The role of amylin, a gut–brain axis hormone, in metabolic and neurological disorders

Abstract

Amylin, also known as islet amyloid polypeptide (IAPP), is a pancreatic β‐cell peptide hormone involved in satiation and control food intake. It is also produced in smaller quantities by neurons, the gastrointestinal tract, and spinal ganglia. Numerous studies have revealed that patients with type 2 diabetes mellitus (T2DM) and cognitive deficits exhibit IAPP deposits in the pancreas, brain, and blood vessels. IAPP has also been shown to exert neuroprotective effects against Alzheimer's disease (AD) and cognitive impairments. The objective of this review paper is to provide recent information about the pathophysiological roles of IAPP in metabolic and in neurological disorders, and its potential as a druggable target. We have reviewed preclinical and clinical human and animal research studies of IAPP. We discuss the IAPP structure, its receptors, and its physiological functions in metabolism, satiation, adiposity, obesity, and in the brain. Then we discuss its role in metabolic and neurological disorders like diabetes, obesity, bone disorder, neurodegeneration, cerebrovascular disorders, depression, alcohol use disorder, epilepsy, and in ovarian cysts. Overall, this review provides information on the progress of research into the roles of IAPP and its receptor in food intake, energy homeostasis, glucose regulation, satiation, and its role in metabolic and neurological disorders making it a potential target for therapeutic approaches. This review also suggests that the utilization of rodents overexpressing human IAPP in neurodegeneration models may unearth some significant therapeutic potentials for neurological disorders.

INTRODUCTION

Amylin, also known as islet amyloid polypeptide (IAPP), deposited in the pancreatic islets of diabetic patients, was first discovered as an “islet hyalinization” in 1900.¹ It wasn't until 1943,² with further confirmation in 1961,³ that this hyalinization was described as amyloid, and similar findings were later reported in diabetic cats in 1981.^4,5 A significant discovery was made in 1986 with the identification of the primary component of this amyloid as a peptide initially termed insulinoma amyloid peptide (IAP), later known as islet amyloid polypeptide or IAPP.⁶ IAPP is a neuroendocrine hormone with anorexigenic properties and is secreted together with insulin by the β-cells of the pancreas.⁷ IAPP is centrally produced in the medial preoptic area, arcuate nucleus, and area postrema areas of the lactating rat brain,⁸ and IAPP gene is expressed in other tissues such as stomach and spinal ganglia in lesser amounts.⁹ IAPP is derived from an 89 residue pre-pro-IAPP protein, processed into a 67 residue pro-IAPP, and subsequently to a mature biologically active 37 amino acid protein monomer through cleavage by prohormone convertase 1/3 (PC1/3), prohormone convertase 2 (PC2),^7,9 and carboxypeptidase-E (Figure 1A–C).¹⁰ Mature human IAPP (hIAPP) has a molecular mass of around 4 kilodaltons, characterized by an intramolecular disulfide bond linking the cysteine residues at positions 2 and 7 and an amide moiety at the c-terminus (Figure 1C,D).¹¹ IAPP shares sequence similarity with calcitonin (CT) peptide family—calcitonin, CT gene-related peptide (CGRPα and CGRPβ), adrenomedullin (AM), and adrenomedullin 2 (AM2).^11,12

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The transcription and expression of IAPP and insulin are regulated by shared promoter regions, and these hormones are concurrently released from islet cells' secretory granules in a consistent IAPP to insulin ratio of about 1:100.^7,13 Stimulants of this joint secretion include glucose, fatty acids and arginine, and during fasting,⁷ and the plasma concentrations of IAPP in rats are between 3 and 5 picomolar, rising to approximately 20 picomolar after elevation in blood sugar level.¹⁴ The metabolism of IAPP involves both renal excretion and proteolytic degradation, resulting in various metabolites.¹¹ Notably, a des-Lys-1 variant retains physiological activity, whereas other proteolytic byproducts are less likely to yield bioactive peptides.¹⁵

Members of the CT peptide family interact with G-protein-coupled receptors that have seven transmembrane domains (Figure 2A). Although IAPP is a hormone, the identification of specific receptors for it proved elusive for a long time, despite the detection of specific binding sites, especially in the brain and renal cortex.¹⁵ This hurdle was resolved with the discovery of three distinct receptor activity-modifying proteins (RAMPs), which are single-domain proteins.¹⁶ These proteins are not receptors themselves; however, they form complexes with CT receptors and modify their ligand affinity¹⁷ (Figure 2A). When a CT receptor binds to one of the RAMPs, it may alter the receptor's affinity, and certain combinations result in high-affinity receptors for IAPP.^18,19 We also checked the IAPP interactions with other proteins using the STRING database () and found that IAPP binds to RAMPs and other proteins (Figure 2B). This mechanism, unique to the CT family, allows for the formation of three IAPP receptors. The roles of RAMPs are multifaceted; they are involved in the transport of receptor proteins to the cell surface, affect glycosylation, and modulation of signaling pathways.^16,20

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IAPP research was initially focused on two primary roles: its function as a soluble, monomeric hormone that regulates glucose levels in the blood and its contribution to the formation of amyloid plaques that impair the pancreas leading to certain types of diabetes.⁷ Recent studies have shown that IAPP plays an important role in gut–brain signaling. This review summarizes the IAPP physiology and its role in both the etiology of, and as a therapeutic target for metabolic and neurological disorders.

PHYSIOLOGICAL ROLES OF IAPP

IAPP is co-secreted with insulin and plays a crucial role in regulating blood glucose levels, food intake, and body mass.¹¹ IAPP is known to affect satiation, inhibit glucagon secretion after meals, slow gastric emptying, and reduce digestive enzyme secretion via both peripheral and central mechanisms.^9,11 After its secretion after food intake, rat IAPP has a brief half-life in plasma of about 13 min.²¹ Originally thought to be produced only in the pancreas, it was subsequently discovered that IAPP is also synthesized in other areas of the gastrointestinal tract and spinal ganglia.^22,23 Recent research has further identified the presence of IAPP mRNA and protein in specific brain regions.²³ Notably, IAPP expression was found to increase significantly in the medial preoptic area of rats and was also prominently expressed alongside prodynorphin in the neurons of the lateral hypothalamic area. This latter finding indicated that IAPP mRNA levels varied significantly depending on factors such as sex, diet, and leptin levels.^23,24

The effect of IAPP on satiation is well-researched, particularly through its activation of noradrenergic neurons in the glucose-sensitive area postrema of the medulla oblongata.²³ Additionally, IAPP stimulation of neurons in area postrema results into neuroaxis activation and sends signals to forebrain including in the nucleus tractus solitarius and the lateral parabrachial nucleus and amygdala, which are key secondary sites for IAPP's action. These sites transmit signals to the lateral hypothalamus and other areas, influencing the sensation of satiation.^23,25 Experiments have shown that acute peripheral administration of IAPP significantly reduces food intake and thus bioenergetic status, an effect that is dose-dependent and can be inhibited by IAPP receptor antagonists.^7,11 Furthermore, IAPP, directly and indirectly, suppresses glucagon secretion from pancreatic α-cells,^26,27 reduces hepatic glucose release after eating, and slows gastric emptying and pancreatic enzyme secretion to lower peak blood glucose levels.¹¹

The concept of “homeostatic eating control” differentiates between two types of signals: adiposity (“tonic”) signals, which are related to long-term body fat regulation, and meal-associated (“episodic”) signals that respond to food intake.²⁸ IAPP has been found to potentially enhance leptin sensitivity in obesity, a condition where leptin, a hormone signaling triglyceride from adipose tissue, often becomes less effective. Experiments in rats have shown that combined administration of leptin and IAPP can lead to weight loss, and diminishes obesity.^29,30 Additionally, IAPP has been observed to increase energy expenditure in animal studies.^31,32

IAPP IN DISEASE STATES

Beyond its function in energy and glucose regulation, hIAPP has the propensity to self-aggregate and is crucial in the development of various diseases.^12,28 In its monomeric form, IAPP is soluble and unfolded; however, it can form oligomers that exhibit a misfolded α-helix structure, which can form into β-sheet-rich fibrils (Figure 3A–C). These fibrils form amyloid deposits that can be toxic in tissues where IAPP is expressed.^11,12 Amyloid refers to a particular state of protein aggregation characterized by molecules arranged in a β-sheet conformation. These molecules are primarily linked through hydrogen bonds, among other types of bonds.^33,34 This aggregation forms thin, stable fibrils approximately 10 nanometers in width, with β-strands aligned perpendicular to the fibril axis known as IAPP-β amyloid (Aβ). In humans, over 25 proteins are known to form amyloid fibrils, and it is expected that more will be identified in future research.^35,36 IAPP amyloid formation occurs exclusively in the islets of pancreas of humans, cats, and primates but it does not occur in rodents. This is attributed to the presence of an amyloidogenic region within the IAPP amino acid sequence of these animals, which is critical for the formation and toxicity of the amyloids.^36–39 Below, we will discuss the role of IAPP in the pathogenesis of various disease conditions.

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IAPP has an amyloidogenic core region between residues 20 and 29 (Figure 3D). We performed sequence alignment for orthologues of the IAPP protein showing conservation of the cysteine 2 and 7 that form a disulfide bridge. Also, the N-terminal and C-terminal residues are mostly conserved as compared to the amyloidogenic region. Interestingly, the rodent residues 24, 25,26, 28, and 29 are different from the hIAPP making it non-amyloidogenic.^40–42 Furthermore, F15L and S20G mutations make it more amyloidogenic, on the contrary, G24P and I26P make it less amyloidogenic as compared to the wild-type IAPP.^43,44 The reported mutations Q43R and S53G in pre-pro-hIAPP or Q10R and S20G in hIAPP are associated with diabetes based on the HGMD database ().

IAPP IN METABOLIC DISORDERS

Diabetes mellitus

The pathogenesis of diabetes mellitus (DM) is a complex multifactorial condition currently under intense ongoing research.^45,46 Two primary factors contribute to this disease; insulin resistance which leads to its reduced effectiveness and higher demand^47,48 and ultimately causes type 2 diabetes mellitus (T2DM), and pancreatic β-cell failure, characterized by a reduction in both β-cell mass and function⁴⁸ and leads to type 1 diabetes mellitus (T1DM). T1DM is in fact a state of hypoamylinemia similar to hypoinsulinemia.⁷ IAPP is the major pathological hallmark of T2DM which we will discuss in detail later. Studies on the function of islets from individuals with T2DM are limited, but findings suggest that these islets show reduced insulin secretion compared to those from healthy controls and do not normalize glucose levels post-transplantation; however, their glucagon response remains normal.⁴⁹

In DM, increased demands on the pancreatic β-cells lead to elevated secretion of both insulin and IAPP, with IAPP levels notably higher during fasting (40 pM) and after meals (90 pM). As the disease progresses, IAPP secretion diminishes due to β-cell exhaustion.^21,27 This persistent elevation in IAPP production can cause processing abnormalities, leading to amyloid deposition both intracellularly and extracellularly as the disease advances and β-cells deteriorate.²⁸ Indeed, amyloid is detected in over 90% of T2DM pancreas, the cytotoxicity of hIAPP aggregates, believed to contribute to β-cell loss, is linked to mechanisms such as overload of endoplasmic reticulum correction mechanisms, disruption of intracellular transport, damage to organelle membranes (e.g., mitochondria), and activation of inflammasomes.^11,28

Moreover, IAPP is considered to be amyloidogenic and has been shown to interact with lipid membranes in pathogenic metabolic pathways.⁵⁰ Genetic mutations such as S20G (Figure 3D) in the human IAPP (hIAPP) gene are associated with early onset or a more severe T2DM. It also increases hIAPP hydrophobicity and amyloidogenic properties and enhances its fibrillogenic potential.^51,52 This mutation results in information of amyloid fibrils at around twice the rate of the wild-type protein leading to significantly higher aggregation and higher cytotoxicity. Aromatic amino acid residue F15 in IAPP is hydrophobic and plays a crucial role in the amyloidogenic pathway.⁴² A study highlighted that an F15L mutation alters the protein's α-helix and β-sheet structures leading to rapid Aβ formation.⁵³

Due to the natural tendency of hIAPP to aggregate, researchers studied an analog that could mimic IAPP's physiological functions without its inherent aggregation properties. Pramlintide emerged as the leading candidate and was patented in 1997. Marketed as Symlin®, it became the first peptide-based antidiabetic drug since insulin's discovery in 1921.^54–57 While no other IAPP-based drugs have been approved since then, several new analogs are showing promise as potential treatments for obesity and diabetes.⁷

Obesity

In obesity, there is a well-documented tendency for resistance to develop against the appetite-suppressing effects of both leptin and insulin as well as hormones related to food signaling like CCK and GLP-1.^58,59 This leptin resistance is often shown by a decrease in the activation of phosphorylated transducer and activator of transcription-3 (pSTAT3). pSTAT3 helps in mediating the leptin regulatory effects on eating.⁶⁰ The reduction in pSTAT3 activity within leptin-sensitive neurons is associated with a reduced inhibitory effect on eating. Additionally, obesity may also hinder the transport of insulin and leptin into the brain by compromising the integrity of the blood–brain barrier.⁶¹ Furthermore, an increase in leptin levels, which is a consequence of reduced sensitivity to the hormone in obesity, tends to further diminish the effectiveness of leptin's action on appetite regulation.⁶²

In studies involving rodents, IAPP treatment has been shown to exert a significant reduction in body weight relative to control vehicle-administered animals. Although IAPP-treated rodents might still gain some absolute body weight, notwithstanding less than the controls.^9,63 These findings may raise concerns about the clinical relevance of IAPP's effects. However, it is important to note a fundamental difference between these animal models and humans; unlike humans, most strains of rodents tend to gain weight continuously throughout their lives.⁹

Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is associated with pregnancy and the inability to produce enough insulin to overcome pregnancy-induced insulin resistance leading to hyperglycemia. While IAPP levels normally rise during pregnancy, GDM does not elevate the IAPP secretion.⁶⁴ Studies have shown that mid-gestation rats respond normally to IAPP-induced satiety which suggests IAPP resistance does not develop during pregnancy.^65,66 This indicates that IAPP changes may not contribute to GDM pathogenesis. However, a recent study using pregnant transgenic mice expressing hIAPP displayed GDM-like symptoms, proposing that hIAPP aggregation could potentially influence GDM or increase the risk of type 2 diabetes post-pregnancy.⁶⁷ This suggests a new rodent model for studying GDM and indicates a possible role for hIAPP aggregation in pregnant women. A GDM model in which the hIAPP is aggregated or factors that leads to hIAPP aggregations will provide more knowledge and a possible target for GDM therapeutics.

Bone metabolism disorders

It has been reported that IAPP may affect bone formation and resorption,⁶⁸ and aberrant IAPP and adiponectin serum levels have been associated with bone metabolism disorders.⁶⁹ Furthermore, IAPP inactivation in CTR receptor-deficient rodents displayed abnormalities in bone, suggesting that IAPP regulates bone metabolism.⁶⁸

Polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of women with a prevalence of 8%–13%.⁷⁰ PCOS is associated with reproductive, metabolic, and psychological features.⁷⁰ PCOS is associated with high IAPP secretion, and hyperamylasemia may be associated with the development of metabolic disorders in women with PCOS.⁷¹

Cardiac dysfunction

Effects of IAPP on the cardiovascular system are primarily thought to be mediated through the activation of CGRP receptors, which are abundantly expressed in the vasculature.⁷² These effects are considered largely pharmacological, as they require high plasma concentrations of IAPP to be observed and an intravenous injection of IAPP results in significant vasodilation that lowers arterial blood pressure along with transient increases in heart rate.⁷³ These vascular effects are likely mediated by CGRP receptors in the heart⁷⁴; however, a higher plasma concentration of IAPP is necessary to cause these effects as these receptors have low potency. Moreover, studies have revealed a 25-fold increase in IAPP expression in the preoptic area of the hypothalamus in lactating rats.^23,75,76

It has been reported that hyperamylinemia contributes to the cardiac dysfunction in obese patients and rats expressing hIAPP. Hyperamylinemia leads to IAPP deposition in the heart, resulting in structural and functional changes in cardiac myocytes through transient Ca²⁺ followed by Ca²⁺-dependent Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) pathway.⁷⁷

This research provides comprehensive insights into the multifactorial pathogenesis of DM, highlighting the roles of insulin resistance, pancreatic β-cell failure, and IAPP amyloid accumulation, particularly in T2DM. It underscores the importance of IAPP and its analogs like pramlintide in therapeutic applications, with promising results shown in obesity and GDM. Additionally, the study touches on the potential of IAPP in addressing bone metabolism disorders and PCOS, suggesting new avenues for treatment and further research. On the contrary, these findings rely heavily on animal model studies, which may not fully translate to human conditions. The complexity of DM pathogenesis and the role of IAPP requires further research to clarify mechanisms and therapeutic efficacy in humans. The potential side effects and long-term impacts of IAPP-based treatments remain underexplored. Further, the link between hIAPP aggregation and metabolic conditions like GDM and PCOS needs more robust evidence to establish causality and therapeutic relevance.

IAPP IN NEUROLOGICAL DISORDERS

Alzheimer's disease

Metabolic disorders and aging can lead to the cerebrovascular accumulation of IAPP amyloid, also called the second amyloid in Alzheimer's disease (AD), which affects the cerebral blood vessels and alters tissue structure. Additionally, the formation of IAPP amyloid in the walls of cerebral blood vessels may hinder the removal of Aβ from the brain, thereby playing a role in the development of AD.⁷⁸

Recent studies indicate potential therapeutic benefits of IAPP and its analog pramlintide in AD^79,80 are often linked with metabolic disorders such as T2DM.²⁸ Notably, individuals with AD and mild cognitive impairment exhibit lower IAPP levels compared to those without cognitive deficits.⁷⁹ This observation prompted research into the effects of chronic pramlintide infusions in rodent models of AD. In the senescence-accelerated prone mouse, a model for sporadic AD, pramlintide treatment improved memory and cognition, evidenced by enhanced performance in the novel object recognition task. This improvement was linked with increased synaptic markers and reduced neuroinflammation and oxidative stress markers in the hippocampus.⁷⁹ Similarly, treatment with IAPP and pramlintide, an IAPP analog, in a transgenic AD model enhanced learning and memory in the Y-maze and Morris water maze tests, along with a decrease in amyloid burden and brain Aβ levels. These findings suggest that IAPP and pramlintide may promote the clearance of Aβ from the brain to the blood, possibly via effects on cerebral vasculature.⁴ Such results point to IAPP and pramlintide as promising candidates for AD treatment, although further research is necessary to further examine their roles in the disease.

Parkinson's disease

The link between DM and Parkinson's disease (PD) risk is still much debated. Population-based cohort studies have suggested an increased risk, while case–control studies often show no elevated risk, underscoring the need for further research to clarify this relationship.^81,82 Sanchez-Gomez et al.⁸³ reported a study cohort consisting of 76 patients with PD and 39 control subjects and found no significant differences in fasting glucose, glycated hemoglobin, or HOMA-IR scores between the PD patients and control group. However, the hIAPP/insulin ratio was higher in PD patients, and the plasma level of hIAPP was higher in older patients. A study has reported that Enterobacteriaceae, prevalent in the gut, can produce functional amyloid proteins known as Curli. These Curli proteins contribute to the formation of α-synuclein (αSyn) in both the gut and the brain. The expression of Curli is necessary for E. coli to worsen αSyn-induced behavioral impairments, including impairments in the intestines and motor functions.⁸⁴ Another in vitro study has revealed that pro-IAPP amyloids hinder the formation of αSyn, while IAPP amyloid enhances αSyn aggregate formation. Conversely, αSyn aggregates promote amyloid formation by pro-IAPP but inhibit IAPP amyloid formation. Additionally, when hIAPP and αSyn monomers are mixed, they co-aggregate faster than either protein alone. This network of interactions indicates that the presence of IAPP can accelerate αSyn amyloid formation, which may explain the higher susceptibility of T2DM patients to developing PD.⁸⁵

Cerebrovascular dementia

Vascular dementia (VD), like AD, is a prominent cause of dementia.⁸⁶ The pathology of VD involves both structural and functional changes to blood vessels, impacting oxygen and nutrient delivery to the brain.⁸⁷ Risk factors for VD include hypertension, diabetes, obesity, and smoking, with VD and cognitive decline progressively seen as complications of diabetes.⁸⁸ Individuals with T2DM or prediabetics still face up to a 2-fold higher risk of developing VD and dementia compared to those without metabolic disorders.⁸⁶ Studies recently indicated that hIAPP aggregates in the small vessels of the brains of patients with dementia and T2DM, mixed IAPP-β amyloid (Aβ) plaques in the brains of patients exhibiting pathological signs of AD. These findings suggest that imbalances in IAPP could play a pathogenic role in the onset and progression of VD.^78,89,90

Depression

A study has reported that Aβ-induced depression is mediated through the CTR receptor, and its inhibition might enhance this phenomenon.⁹¹ Another study reported that AC187, a potent IAPP receptor antagonist, substantially abrogated the antidepressant effects of sCT (salmon calcitonin). This suggests that sCT likely alleviates depressive-like symptoms through the IAPP signaling pathway. Based on these observations, sCT could be viewed as a promising therapeutic option for treating depressive disorders in future studies.⁹²

Alcohol use disorder (AUD)

Alcohol use disorder (AUD) is a widespread chronic condition with significant health, psychological, economic, and social impacts. IAPP, primarily produced alongside insulin after eating, is known to curb hedonic eating and enhance satiety, and is found in the cerebrospinal fluid.⁹⁰ Research in rodents indicates that IAPP might also influence the reward responses associated with substances like alcohol. sCT has been shown to decrease food intake by acting on central IAPP receptors. Studies using male mice have demonstrated that intraperitoneal injections of sCT can prevent the dopamine release typically triggered by alcohol. AM1213, a more selective AMYR agonist than sCT, was administered daily to both female and male rats and resulted in a reduction in alcohol consumption, although this effect was only observed during the first 2 days of treatment.^92–95

Epilepsy

A study investigated the serum IAPP concentration in epilepsy. The study comprised 45 epileptic patients and 60 control subjects. They found a statistically significant difference in IAPP serum level, with serum IAPP levels for epileptic patients higher than those of the control subjects. The pathological effect of Aβ aggregates is based on the toxic soluble oligomers that disrupt Ca²⁺ homeostasis and compromise the viability of various cells, including astrocytes and neurons.⁹⁶

This highlights the potential therapeutic benefits of IAPP and its analog pramlintide in AD, PD, VD, depression, and AUD. IAPP in animal models show improvements in memory, cognition, and reduction in pathological protein aggregates, and may play a role in mitigating depressive symptoms and reducing alcohol consumption. On the other hand, these findings are largely based on animal models, with limited human data available. The mechanisms through which IAPP and pramlintide exert their beneficial effects are complex and not fully understood, and require further research. Additionally, the link between diabetes, metabolic disorders, and neurodegenerative diseases such as AD and PD remains much debated and requires more research.

OUTLOOK

IAPP, a neuroendocrine hormone that is co-secreted with insulin, shares sequence similarities with other CT family peptides and affects glucose levels and satiety. IAPP and insulin are regulated by shared promoter regions and released at a consistent ratio, with IAPP levels rising after food intake. The discovery of RAMPs has advanced the understanding of IAPP. FDA-approved pramlintide, an IAPP analog with no aggregation properties, was approved for the regulation of hyperglycemia and the treatment of T2DM. However, many more IAPP analogs must be further explored for their therapeutic potential. There is a need for research on IAPP analogs that are long-acting as compared to pramlintide. Cagrilintide, a long-acting IAPP agonist, along with semaglutide (CariSema) is being tested for its anti-T2DM and anti-obesity potentials. An important area of in-depth research would be the use of AD rodent models expressing hIAPP, which has amyloidogenic properties as compared to the rodent IAPP. Moreover, hIAPP overexpressing AD, PD, CD, and other neurological mouse models are likely to provide a ,much useful information, and are potential therapeutic pre-clinical models for these disease conditions.

AUTHOR CONTRIBUTIONS

Tahir Muhammad wrote the preliminary manuscript and prepared figures, Stephen F. Pastore, Katrina Good and Wai Haung Yu reviewed and edited the manuscript. John B. Vincent reviewed, edited and supervised the final draft.

ACKNOWLEDGMENTS

We would like to acknowledge Dr. Stefan Kloiber, Dr. Daniel Mueller, and Dr. Victor Tang at the Centre for Addiction and Mental Health (CAMH) for their help in conceiving the idea and providing their valuable input on the abstract in the preliminary draft.

CONFLICT OF INTEREST STATEMENT

There are no conflicts of interest.

DATA AVAILABILITY STATEMENT

This review article presents no new data.

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