamines; Vasoconstriction; Receptor, Serotonin, 5-HT1F
PubMed: 32522164
DOI: 10.1186/s10194-020-01132-3 -
Journal of Psychopharmacology (Oxford,... Nov 2014Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To... (Clinical Trial)
Clinical Trial
Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.
Topics: Attitude; Behavior, Addictive; Biomarkers; Carbon Monoxide; Cognitive Behavioral Therapy; Combined Modality Therapy; Cotinine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Nicotinic Agonists; Pilot Projects; Psilocybin; Serotonin Receptor Agonists; Smoking Cessation; Tobacco Use Disorder; Treatment Outcome
PubMed: 25213996
DOI: 10.1177/0269881114548296 -
Neurotherapeutics : the Journal of the... Apr 2010
Topics: Headache; Humans; Neuropeptides; Nitric Oxide Synthase; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists
PubMed: 20430312
DOI: 10.1016/j.nurt.2010.03.007 -
ACS Chemical Neuroscience Jan 2023Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen,...
Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT receptor agonist, exhibits modest selectivity over 5-HT receptors, has no relevant activity at 5-HT and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (G, G, and β-arrestin2) coupled to 5-HT receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between G activation and β-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson's disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne's lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT agonists, with considerable therapeutic potential across psychiatric and neurological indications.
Topics: Humans; Mice; Animals; Rabbits; Dogs; Aged; Serotonin; Serotonin 5-HT2 Receptor Agonists; Parkinson Disease; Molecular Docking Simulation; Hallucinogens; Serotonin Receptor Agonists; Receptor, Serotonin, 5-HT2A
PubMed: 36521179
DOI: 10.1021/acschemneuro.2c00597 -
Journal of Psychiatry & Neuroscience :... Jan 1999
Topics: Comorbidity; Humans; Obsessive-Compulsive Disorder; Psychiatric Status Rating Scales; Serotonin Receptor Agonists; Treatment Outcome
PubMed: 9987202
DOI: No ID Found -
European Journal of Applied Physiology Feb 2021High-level spinal cord injury (SCI) can result in spinal and supraspinal respiratory control deficits leading to insufficient ventilatory responses to exercise and...
PURPOSE
High-level spinal cord injury (SCI) can result in spinal and supraspinal respiratory control deficits leading to insufficient ventilatory responses to exercise and training-related adaptations. We hypothesized a serotonin agonist, known to improve respiratory function in animal models, would improve adaptations to whole-body functional electrical stimulation (FES) exercise training in patients with acute high-level SCI.
METHODS
We identified 10 patients (< 2 years of injury with SCI from C4 to T3) in our program who had performed 6 months of FES-row training while on Buspirone (29 ± 17 mg/day) between 2012 and 2018. We also identified well-matched individuals who trained for six months but not on Buspirone (n = 11). A peak incremental FES-rowing exercise test and resting pulmonary function test had been performed before and after training.
RESULTS
Those on Buspirone demonstrated greater increases in peak oxygen consumption (VOpeak: + 0.24 ± 0.23 vs. + 0.10 ± 0.13 L/min, p = 0.08) and peak ventilation (VEpeak: + 6.5 ± 8.1 vs. - 0.7 ± 6.9 L/min, p < 0.05) compared to control. In addition, changes in VOpeak and VEpeak were correlated across all patients (r = 0.63, p < 0.01), but most strongly in those on Buspirone (r = 0.85, p < 0.01). Furthermore, changes in respiratory function correlated with increased peak tidal volume in the Buspirone group (r > 0.66, p < 0.05).
CONCLUSION
These results suggest Buspirone improves cardiorespiratory adaptations to FES-exercise training in individuals with acute, high-level SCI. The strong association between increases in ventilatory and aerobic capacities suggests improved respiratory function is a mechanism; however, controlled studies are needed to determine if this preliminary finding is reproducible.
Topics: Adult; Electric Stimulation; Electric Stimulation Therapy; Exercise; Exercise Test; Exercise Therapy; Exercise Tolerance; Female; Heart; Humans; Male; Oxygen Consumption; Respiration; Retrospective Studies; Serotonin; Serotonin Receptor Agonists; Spinal Cord Injuries
PubMed: 33099664
DOI: 10.1007/s00421-020-04536-w -
Expert Opinion on Drug Discovery 2016Major depressive disorder (MDD) is the leading cause of disability worldwide, and according to the STAR*D trial, only 33% of patients with MDD responded to initial drug... (Review)
Review
INTRODUCTION
Major depressive disorder (MDD) is the leading cause of disability worldwide, and according to the STAR*D trial, only 33% of patients with MDD responded to initial drug therapy. Augmentation of the leading class of antidepressant treatment, selective serotonin reuptake inhibitors (SSRIs), with the 5-HT1A receptor agonist buspirone has been shown to be effective in treating patients that do not respond to initial SSRI therapy. This suggests that newer treatments may improve the clinical picture of MDD. The US Food and Drug Administration (FDA) approved the antidepressant drug vilazodone (EMD 68843), a novel SSRI and 5-HT1A receptor partial agonist. Vilazodone has a half-life between 20-24 hours, reaches peak plasma concentrations at 3.7-5.3 hours, and is primarily metabolized by the hepatic CYP450 3A4 enzyme system.
AREAS COVERED
The authors review the preclinical and clinical profile of vilazodone. The roles of serotonin, the 5-HT1A receptor, and current pharmacotherapy approaches for MDD are briefly reviewed. Next, the preclinical pharmacological, behavioral, and physiological effects of vilazodone are presented, followed by the pharmacokinetic properties and metabolism of vilazodone in humans. Last, a brief summary of the main efficacy, safety, and tolerability outcomes of clinical trials of vilazodone is provided.
EXPERT OPINION
Vilazodone has shown efficacy versus placebo in improving depression symptoms in several double-blind, placebo-controlled trials. The long-term safety and tolerability of vilazodone treatment has also been established. Further studies are needed that directly compare patients treated with an SSRI (both with and without an adjunctive 5-HT1A partial agonist) versus patients treated with vilaozodone.
Topics: Animals; Antidepressive Agents; Depressive Disorder, Major; Humans; Serotonin 5-HT1 Receptor Agonists; Selective Serotonin Reuptake Inhibitors; Vilazodone Hydrochloride
PubMed: 26971593
DOI: 10.1517/17460441.2016.1160051 -
The Journal of Headache and Pain May 2019The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache... (Review)
Review
BACKGROUND
The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs are currently being developed, among which the small molecule CGRP receptor antagonists, gepants, and the 5-HT receptor agonist lasmiditan. Whether treatment with these drugs carries the same risk for developing MOH is currently unknown.
MAIN BODY
Pathophysiological studies on MOH in animal models have suggested that decreased 5-hydroxytryptamine (5-HT, serotonin) levels, increased calcitonin-gene related peptide (CGRP) expression and changes in 5-HT receptor expression (lower 5-HT and higher 5-HT expression) may be involved in MOH. The decreased 5-HT may increase cortical spreading depression frequency and induce central sensitization in the cerebral cortex and caudal nucleus of the trigeminal tract. Additionally, low concentrations of 5-HT, a feature often observed in MOH patients, could increase CGRP expression. This provides a possible link between the pathways of 5-HT and CGRP, targets of lasmiditan and gepants, respectively. Since lasmiditan is a 5-HT receptor agonist and gepants are CGRP receptor antagonists, they could have different risks for developing MOH because of the different (over) compensation mechanisms following prolonged agonist versus antagonist treatment.
CONCLUSION
The acute treatment of migraine will certainly improve with the advent of two novel classes of drugs, i.e., the 5-HT receptor agonists (lasmiditan) and the small molecule CGRP receptor antagonists (gepants). Data on the effects of 5-HT receptor agonism in relation to MOH, as well as the effects of chronic CGRP receptor blockade, are awaited with interest.
Topics: Animals; Calcitonin Gene-Related Peptide Receptor Antagonists; Headache Disorders, Secondary; Humans; Migraine Disorders; Prescription Drug Overuse; Serotonin Receptor Agonists
PubMed: 31096904
DOI: 10.1186/s10194-019-1007-y -
Pharmacology & Therapeutics May 1995Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on... (Review)
Review
Recent, rapid progress in the molecular biology of serotonin (5-HT) receptors requires conceptual re-thinking with respect to receptor classification. Thus, based on operational criteria (agonist and antagonist rank order), as well as transduction mechanisms involved and the structure of the receptor protein, the Nomenclature Committee of the Serotonin Club has proposed the following classification and nomenclature: the main receptor types 5-HT1 to 5-HT4, recombinant receptors (e.g. 5-ht5 to 5-ht7) and 'orphan' receptors. The aim of the present review is to discuss the events leading to this classification, the criteria for and functional responses mediated by various 5-HT receptors, as well as the therapeutic possibilities with 5-HT ligands.
Topics: Animals; Anxiety Disorders; Depressive Disorder; Humans; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists
PubMed: 7667401
DOI: 10.1016/0163-7258(94)00005-n -
BioMed Research International 2021Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT receptor agonist appears more promising... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT receptor agonist appears more promising for aborting migraine attacks.
OBJECTIVE
To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks.
METHODS
The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model.
RESULTS
Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75, 95% CI (0.61, 0.92), = 0.007; 200 mg: RR = 0.81, 95% CI (0.66, 0.99), = 0.04) at 2-24 h postdose, compared with placebo. Safety data showed that the proportion of patients reporting at least one treatment-emergent adverse event (TEAE) and the incidence of most common TEAEs such as dizziness, paresthesia, fatigue, somnolence, and nausea was higher in the lasmiditan groups (50 mg, 100 mg, and 200 mg), compared with placebo. There was no significant difference between lasmiditan and placebo in terms of cardiovascular-related TEAEs (RR = 2.75, 95% CI (0.81, 9.37), = 0.11). Compared with lasmiditan 100 mg, lasmiditan 200 mg was more effective in pain freedom at 2 h after the first dose (RR = 0.83, 95% CI (0.74, 0.94), = 0.004) but associated with a higher risk of reporting at least one TEAE (RR = 0.88, 95% CI (0.81, 0.96), = 0.006).
CONCLUSIONS
Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.
Topics: Adult; Benzamides; Cardiovascular Diseases; Confidence Intervals; Disability Evaluation; Female; Humans; Male; Migraine Disorders; Piperidines; Publication Bias; Pyridines; Receptors, Serotonin; Risk; Serotonin Receptor Agonists; Treatment Outcome; Receptor, Serotonin, 5-HT1F
PubMed: 34660796
DOI: 10.1155/2021/6663591