Answered on July 16, 2025

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5-hydroxytryptamine 2B (5-HT2B) receptor agonism is directly implicated in the pathogenesis of valvular heart disease (VHD) through the induction of valvular interstitial cell proliferation and extracellular matrix remodeling, leading to fibrotic thickening and dysfunction of cardiac valves. This mechanism has been established in both drug-induced and carcinoid-related valvulopathies.
Agonists of the 5-HT2B receptor, including certain serotonergic medications (e.g., fenfluramine, ergot derivatives, some dopamine agonists), stimulate mitogenic pathways in valvular interstitial cells, resulting in fibroblast proliferation and increased collagen synthesis. This process leads to leaflet thickening, retraction, and ultimately valvular regurgitation or stenosis. The molecular basis involves activation of downstream signaling cascades such as the mitogen-activated protein kinase (MAPK) pathway and upregulation of pro-fibrotic genes.[1-5]
The association is supported by clinical, pharmacological, and pathological evidence: drugs known to cause VHD are potent 5-HT2B receptor agonists, and their use is consistently linked to valvular fibrosis that is histologically indistinguishable from that seen in carcinoid heart disease, where serotonin excess is the driver.[1-4][6-8] Notably, medications that do not activate the 5-HT2B receptor are not associated with this risk.[2-3][9]
In summary, 5-HT2B receptor agonism is a key molecular trigger for drug-induced and serotonin-mediated valvular heart disease, and screening for 5-HT2B agonist activity is now considered essential in drug safety assessment for agents with serotonergic properties.[2-3][8-9]

1.
Serotonin Receptors and Heart Valve Disease--It Was Meant 2B.

Hutcheson JD, Setola V, Roth BL, Merryman WD.

Pharmacology & Therapeutics. 2011;132(2):146-57. doi:10.1016/j.pharmthera.2011.03.008.

Leading Journal

Carcinoid heart disease was one of the first valvular pathologies studied in molecular detail, and early research identified serotonin produced by oncogenic enterochromaffin cells as the likely culprit in causing changes in heart valve tissue. Researchers and physicians in the mid-1960s noted a connection between the use of several ergot-derived medications with structures similar to serotonin and the development of heart valve pathologies similar to those observed in carcinoid patients. The exact serotonergic target that mediated valvular pathogenesis remained a mystery for many years until similar cases were reported in patients using the popular diet drug Fen-Phen in the late 1990s. The Fen-Phen episode sparked renewed interest in serotonin-mediated valve disease, and studies led to the identification of the 5-HT(2B) receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT(2B) receptor, and consequently, the use of many of these molecules has been linked to heart valve disease. Herein, we: review the molecular properties of the 5-HT(2B) receptor including factors that differentiate the 5-HT(2B) receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT(2B) receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT(2B) receptor activity, and speculate on potential therapeutic benefits of 5-HT(2B) receptor targeting.

2.
Evidence for Possible Involvement of 5-Ht(2b) Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications.

Rothman RB, Baumann MH, Savage JE, et al.

Circulation. 2000;102(23):2836-41. doi:10.1161/01.cir.102.23.2836.

Leading Journal

Background: Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis.

Methods And Results: Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (+/-)-fenfluramine; (+)-fenfluramine; (-)-fenfluramine; its metabolites (+/-)-norfenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (+/-)-, (+)-, and (-)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT(2B) receptor and were partial to full agonists at the 5-HT(2B) receptor.

Conclusions: Our data imply that activation of 5-HT(2B) receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT(2B) receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT(2B) receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT(2B) receptors.

3.
Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine(2B) Receptor Agonists: Implications for Drug Safety Assessment.

Huang XP, Setola V, Yadav PN, et al.

Molecular Pharmacology. 2009;76(4):710-22. doi:10.1124/mol.109.058057.

Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT(2B)) receptor agonists. We have shown that activation of 5-HT(2B) receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT(2B) receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT(2B) receptor agonists (hits); 14 of these had previously been identified as 5-HT(2B) receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT(2B) receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT(2B) receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.

4.
Possible Role of Valvular Serotonin 5-Ht(2b) Receptors in the Cardiopathy Associated With Fenfluramine.

Fitzgerald LW, Burn TC, Brown BS, et al.

Molecular Pharmacology. 2000;57(1):75-81.

Dexfenfluramine was approved in the United States for long-term use as an appetite suppressant until it was reported to be associated with valvular heart disease. The valvular changes (myofibroblast proliferation) are histopathologically indistinguishable from those observed in carcinoid disease or after long-term exposure to 5-hydroxytryptamine (5-HT)(2)-preferring ergot drugs (ergotamine, methysergide). 5-HT(2) receptor stimulation is known to cause fibroblast mitogenesis, which could contribute to this lesion. To elucidate the mechanism of "fen-phen"-associated valvular lesions, we examined the interaction of fenfluramine and its metabolite norfenfluramine with 5-HT(2) receptor subtypes and examined the expression of these receptors in human and porcine heart valves. Fenfluramine binds weakly to 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. In contrast, norfenfluramine exhibited high affinity for 5-HT(2B) and 5-HT(2C) receptors and more moderate affinity for 5-HT(2A) receptors. In cells expressing recombinant 5-HT(2B) receptors, norfenfluramine potently stimulated the hydrolysis of inositol phosphates, increased intracellular Ca(2+), and activated the mitogen-activated protein kinase cascade, the latter of which has been linked to mitogenic actions of the 5-HT(2B) receptor. The level of 5-HT(2B) and 5-HT(2A) receptor transcripts in heart valves was at least 300-fold higher than the levels of 5-HT(2C) receptor transcript, which were barely detectable. We propose that preferential stimulation of valvular 5-HT(2B) receptors by norfenfluramine, ergot drugs, or 5-HT released from carcinoid tumors (with or without accompanying 5-HT(2A) receptor activation) may contribute to valvular fibroplasia in humans.

5.
Serotonin Transporter Deficiency in Mice Results in an Increased Susceptibility to HTR2B-dependent Pro-Fibrotic Mechanisms in the Cardiac Valves and Left Ventricular Myocardium.

Castillero E, Camillo C, Levine D, et al.

Cardiovascular Pathology : The Official Journal of the Society for Cardiovascular Pathology. 2025 Jan-Feb;74:107689. doi:10.1016/j.carpath.2024.107689.

Increased serotonin (5HT) concentration and signaling, can lead to pathological remodeling of the cardiac valves. We previously showed that a reduction of the 5HT transporter (SERT) expression in the mitral valve (MV) contributes to the progression of degenerative MV regurgitation (MR). We sought to investigate the myocardial and valvular phenotype of SERT-/- mice in order to identify remodeling mechanisms specific to the MV and left ventricular (LV) remodeling. Using 8- and 16-week-old WT and SERT-/- mice we show that male and female animals deficient of SERT have pathological remodeling of the cardiac valves, myocardial fibrosis, diminished ejection fraction and altered left ventricular dimensions. In the MV and intervalvular area of the aortic valve (AV)-MV, gene expression, including Col1a1 mRNA, was progressively altered with age up until 16 weeks of age. In contrast, in the AV and myocardium, most gene expression changes occurred earlier and plateaued by 8 weeks. To explore basal differences in susceptibility to remodeling stimuli among cardiac valves, valve interstitial cells (VIC) were isolated from AV, MV, tricuspid valve (TV), pulmonary valve (PV) and fibroblasts (Fb) from the myocardial apex from 16 weeks old wild type (WT) mice. After 24h stimulation with 10 µM of 5HT, the gene expression of Col1a1 and Acta2 were upregulated in MVIC to a higher degree than in VIC from other valves and Fb. Treatment with TGFβ1 similarly upregulated Cola1 and Acta2 in MVIC and AVIC, while the increase was milder in right heart VIC and Fb. Experiments were also carried out with human VIC. In comparison to mice, human left heart VIC were more sensitive to 5HT and TGFβ1, upregulating COL1A1 and ACTA2; TGFβ1 upregulated HTR2B expression in all VIC. Our results support the hypothesis that a deleterious cardiac effect of SERT downregulation may be mediated by increased susceptibility to HTR2B-dependent pro-fibrotic mechanisms, which are distinct among VIC populations and cardiac fibroblasts, regardless of SERT activity. Given that HTR2B mechanisms involved in VIC and myocardial remodeling response are due to both 5HT and also to downstream related TGFβ1 and TNFα activity, targeting HTR2B could be a therapeutic strategy for dual treatment of MR and LV remodeling.

6.
Serotonin Contribution to Cardiac Valve Degeneration: New Insights for Novel Therapies?.

Ayme-Dietrich E, Lawson R, Da-Silva S, Mazzucotelli JP, Monassier L.

Pharmacological Research. 2019;140:33-42. doi:10.1016/j.phrs.2018.09.009.

Leading Journal

Heart valve disease (HVD) is a complex entity made by different pathological processes that ultimately lead to the abnormal structure and disorganization of extracellular matrix proteins resulting to dysfunction of the leaflets. At its final evolutionary step, treatments are limited to the percutaneous or surgical valve replacement, whatever the original cause of the degeneration. Understanding early molecular mechanisms that regulate valve interstitial cells remodeling and disease progression is challenging and could pave the way for future drugs aiming to prevent and/or reverse the process. Some valve degenerative processes such as the carcinoid heart disease, drug-induced valvulopathy and degenerative mitral valve disease in small-breed dogs are clearly linked to serotonin. The carcinoid heart is typically characterized by a right-sided valve dysfunction, observed in patients with carcinoid tumors developed from serotonin-producing gut enterochromaffin cells. Fenfluramine or ergot derivatives were linked to mitral and aortic valve dysfunction and share in common the pharmacological property of being 5-HT receptor agonists. Finally, some small-breed dogs, such as the Cavalier King Charles Spaniel are highly prone to degenerative mitral valve disease with a prevalence of 40% at 4 years-old, 70% at 7 years-old and 100% in 10-year-old animals. This degeneration has been linked to high serum serotonin, 5-HT receptor overexpression and SERT downregulation. Through the comprehension of serotonergic mechanisms involved into these specific situations, new therapeutic approaches could be extended to HVD in general. More recently, a serotonin dependent/ receptor independent mechanism has been suggested in congenital mitral valve prolapse through the filamin-A serotonylation. This review summarizes clinical and molecular mechanisms linking the serotonergic system and heart valve disease, opening the way for future pharmacological research in the field.

7.
Role of Serotoninergic Pathways in Drug-Induced Valvular Heart Disease and Diagnostic Features by Echocardiography.

Smith SA, Waggoner AD, de las Fuentes L, Davila-Roman VG.

Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2009;22(8):883-9. doi:10.1016/j.echo.2009.05.002.

Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes, such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators or inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson's disease), can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies have suggested that both right-sided and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit, which is widely expressed in a variety of tissues, including liver, lung, heart, and coronary and pulmonary arteries; it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review, the authors discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy, with an emphasis on echocardiographic diagnosis.

8.
Drug-Associated Valvular Heart Diseases and Serotonin-Related Pathways: A Meta-Analysis.

Fortier JH, Pizzarotti B, Shaw RE, et al.

Heart (British Cardiac Society). 2019;105(15):1140-1148. doi:10.1136/heartjnl-2018-314403.

Objective: Serotonergic appetite suppressants and ergot-derived dopamine agonists have been associated with drug-induced valvular heart disease. The purpose of this meta-analysis is to synthesise the current evidence of a link between several medications affecting sertonergic pathways and valvular heart disease.

Methods: PubMed was searched to identify studies evaluating an association between medications with serotonergic activity and cardiac valvular pathology. Case reports, uncontrolled studies and in vitro studies were excluded. Relevant studies were assessed for quality and potential bias; those of adequate quality were included in a quantitative synthesis. Sensitivity analyses were conducted, and potential publication bias was examined.

Results: There was a consistent, significant relationship between certain medications and heart valve disease, including serotonergic medications (OR 3.30, 95% CI 1.99 to 5.49) and dopaminergic medications (OR 2.56, 95% CI 1.68 to 3.91). Subanalyses, including analyses that limited exposure to a single medication or effects to a single heart valve were also consistently significant. Most studies were retrospective or observational in nature, with a higher risk of selection and presentation biases. There was significant heterogeneity and variability between studies, particularly when it came to dose and duration of exposure.

Conclusions: There was a consistent, significant association between many medications that affect serotonergic pathways and valvular heart disease. Although many of these medications have been withdrawn from the market, some small studies suggest that recreational drug 3,4-methylenedioxy​methamphetamine and widely prescribed selective serotonin reuptake inhibitors may affect similar pathways.

9.

Some antipsychotic drugs are known to cause valvular heart disease by activating serotonin 5-HT(2B) receptors. We have developed and validated binary classification QSAR models capable of predicting potential 5-HT(2B) actives. The classification accuracies of the models built to discriminate 5-HT(2B) actives from the inactives were as high as 80% for the external test set. These models were used to screen in silico 59,000 compounds included in the World Drug Index, and 122 compounds were predicted as actives with high confidence. Ten of them were tested in radioligand binding assays and nine were found active, suggesting a success rate of 90%. All validated actives were then tested in functional assays, and one compound was identified as a true 5-HT(2B) agonist. We suggest that the QSAR models developed in this study could be used as reliable predictors to flag drug candidates that are likely to cause valvulopathy.

Answered on July 16, 2025

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Ergot-derived dopamine agonists (such as cabergoline, pergolide, and ergotamine), serotonergic appetite suppressants (notably fenfluramine and dexfenfluramine), and certain ergot alkaloids (such as methysergide) are the drug classes most commonly acting as 5-hydroxytryptamine 2B (5-HT2B) receptor agonists in clinical use.[1-6]
These drugs or their active metabolites directly stimulate 5-HT2B receptors expressed on cardiac valvular interstitial cells, leading to mitogenic signaling, fibroblast proliferation, and extracellular matrix deposition. This process results in valvular thickening and dysfunction, manifesting clinically as regurgitant valvular heart disease. The risk is dose- and duration-dependent, and the valvulopathy is histopathologically similar to that seen in carcinoid heart disease, which is also mediated by serotonin excess and 5-HT2B activation.[2-6]
Non-ergot dopamine agonists (e.g., ropinirole, pramipexole) and selective serotonin reuptake inhibitors (SSRIs) do not exhibit significant 5-HT2B agonism and are not associated with this risk.[1-2][6] Screening for 5-HT2B agonist activity is now considered essential in drug development to mitigate the risk of drug-induced valvular heart disease.[1-3]

1.
Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine(2B) Receptor Agonists: Implications for Drug Safety Assessment.

Huang XP, Setola V, Yadav PN, et al.

Molecular Pharmacology. 2009;76(4):710-22. doi:10.1124/mol.109.058057.

Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT(2B)) receptor agonists. We have shown that activation of 5-HT(2B) receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT(2B) receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT(2B) receptor agonists (hits); 14 of these had previously been identified as 5-HT(2B) receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT(2B) receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT(2B) receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.

2.
Evidence for Possible Involvement of 5-Ht(2b) Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications.

Rothman RB, Baumann MH, Savage JE, et al.

Circulation. 2000;102(23):2836-41. doi:10.1161/01.cir.102.23.2836.

Leading Journal

Background: Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis.

Methods And Results: Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (+/-)-fenfluramine; (+)-fenfluramine; (-)-fenfluramine; its metabolites (+/-)-norfenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (+/-)-, (+)-, and (-)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT(2B) receptor and were partial to full agonists at the 5-HT(2B) receptor.

Conclusions: Our data imply that activation of 5-HT(2B) receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT(2B) receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT(2B) receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT(2B) receptors.

3.
Serotonin Receptors and Heart Valve Disease--It Was Meant 2B.

Hutcheson JD, Setola V, Roth BL, Merryman WD.

Pharmacology & Therapeutics. 2011;132(2):146-57. doi:10.1016/j.pharmthera.2011.03.008.

Leading Journal

Carcinoid heart disease was one of the first valvular pathologies studied in molecular detail, and early research identified serotonin produced by oncogenic enterochromaffin cells as the likely culprit in causing changes in heart valve tissue. Researchers and physicians in the mid-1960s noted a connection between the use of several ergot-derived medications with structures similar to serotonin and the development of heart valve pathologies similar to those observed in carcinoid patients. The exact serotonergic target that mediated valvular pathogenesis remained a mystery for many years until similar cases were reported in patients using the popular diet drug Fen-Phen in the late 1990s. The Fen-Phen episode sparked renewed interest in serotonin-mediated valve disease, and studies led to the identification of the 5-HT(2B) receptor as the likely molecular target leading to heart valve tissue fibrosis. Subsequent studies have identified numerous other activators of the 5-HT(2B) receptor, and consequently, the use of many of these molecules has been linked to heart valve disease. Herein, we: review the molecular properties of the 5-HT(2B) receptor including factors that differentiate the 5-HT(2B) receptor from other 5-HT receptor subtypes, discuss the studies that led to the identification of the 5-HT(2B) receptor as the mediator of heart valve disease, present current efforts to identify potential valvulopathogens by screening for 5-HT(2B) receptor activity, and speculate on potential therapeutic benefits of 5-HT(2B) receptor targeting.

4.
Role of Serotoninergic Pathways in Drug-Induced Valvular Heart Disease and Diagnostic Features by Echocardiography.

Smith SA, Waggoner AD, de las Fuentes L, Davila-Roman VG.

Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. 2009;22(8):883-9. doi:10.1016/j.echo.2009.05.002.

Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes, such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators or inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson's disease), can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies have suggested that both right-sided and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit, which is widely expressed in a variety of tissues, including liver, lung, heart, and coronary and pulmonary arteries; it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review, the authors discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy, with an emphasis on echocardiographic diagnosis.

5.
Possible Role of Valvular Serotonin 5-Ht(2b) Receptors in the Cardiopathy Associated With Fenfluramine.

Fitzgerald LW, Burn TC, Brown BS, et al.

Molecular Pharmacology. 2000;57(1):75-81.

Dexfenfluramine was approved in the United States for long-term use as an appetite suppressant until it was reported to be associated with valvular heart disease. The valvular changes (myofibroblast proliferation) are histopathologically indistinguishable from those observed in carcinoid disease or after long-term exposure to 5-hydroxytryptamine (5-HT)(2)-preferring ergot drugs (ergotamine, methysergide). 5-HT(2) receptor stimulation is known to cause fibroblast mitogenesis, which could contribute to this lesion. To elucidate the mechanism of "fen-phen"-associated valvular lesions, we examined the interaction of fenfluramine and its metabolite norfenfluramine with 5-HT(2) receptor subtypes and examined the expression of these receptors in human and porcine heart valves. Fenfluramine binds weakly to 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. In contrast, norfenfluramine exhibited high affinity for 5-HT(2B) and 5-HT(2C) receptors and more moderate affinity for 5-HT(2A) receptors. In cells expressing recombinant 5-HT(2B) receptors, norfenfluramine potently stimulated the hydrolysis of inositol phosphates, increased intracellular Ca(2+), and activated the mitogen-activated protein kinase cascade, the latter of which has been linked to mitogenic actions of the 5-HT(2B) receptor. The level of 5-HT(2B) and 5-HT(2A) receptor transcripts in heart valves was at least 300-fold higher than the levels of 5-HT(2C) receptor transcript, which were barely detectable. We propose that preferential stimulation of valvular 5-HT(2B) receptors by norfenfluramine, ergot drugs, or 5-HT released from carcinoid tumors (with or without accompanying 5-HT(2A) receptor activation) may contribute to valvular fibroplasia in humans.

6.
Drug-Associated Valvular Heart Diseases and Serotonin-Related Pathways: A Meta-Analysis.

Fortier JH, Pizzarotti B, Shaw RE, et al.

Heart (British Cardiac Society). 2019;105(15):1140-1148. doi:10.1136/heartjnl-2018-314403.

Objective: Serotonergic appetite suppressants and ergot-derived dopamine agonists have been associated with drug-induced valvular heart disease. The purpose of this meta-analysis is to synthesise the current evidence of a link between several medications affecting sertonergic pathways and valvular heart disease.

Methods: PubMed was searched to identify studies evaluating an association between medications with serotonergic activity and cardiac valvular pathology. Case reports, uncontrolled studies and in vitro studies were excluded. Relevant studies were assessed for quality and potential bias; those of adequate quality were included in a quantitative synthesis. Sensitivity analyses were conducted, and potential publication bias was examined.

Results: There was a consistent, significant relationship between certain medications and heart valve disease, including serotonergic medications (OR 3.30, 95% CI 1.99 to 5.49) and dopaminergic medications (OR 2.56, 95% CI 1.68 to 3.91). Subanalyses, including analyses that limited exposure to a single medication or effects to a single heart valve were also consistently significant. Most studies were retrospective or observational in nature, with a higher risk of selection and presentation biases. There was significant heterogeneity and variability between studies, particularly when it came to dose and duration of exposure.

Conclusions: There was a consistent, significant association between many medications that affect serotonergic pathways and valvular heart disease. Although many of these medications have been withdrawn from the market, some small studies suggest that recreational drug 3,4-methylenedioxy​methamphetamine and widely prescribed selective serotonin reuptake inhibitors may affect similar pathways.

Answered on July 16, 2025

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Lysergic acid diethylamide (LSD) and psilocybin both act as 5-hydroxytryptamine 2B (5-HT2B) receptor agonists. LSD is a potent agonist at the 5-HT2B receptor, as demonstrated by structural and functional studies showing direct activation and signaling through this receptor subtype. Psilocybin, via its active metabolite psilocin, also exhibits agonist activity at 5-HT2B receptors, although its primary psychoactive effects are mediated through 5-HT2A receptor agonism.[1-7]
Both compounds display non-selective agonism across several serotonin receptor subtypes, including 5-HT2A, 5-HT2B, and 5-HT2C, but with varying affinities and efficacies.[5-7] The clinical relevance of 5-HT2B agonism is primarily related to the risk of drug-induced valvular heart disease, which is a concern for agents with high affinity and sustained activation of this receptor. However, the risk associated with typical psychedelic dosing of LSD or psilocybin in clinical or research settings remains unclear, as most evidence of valvulopathy is linked to chronic exposure to potent 5-HT2B agonists such as ergot derivatives and certain appetite suppressants.[5-6]

1.
Signaling Snapshots of a Serotonin Receptor Activated by the Prototypical Psychedelic LSD.

Cao C, Barros-Álvarez X, Zhang S, et al.

Neuron. 2022;110(19):3154-3167.e7. doi:10.1016/j.neuron.2022.08.006.

Leading Journal

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT serotonin receptor (HTR2A), the 5-HT serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

2.
Structural Features for Functional Selectivity at Serotonin Receptors.

Wacker D, Wang C, Katritch V, et al.

Science (New York, N.Y.). 2013;340(6132):615-9. doi:10.1126/science.1232808.

Leading Journal

Drugs active at G protein-coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-HT2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT2B receptor bound to ERG and compared it with the 5-HT1B/ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.

3.
Crystal Structure of an LSD-Bound Human Serotonin Receptor.

Wacker D, Wang S, McCorvy JD, et al.

Cell. 2017;168(3):377-389.e12. doi:10.1016/j.cell.2016.12.033.

Leading Journal

The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP.

4.
Agonist-Directed Trafficking of Signalling at Serotonin 5-Ht2a, 5-Ht2b and 5-Ht2c-VSV Receptors Mediated Gq/­11 Activation and Calcium Mobilisation in CHO Cells.

Cussac D, Boutet-Robinet E, Ailhaud MC, et al.

European Journal of Pharmacology. 2008;594(1-3):32-8. doi:10.1016/j.ejphar.2008.07.040.

Several examples of agonist-directed trafficking of receptor signalling at 5-HT2A and 5-HT2C receptors have been reported that involve independent downstream transduction pathways. We now report the functional selectivity of a series of chemically diverse agonists at human (h)5-HT2A, h5-HT2B and h5-HT2C-VSV by examining two related responses, the upstream activation of Gq/11 proteins in comparison with its associated cascade of calcium mobilisation. At the h5-HT2A receptor, d-lysergic acid diethylamide (LSD) and the antiparkinsonian agents lisuride, bromocriptine and pergolide exhibit a higher potency for Gq/11 activation than calcium release in contrast with all the other tested ligands such as 5-HT, mCPP and BW723C86, that show an opposite preference of signalling pathway. Comparable observations are made at h5-HT2B and h5-HT2C-VSV receptors, suggesting a similar mechanism of functional selectivity for the three serotonin receptors. Interestingly, the non-hallucinogenic compound lisuride behaves as a partial agonist for both Gq/11 activation and calcium release at the three 5-HT2 receptors, in contrast with DOI, LSD, pergolide and bromocriptine, which are known to provoke hallucinations, and behave as more efficacious agonists. Hence, a functional selectivity for Gq/11 activation together with a threshold of efficacy at h5-HT2A (and possibly h5-HT2B and/or h5-HT2C-VSV) may contribute to hallucinogenic liability. Thus, our results extend the notion of agonist-directed trafficking of receptor signalling to all the 5-HT2-receptor family and indicate that measures of Gq/11 activation versus calcium release may be useful to identify more effective therapeutic drugs with limited side effects.

5.
Receptor Interaction Profiles of Novel Psychoactive Tryptamines Compared With Classic Hallucinogens.

Rickli A, Moning OD, Hoener MC, Liechti ME.

European Neuropsychopharmacology : The Journal of the European College of Neuropsychopharmacology. 2016;26(8):1327-37. doi:10.1016/j.euroneuro.2016.05.001.

The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4-methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic receptors. In conclusion, the receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties.

6.
Chemistry and Structure-Activity Relationships of Psychedelics.

Nichols DE.

Current Topics in Behavioral Neurosciences. 2018;36:1-43. doi:10.1007/7854_2017_475.

This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT receptor is the principal mechanism of action for psychedelics, compounds with 5-HT agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.

7.
Differential Contributions of Serotonin Receptors to the Behavioral Effects of Indoleamine Hallucinogens in Mice.

Halberstadt AL, Koedood L, Powell SB, Geyer MA.

Journal of Psychopharmacology (Oxford, England). 2011;25(11):1548-61. doi:10.1177/0269881110388326.

Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a hallucinogen that acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors. Psilocin is the active metabolite of psilocybin, a hallucinogen that is currently being investigated clinically as a potential therapeutic agent. In the present investigation, we used a combination of genetic and pharmacological approaches to identify the serotonin (5-HT) receptor subtypes responsible for mediating the effects of psilocin on head twitch response (HTR) and the behavioral pattern monitor (BPM) in C57BL/6J mice. We also compared the effects of psilocin with those of the putative 5-HT(2C) receptor-selective agonist 1-methylpsilocin and the hallucinogen and non-selective serotonin receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Psilocin, 1-methylpsilocin, and 5-MeO-DMT induced the HTR, effects that were absent in mice lacking the 5-HT(2A) receptor gene. When tested in the BPM, psilocin decreased locomotor activity, holepoking, and time spent in the center of the chamber, effects that were blocked by the selective 5-HT(1A) antagonist WAY-100635 but were not altered by the selective 5-HT(2C) antagonist SB 242,084 or by 5-HT(2A) receptor gene deletion. 5-MeO-DMT produced similar effects when tested in the BPM, and the action of 5-MeO-DMT was significantly attenuated by WAY-100635. Psilocin and 5-MeO-DMT also decreased the linearity of locomotor paths, effects that were mediated by 5-HT(2C) and 5-HT(1A) receptors, respectively. In contrast to psilocin and 5-MeO-DMT, 1-methylpsilocin (0.6-9.6 mg/kg) was completely inactive in the BPM. These findings confirm that psilocin acts as an agonist at 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors in mice, whereas the behavioral effects of 1-methylpsilocin indicate that this compound is acting at 5-HT(2A) sites but is inactive at the 5-HT(1A) receptor. The fact that 1-methylpsilocin displays greater pharmacological selectivity than psilocin indicates that 1-methylpsilocin represents a potentially useful alternative to psilocybin for development as a potential therapeutic agent.

Answered on July 16, 2025

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The primary clinical implication of 5-hydroxytryptamine 2B (5-HT2B) receptor agonism resulting from the use of lysergic acid diethylamide (LSD) and psilocybin is a theoretical risk of drug-induced valvular heart disease (VHD), as 5-HT2B activation on cardiac valvular interstitial cells is a well-established mechanism for valvulopathy with other serotonergic agents. However, the clinical literature to date does not report cases of VHD associated with typical, intermittent psychedelic dosing of LSD or psilocybin in humans.[1-4]
LSD and psilocybin are both non-selective serotonin receptor agonists, with demonstrated activity at 5-HT2B receptors in vitro and in animal models.[1-4] Chronic or high-dose exposure to potent 5-HT2B agonists (e.g., ergot-derived dopamine agonists, fenfluramine) is associated with a dose- and duration-dependent risk of valvular fibrosis and regurgitation. In contrast, the dosing regimens used in contemporary clinical trials and therapeutic settings for LSD and psilocybin involve single or infrequent administrations, which are not known to produce cumulative 5-HT2B-mediated valvular toxicity.[5-7]
Current clinical studies of LSD and psilocybin have not identified valvular heart disease as an adverse event, but long-term safety data are limited, and the risk may be greater with repeated or high-dose use.[5-6][8] Given the established mechanism of 5-HT2B agonist-induced valvulopathy, ongoing vigilance and cardiac monitoring may be warranted in research or clinical protocols involving repeated psychedelic administration, especially in populations with pre-existing cardiac risk factors.[8]
In summary, theoretical risk of valvular heart disease exists due to 5-HT2B agonism by LSD and psilocybin, but this has not been observed in clinical practice with current dosing paradigms.[1-5][8]

1.
Signaling Snapshots of a Serotonin Receptor Activated by the Prototypical Psychedelic LSD.

Cao C, Barros-Álvarez X, Zhang S, et al.

Neuron. 2022;110(19):3154-3167.e7. doi:10.1016/j.neuron.2022.08.006.

Leading Journal

Serotonin (5-hydroxytryptamine [5-HT]) 5-HT2-family receptors represent essential targets for lysergic acid diethylamide (LSD) and all other psychedelic drugs. Although the primary psychedelic drug effects are mediated by the 5-HT serotonin receptor (HTR2A), the 5-HT serotonin receptor (HTR2B) has been used as a model receptor to study the activation mechanisms of psychedelic drugs due to its high expression and similarity to HTR2A. In this study, we determined the cryo-EM structures of LSD-bound HTR2B in the transducer-free, Gq-protein-coupled, and β-arrestin-1-coupled states. These structures provide distinct signaling snapshots of LSD's action, ranging from the transducer-free, partially active state to the transducer-coupled, fully active states. Insights from this study will both provide comprehensive molecular insights into the signaling mechanisms of the prototypical psychedelic LSD and accelerate the discovery of novel psychedelic drugs.

2.
Chemistry and Structure-Activity Relationships of Psychedelics.

Nichols DE.

Current Topics in Behavioral Neurosciences. 2018;36:1-43. doi:10.1007/7854_2017_475.

This chapter will summarize structure-activity relationships (SAR) that are known for the classic serotonergic hallucinogens (aka psychedelics), focusing on the three chemical types: tryptamines, ergolines, and phenethylamines. In the brain, the serotonin 5-HT receptor plays a key role in regulation of cortical function and cognition, and also appears to be the principal target for hallucinogenic/psychedelic drugs such as LSD. It is one of the most extensively studied of the 14 known types of serotonin receptors. Important structural features will be identified for activity and, where possible, those that the psychedelics have in common will be discussed. Because activation of the 5-HT receptor is the principal mechanism of action for psychedelics, compounds with 5-HT agonist activity generally are quickly discarded by the pharmaceutical industry. Thus, most of the research on psychedelics can be related to activation of 5-HT receptors. Therefore, much of the discussion will include not only clinical or anecdotal studies, but also will consider data from animal models as well as a certain amount of molecular pharmacology where it is known.

3.
Hallucinogens and Serotonin 5-Ht Receptor-Mediated Signaling Pathways.

López-Giménez JF, González-Maeso J.

Current Topics in Behavioral Neurosciences. 2018;36:45-73. doi:10.1007/7854_2017_478.

The neuropsychological effects of naturally occurring psychoactive chemicals have been recognized for millennia. Hallucinogens, which include naturally occurring chemicals such as mescaline and psilocybin, as well as synthetic compounds, such as lysergic acid diethylamide (LSD), induce profound alterations of human consciousness, emotion, and cognition. The discovery of the hallucinogenic effects of LSD and the observations that LSD and the endogenous ligand serotonin share chemical and pharmacological profiles led to the suggestion that biogenic amines like serotonin were involved in the psychosis of mental disorders such as schizophrenia. Although they bind other G protein-coupled receptor (GPCR) subtypes, studies indicate that several effects of hallucinogens involve agonist activity at the serotonin 5-HT receptor. In this chapter, we review recent advances in understanding hallucinogen drug action through characterization of structure, neuroanatomical location, and function of the 5-HT receptor.

4.
Receptor Interaction Profiles of Novel Psychoactive Tryptamines Compared With Classic Hallucinogens.

Rickli A, Moning OD, Hoener MC, Liechti ME.

European Neuropsychopharmacology : The Journal of the European College of Neuropsychopharmacology. 2016;26(8):1327-37. doi:10.1016/j.euroneuro.2016.05.001.

The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4-methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic receptors. In conclusion, the receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties.

5.
Therapeutic Use of Serotoninergic Hallucinogens: A Review of the Evidence and of the Biological and Psychological Mechanisms.

Dos Santos RG, Hallak JEC.

Neuroscience and Biobehavioral Reviews. 2020;108:423-434. doi:10.1016/j.neubiorev.2019.12.001.

Leading Journal

Serotoninergic hallucinogens include drugs such as lysergic acid diethylamide (LSD), dimethyltryptamine (DMT) and psilocybin. Recent trials with single/few doses of these compounds show that they induce rapid and sustained antidepressive, anxiolytic, and antiaddictive effects. These effects are also observed in religious groups using the DMT-containing brew ayahuasca. The agonist action of these substances on 5-HT receptors expressed in frontal and limbic areas increase glutamatergic transmission and neuroplasticity. These neurochemical effects are associated with acute alterations on self-perception and increases in introspection and positive mood, and with subacute and long-term decreases in psychiatric symptoms, increases in some personality traits such as openness, improvements in emotional processing, and increases in empathy. These are preliminary but promising results that should be further explored in controlled trials with larger sample sizes, especially considering that these compounds could be beneficial in the treatment of treatment-resistant psychiatric disorders.

6.
New Paradigms of Old Psychedelics in Schizophrenia.

Mahmood D, Alenezi SK, Anwar MJ, et al.

Pharmaceuticals (Basel, Switzerland). 2022;15(5):640. doi:10.3390/ph15050640.

Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and mescaline exhibit intense effects on the human brain and behaviour. In recent years, there has been a surge in studies investigating these drugs because clinical studies have shown that these once banned drugs are well tolerated and efficacious in medically supervised low doses called microdosing. Psychedelics have demonstrated efficacy in treating neuropsychiatric maladies such as difficult to treat anxiety, depression, mood disorders, obsessive compulsive disorders, suicidal ideation, posttraumatic stress disorder, and also in treating substance use disorders. The primary mode of action of psychedelics is activation of serotonin 5-HT receptors affecting cognition and brain connectivity through the modulation of several downstream signalling pathways via complex molecular mechanisms. Some atypical antipsychotic drugs (APDs) primarily exhibit pharmacological actions through 5-HT receptors, which are also the target of psychedelic drugs. Psychedelic drugs including the newer second generation along with the glutamatergic APDs are thought to mediate pharmacological actions through a common pathway, i.e., a complex serotonin-glutamate receptor interaction in cortical neurons of pyramidal origin. Furthermore, psychedelic drugs have been reported to act via a complex interplay between 5HT, mGlu2/3, and NMDA receptors to mediate neurobehavioral and pharmacological actions. Findings from recent studies have suggested that serotoninergic and glutamatergic neurotransmissions are very closely connected in producing pharmacological responses to psychedelics and antipsychotic medication. Emerging hypotheses suggest that psychedelics work through brain resetting mechanisms. Hence, there is a need to dig deeply into psychedelic neurobiology to uncover how psychedelics could best be used as scientific tools to benefit psychiatric disorders including schizophrenia.

7.
Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action.

Canal CE.

Handbook of Experimental Pharmacology. 2018;252:227-260. doi:10.1007/164_2018_107.

Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.

8.
Anaesthetic Implications of Psilocybin and Lysergic Acid Diethylamide: What Is Old Is Now New: A Narrative Review on Psychedelics and Anaesthesia.

Dave M, Shore R, Cupido T, Haley C, Clinkard D.

European Journal of Anaesthesiology. 2025;42(5):430-434. doi:10.1097/EJA.0000000000002138.

New Research

Psychedelic drugs, known for their perception-altering properties, are gaining popularity in the treatment of mental health and pain disorders. As exploratory studies demonstrate clinical efficacy with few adverse events, it is expected that more patients will ingest psychedelic drugs. For therapeutic reasons, as with any drug, anaesthesiologists must be aware of its physiological effects and contraindications to ensure the safe provision of anaesthesia. Psilocybin is a 5HT 1A and 5HT 2A serotonin receptor agonist thought to act on excitatory and inhibitory neurons in the brain. Acute ingestion causes sympathetic nervous system activation, which can precipitate haemodynamic instability. Activation of the 5HT serotonin receptors can also place the patient at risk of serotonin syndrome. Chronic use increases plasma concentrations of cortisol, which has implications on prophylactic stress-dosing of glucocorticoids preoperatively. Lysergic acid diethylamide (LSD), a synthetic psychoactive substance, is also a 5HT2 A agonist. LSD has been shown to potentiate opioid analgesics, and monoamine oxidase (MAO) inhibition. Historical reports suggest that LSD has anticholinesterase activity and can prolong neuromuscular block with depolarising muscle relaxants. Mescaline is a poorly understood psychedelic with similar autonomic effects. Historical studies have shown decreased neuromuscular transmission and an association with malignant hyperthermia. When managing patients who have consumed psychedelics drugs, it is important to consider delaying surgery whenever possible, to allow acute intoxication to wane. A high degree of suspicion and an understanding of management principles is vital to the safe conduct of anaesthesia. Future research should explore therapeutic doses of psychedelic drugs to understand physiologic effects at various concentrations.