Multidimensional Evaluation of Lisdexamfetamine: Pharmacology, Therapeutic Use, Toxicity and Forensic Implications

ABSTRACT

Lisdexamfetamine (LDX), a prodrug of d‐amphetamine, is widely used in the pharmacological treatment of neuropsychiatric disorders such as attention‐deficit/hyperactivity disorder (ADHD) and binge eating disorder (BED). Chemically, it consists of the amino acid lysine linked to d‐amphetamine. Its enzymatic conversion to d‐amphetamine sets the stage for a prolonged and controlled release, influencing its clinical profile and differentiating it from other stimulant medications. As a central nervous system stimulant, LDX primarily acts by increasing the release of neurotransmitters, particularly dopamine and noradrenaline, in the brain. Clinically, this enhanced availability of neurotransmitters is believed to contribute to improvements in attention, focus and impulse control in individuals with ADHD. The side effects of LDX include insomnia, decreased appetite, weight loss and xerostomia. This work reviews the pharmacological mechanisms, clinical applications and forensic considerations associated with its use. It is expected that clinicians, researchers and policymakers have a comprehensive understanding of the pharmacological and toxicological aspects of LDX.

Summary

Lisdexamfetamine (LDX) is a medication mostly used to treat attention‐deficit/hyperactivity disorder (ADHD) and binge eating disorder (BED). Once administered, LDX is slowly converted into a substance called d‐amphetamine in the body. This helps improve attention, focus and control of impulses by increasing certain chemicals in the brain, like dopamine and norepinephrine. Common side effects include sleep disturbances, loss of appetite, weight loss and dry mouth. This article fully reviews how LDX works clinically, what it is used for, and important safety information.

Structure of lisdexamfetamine dimesylate, its active metabolite d‐amphetamine and the essential amino acid l‐lysine, along with the mechanism of action and primary pharmacological and adverse effects associated with lisdexamfetamine dimesylate. TAAR ₁ , trace amine‐associated receptor; VMAT, vesicular monoamine transporter; DAT, dopamine transporter; NAT, noradrenaline transporter; SERT, serotonin transporter; MAO, monoamine oxidase.

1. Introduction

Over the past few decades, new treatments for various neuropsychiatric disorders have emerged, targeting the complex interplay of neurotransmitter systems underlying cognitive and behavioural functions. Among these, lisdexamfetamine (LDX) has gained interest for its mechanism of action and therapeutic versatility for the treatment of attention‐deficit/hyperactivity disorder (ADHD) and binge eating disorder (BED) [1]. It is considered an alternative treatment for ADHD to methylphenidate or atomoxetine (Figure 1), two more conventional treatments, when these two pharmaceuticals do not have the desired therapeutic efficacy [2]. Clinically, it is administered for the treatment of ADHD in children aged 6 years and older when treatment with methylphenidate does not provide an adequate response [3] and has been indicated as a first‐line treatment in adults [4, 5]. LDX has become a subject of increased interest for its unique pharmacokinetic and pharmacodynamic properties. It comprises an essential amino acid, l‐lysine, covalently linked to d‐amphetamine. As a prodrug of d‐amphetamine, LDX undergoes enzymatic hydrolysis at a limited speed in the bloodstream to its active form and l‐lysine. In comparison to immediate‐release d‐amphetamine, LDX is approximately 50%–60% less potent and presents a delayed time of peak effect [6, 7]. This distinctive metabolic pathway contributes to a prolonged duration of action and may explain LDX's lower ‘drug liking’ scores in comparison to immediate‐release d‐amphetamine [7]. Doubts persist about whether the therapeutic potential of LDX is due solely to d‐amphetamine or if l‐lysine also plays an important pharmacological role. Indeed, a study aimed to evaluate the levels of circulating amino acids in the serum of children with ADHD without any specific treatment concluded that there was a significant relationship between low levels of lysine and ADHD [8]. Low lysine levels appear to be a consequence of ADHD rather than a causative factor. Moreover, supplementation with lysine for the treatment of ADHD has been suggested based on observations that treatment with l‐lysine and l‐arginine (1.32 g twice daily) reduces anxiety [9]. This is likely related to the role of l‐lysine in neurotransmitter regulation and stress reduction. However, the precise mechanisms behind these benefits remain to be fully understood. As such, l‐lysine is not considered a primary treatment for ADHD but may be explored as a complementary supplement in some cases. Additionally, the lack of data on plasma lysine concentrations following therapeutic LDX administration makes it challenging to compare these levels with those resulting from direct lysine supplementation.

FIGURE 1.

Chemical structures of drugs used to treat attention‐deficit hyperactivity disorder.

Despite the increased interest that LDX has gained in clinical settings, pharmacokinetics, mechanisms of action, clinical applications, efficacy and potential misuse still deserve further clarification. Therefore, as with any other pharmaceutical, ongoing research on pharmacovigilance is essential to understand the possible benefits, risks and applications of LDX. This work aims to thoroughly review all data on LDX pharmacokinetics and pharmacodynamics, neurobiological mechanisms, clinical efficacy, adverse effects, possible interactions with other drugs, potential off‐label uses and forensic aspects. In addition, future directions in the evolving field of neuropsychopharmacology are also discussed.

2. Methods

An exhaustive search of English literature was carried out. Briefly, all information related to LDX was searched in PubMed (USA National Library of Medicine) without a limiting period regarding the historical background, chemical aspects, formulations, pharmacokinetics, pharmacodynamics, as well as its usefulness, clinical efficacy and adverse effects inherent to its exposure. For the bibliographic search, the following keywords, individually or in combination, were used: ‘lisdexamfetamine’, ‘lisdexamfetamine dimesylate’, ‘LDX’, ‘ADHD’, ‘pharmacokinetics’, ‘pharmacodynamics’, ‘forensic implications’, ‘abuse’, ‘clinical applications’, ‘clinical efficacy’ and ‘adverse effects’. Only articles published in English were considered. A total of 113 articles were included in the writing of this scoping review.

3. Development and Historical Background of LDX

This drug was developed to achieve a more effective substance with a longer‐acting potential and lower potential for abuse and addiction in comparison to d‐amphetamine [10]. New River Pharmaceuticals, United States (US), initially developed LDX in the late 1990s. In 2007, shortly before it began to be commercialized, New River Pharmaceuticals was acquired by Shire Pharmaceuticals, US, which was acquired by Takeda Pharmaceuticals (Japan), in 2019. In February 2007, the US Food and Drug Administration (FDA) approved LDX for treating adult ADHD [11]. In January 2015, LDX was approved by the FDA for treating BED in adults [12]. The US patent protection for LDX expired on February 24, 2023 (Food and Drug Administration, 2015b) [3]. LDX has been sold under various brands such as Aduvanz, Elvanse, Juneve, Samexid, Tyvense, Venvanse and Vyvanse.

4. Chemical Aspects and Formulations

LDX dimesylate [(2S)‐2,6‐diamino‐N‐[(2S)‐1‐phenylpropan‐2‐yl]hexanamide methanesulfonate] (Figure 1) is administered in doses of 30, 50 or 70 mg per day [13]. It is available in capsules or chewable tablets of 10, 20, 30, 40, 50 and 60 mg; in the case of capsules, 70 mg is also available [14]. Salt formation is widely used in the pharmaceutical industry to enhance or alter the physicochemical properties (e.g., to improve aqueous solubility of weakly acidic and basic drugs), characteristics of formulation, biopharmaceutical attributes (including safety and tolerability) and therapeutic performance of ionizable drug compounds. The most commonly used counterions for basic drug molecules have included hydrochloride, mesylate, hydrobromide, acetate and fumarate, while sodium, calcium and potassium continue to be the most common counterions for weakly acidic drugs [15, 16]. It also addresses other physicochemical and biological challenges, including stability, toxicity and manufacturing‐related issues [17]. While all of the salt forms (hydrochloride, hydrobromide, methanesulfonate, mesylate and camphorsulfonate) increased the solubility of the parent drug, mesylate salt consistently produced a higher solubility of 39 mg/mL at 25°C. Since LDX is formulated as a dimesylate salt, a particular focus is devoted to this counterion. Mesylate is a salt or an ester of methanesulfonic acid (CH₃SO₃H; mesyl). When in the salt form, it is presented as an anion (methanesulfonate; CH₃SO₃ ⁻), and when in ester form, mesylate is a group of organic compounds that share a common functional group with the general structure CH₃SO₂O − R, abbreviated MsO − R, where R is an organic substituent [17]. Several marketed medications are formulated as mesylate salts [16, 18]. As discussed below, genotoxic concerns have been highlighted for mesylates [15, 18].

5. Pharmacokinetics

The primary factor behind the LDX's attractiveness is its pharmacokinetics, namely its rapid uptake from the small intestine and the prolonged release due to its rate‐limiting hydrolysis of d‐amphetamine with a reduced potential for abuse [19, 20]. Moreover, LDX has a low potential for pharmacokinetic drug–drug interactions since it is neither a substrate nor an inhibitor of the cytochrome P450 enzymes [21]. The once‐a‐day treatment regimen also facilitates parental supervision [22], and opening the capsule or dissolving it in water does not increase the active metabolite's effect or concentration [7].

5.1. Absorption and Distribution

After oral administration, LDX is rapidly absorbed from the gastrointestinal tract, reaching a peak plasma concentration (C _max) around 1 h after administration (time to maximum plasma concentration [t _max] 1.0–2.1 h) [19, 23, 24, 25]. The absorption of LDX is thought to involve a carrier‐mediated active transport, namely the peptide transporter 1 (PepT1) present in the small intestine. This transport‐mediated process limits the absorption rate and, consequently, the speed of distribution and metabolism of LDX to d‐amphetamine [19, 26]. Furthermore, LDX concentrations in portal blood were approximately 10 times higher than those in systemic circulation, suggesting that LDX undergoes pre‐systemic conversion to d‐amphetamine in the rat model [25]. During regional perfusion of isolated intestinal segments in rats, LDX absorption was observed in the duodenum, jejunum and ileum. Very little plasma LDX and d‐amphetamine were observed during colonic perfusion. Furthermore, plasma concentrations of d‐amphetamine increased steadily throughout the experiment after perfusion of all segments except the colon [25]. Total LDX was transported across the epithelial layer of Caco‐2 cells, although the apparent permeability rate (Papp) was low [25]. An open‐label, randomized crossover study [26] evaluated the pharmacokinetics of LDX administered and released regionally in the gastrointestinal tract. Capsules containing radiolabeled LDX (50 mg) were administered to the proximal small bowel, distal small bowel and ascending colon for separate periods. Oral administration of LDX or targeted administration for small systemic exposure similar to d‐amphetamine exposure indicates good absorption and reduced absorption following colonic administration. Another study by Krishnan and colleagues [27] aimed to evaluate the relative bioavailability of d‐amphetamine from LDX in 18 healthy adult volunteers. Among other findings, the authors concluded that no dietary effect on d‐amphetamine was observed when LDX 70 mg was administered to healthy adults based on systemic exposure. The plasma t _max for d‐amphetamine occurred 1 h later following administration of LDX 100 mg (range 3.78–4.25 h) than for an equivalent dose of d‐amphetamine sulphate (40 mg; 1.88–2.74 h), suggesting that the systemic delivery of d‐amphetamine from LDX is a rate‐limiting step [28]. The t _max of d‐amphetamine was similar when taken in solution or on an empty stomach and was greater by approximately 1 h when taken with food [27].

The finding that d‐amphetamine is produced from LDX within the cytosol of red blood cells prompted investigation into how LDX is transported across the red blood cell membrane. The dipeptide‐like characteristics of LDX, the known ability of red blood cells to absorb cationic dipeptides [29] and the presence of high‐affinity amino acid transporters in the red blood cell plasma membrane [29, 30, 31] are suggestive of a mechanism for future investigation. The rapid production of d‐amphetamine from LDX in whole blood and intact red blood cells suggests that the transport of LDX across the red blood cell membrane is not rate limiting [25].

5.2. Metabolism

In the inactive prodrug LDX, a peptide bond links the amino group of d‐amphetamine to the carboxyl group of l‐lysine. LDX metabolism is rate‐limited and occurs through enzymatic hydrolysis in the cytosol of erythrocytes into l‐lysine and d‐amphetamine by an unidentified aminopeptidase (Figure 2) [25, 30]. Although the enzymes involved in metabolism are not clear, it is known that cytochrome P450 (CYP450) enzymes do not metabolize LDX into d‐amphetamine [19, 21].

FIGURE 2.

—Lisdexamfetamine dimesylate metabolism. An unknown aminopeptidase converts LDX into d‐amphetamine. d‐Amphetamine can be oxidized at the β‐position by dopamine beta‐hydroxylase (DBH) to norephedrine or at the p‐position (p‐hydroxylation) by cytochrome P450 (CYP) 2D6 to 4‐hydroxyamphetamine, which in turn can be oxidized at the β‐position by DBH to 4‐hydroxynorephedrine. Alternatively, d‐amphetamine can be deaminated by flavin‐containing monooxygenase 3 (FMO3) to phenylacetone, which can be oxidized to benzoic acid; the latter can be conjugated with glycine by xenobiotic/medium‐chain fatty acid‐ligase (XM‐ligase) glycine‐N‐acyltransferase (GLYAT) to produce hippuric acid.

Pennick et al. [25] investigated LDX metabolism in tissues and blood fractions from rats and human donors incubated with LDX (1.0 μg/mL). Additionally, the stability of LDX (1 μg/mL) was studied in the presence of three hydrolytic peptidase enzymes: human dipeptidyl peptidase IV, cathepsin G and elastase. LDX was metabolised in rat liver tissue and whole blood, with a t _1/2 of 2.5 and 1.0 h, respectively. In contrast, LDX was stable, and d‐amphetamine formation was negligible in incubations with intestines, pancreas and lower plasma homogenates; incubations with kidney and colon homogenates could slowly metabolize LDX over time. In incubations with red blood cells, LDX was rapidly converted, and d‐amphetamine formation increased simultaneously, leading the authors to conclude that human erythrocytes metabolised LDX. Moreover, the rate of LDX hydrolysis tended to decrease as the RBC fractions were diluted, although there was still substantial conversion at lower concentrations of red blood cell fractions. Red blood cell lysis did not affect the LDX conversion rate, and adding ethylenediaminetetraacetic acid (EDTA) to reconstructed red blood cells did not inhibit the rate of LDX hydrolysis. The t _1/2 of LDX in red blood cell incubations averaged 1.0 h (0.87 and 1.10 h for red blood cells fractions from two human donors). LDX concentrations were stable, and d‐amphetamine formation was negligible in incubations with peripheral blood mononuclear cells, polymorphonuclear cells and platelets. Results also evidenced that the rate of LDX hydrolysis was haematocrit‐dependent, but substantial conversion to d‐amphetamine remained when haematocrit values were only 10% or 25% of normal. Regarding the stability of LDX in the presence of dipeptidyl/peptidase IV, cathepsin G and elastase, the formation of d‐amphetamine is negligible, and LDX was also stable in SGF and SIF for up to 60 min, and with trypsin, even when very high concentrations of trypsin were used. Another study supports the idea that LDX is metabolised by an aminopeptidase in erythrocytes [30]. Analysis of LDX hydrolysis in whole and fractionated human blood suggested that LDX had a t _1/2 of 1.6 h. In plasma, LDX remained completely stable for 4 h, with d‐amphetamine concentrations staying below the detection limit (10 ng/mL). The authors concluded that the hydrolysis of LDX occurs in the cytosolic extract and lysate of human red blood cells, but not in the membrane fraction. Their findings suggest that an aminopeptidase is responsible for cleaving the peptide bond in LDX. Furthermore, the results point to a protease activity—likely a metallo‐aminopeptidase—rather than carboxylesterase or amidase, as the enzyme mediating LDX hydrolysis. Nevertheless, purified recombinant aminopeptidase B was not able to release d‐amphetamine from LDX in vitro. Indeed, peptidase activity of red blood cell cytosol has been described [31] and proteomic studies have identified peptidases in the cytosol [32]. Moreover, aminopeptidase B is a red blood cell cytosolic enzyme with a preference for lysine [33] and was, therefore, considered a likely candidate to mediate LDX hydrolysis. Recombinant human aminopeptidase B failure to convert LDX to d‐amphetamine in vitro suggests that other candidate peptidases (e.g., leukotriene A4 hydrolase) remain to be investigated. d‐Amphetamine is further metabolised by oxidative deamination, ring hydroxylation and methylation of one of the hydroxy groups and N‐demethylation. In the subsequent phase, they are mainly excreted as glucuronide and/or sulphate conjugates. Phenylpropanolamine (also known as norephedrine) is not substantially further metabolised, with hippuric acid (via oxidative deamination of the side chain) and 4‐hydroxynorephedrine (via p‐hydroxylation; also known as p‐hydroxynorephedrine) being the main metabolites [34, 35].

5.3. Excretion

Krishnan et al. [19] also evaluated the excretion of LDX and d‐amphetamine. The six volunteer participants were selected to receive 70 mg of ¹⁴C‐labelled LDX dimesylate to determine the recovery of radioactivity. They concluded that approximately 96.4% of the radioactivity was recovered in the urine, and only 0.3% was recovered in the faeces. These results suggest that LDX is not bioaccumulated. In the 0 to 48‐h urine samples, 79.4% of the oral dose radioactivity was recovered, 41.5% as d‐amphetamine, 24.8% as hippuric acid and only 2.2% represented intact LDX. The remaining 8.9% was related to unknown or unidentified metabolites [19]. This suggests that d‐amphetamine is the main metabolite of LDX in urine. After the peak, LDX plasma concentrations decrease rapidly, with a mean elimination half‐life (t _1/2) of 0.4–0.9 h [19, 23].

5.4. Interactions

The results of a study in 30 healthy volunteers using a concentration range between 1 and 100 ng/mL found that LDX did not alter the activity of cytochrome P450 enzymes, namely the CYP1A2, CYP2D6 and CYP3A4isoforms [36]. Therefore, it is not expected that there will be a drug–drug interaction when taking LDX concomitantly with substances that are metabolised by these enzymes. Compounds that alter urinary pH can affect the urinary excretion and half‐life of the primary active metabolite, d‐amphetamine; acidification with ascorbic acid and ammonium chloride or alkalinization with antacids like sodium bicarbonate decreases or increases the half‐life of d‐amphetamine, respectively [34]. LDX administration is also contraindicated within 14 days after monoamine oxidase inhibitors (MAOIs) since the effect persists until the enzyme has been resynthesized. Therefore, it is essential to avoid the risk of an increase of monoamines such as dopamine, serotonin and noradrenaline and, consequently, the risk of intense headaches and other symptoms of hypertensive crisis, potentially leading to death [37]. Some studies exploring the use of LDX in pregnancy have supported an increased risk of pre‐eclampsia and premature birth. It is, therefore, not advisable to take this drug during pregnancy or lactation, as amphetamines are excreted in breast milk [38].

6. Pharmacodynamics

The stimulating activity of LDX in the central nervous system (CNS) is due to interference with seven protein targets. It activates the trace amine‐associated receptor 1 (TAAR₁), inhibits the flavin‐containing amine oxidases (MAO)_A and MAO_B and reverses the direction of the synaptic vesicular monoamine transporter 2 (VMAT₂; SLC18A2), dopamine transporter (DAT; SLC6A3), noradrenaline transporter (NAT; SLC6A2) and serotonin transporter (SERT; SLC6A4) (Figure 3) [1, 6].

FIGURE 3.

—Main targets of d‐amphetamine, the active metabolite of lisdexamfetamine dimesylate, and their impact on mood and cognitive function. d‐Amphetamine interferes with dopamine transporter (DAT), serotonin transporter (SERT), noradrenaline transporter (NAT), vesicular monoamine transporter 2 (VMAT₂), monoamine oxidase (MAO) and trace amine‐associated receptor 1 (TAAR₁). The relevance of these targets for attention, irritability and appetite is displayed, as well as the main roles of dopamine, serotonin and noradrenaline in motivation, behaviour and cognition. Adapted from Quintero et al. [1].

LDX directly controls the presynaptic neuronal transmission, increasing dopamine in the synaptic cleft, improving attention deficit disorder and cognitive functions and reducing hyperactivity [39]. In its direct influence, LDX regulates presynaptic transporters by reversing the transport mediated by DAT, NAT and SERT [40], increasing dopamine, noradrenaline and serotonin levels in the synaptic cleft (Figure 4) [6, 41].

FIGURE 4.

—Mechanism of action of d‐amphetamine, the active metabolite of lisdexamfetamine dimesylate. d‐Amphetamine increases dopamine (DA) in the synaptic cleft due to the activation of trace amine‐associated receptor 1 (TAAR₁), resulting in the efflux of monoamines from presynaptic vesicles. Increased dopaminergic transmission also results from the inhibition of vesicular monoamine transporter 2 (VMAT₂), inducing the release of DA from vesicular storage and the consequent release of cytosolic DA through the reverse transport of dopamine transporter (DAT) and the inhibition of monoamine oxidase (MAO)_A and MAO_B. 5‐HT, serotonin; NA, noradrenaline; SERT, serotonin transporter; NAT, noradrenaline transporter; PK, protein kinase. Adapted from Quintero et al. [1].

The increase in dopamine in the synaptic cleft, promoted by LDX, may also be due to an activation of the TAAR₁ protein, an amine receptor, which results in an efflux of monoamine neurotransmitters, mainly dopamine, from presynaptic vesicles [42, 43]. Upon activation of TAAR₁, phosphorylation and activation of protein kinases A and C (PKA and PKC) occur due to intracellular cyclic adenosine monophosphate (cAMP) signalling [44, 45, 46]. PKC activation intensifies the direct blockade of monoamine transporters by LDX. This improves the neurotransmission imbalance characteristic of ADHD by decreasing the expression of DAT, NAT and SERT on the cell surface [20, 47, 48]. Furthermore, PKC plays a critical role in modulating dopamine efflux in ADHD by influencing key intracellular signalling pathways; specifically, PKC activation can lead to the stimulation of the p38 mitogen‐activated protein kinase (p38 MAPK) pathway, which in turn mediates the inactivation of protein kinase B (AKTs). AKT is essential for the proper trafficking and surface redistribution of the dopamine transporter (DAT), as it promotes actin cytoskeleton reorganization—a prerequisite for the mobilization of DAT to the neuronal plasma membrane [49]. Therefore, when AKT activity is suppressed, this actin‐dependent redistribution of DAT is impaired, resulting in deficient dopamine reuptake and dysregulated dopamine signalling, a hallmark of ADHD pathophysiology [50].

The increased dopaminergic transmission also arises from the inhibition of VMAT2, inducing the release of dopamine from the vesicular storage and the consequent release of cytosolic dopamine via transporter‐mediated reverse flux through DAT [51, 52], and the inhibition of MAO_A and MAO_B [6]. The increased dopaminergic transmission induced by LDX manifests in the two main pathways of cognition and memory, the mesolimbic and mesocortical pathways [42]. Dopamine D₁ receptors and α₂‐adrenoreceptors mediate the cognitive enhancement caused by LDX in postsynaptic neurons [53]. The effect of dopamine on dopamine D₁ receptors increases locomotor activity [54], and the effect on α₂‐adrenoreceptors results in an inhibition of the spontaneous firing rate of neurons in the locus ceruleus, which could improve the effectiveness of LDX in controlling symptoms of ADHD [55]. LDX also induces upregulation of α_2A, α_2B, α_2C, dopamine D₁ and D₅ receptors [42, 56, 57].

In addition, LDX increases several inflammatory mediators, such as interleukin (IL)‐4, IL‐6 and IL‐10 [1]. As with methylphenidate, tumour necrosis factor α (TNF‐α) expression seems to be induced after treatment with LDX [58]. However, a recent study, which used adult male Wistar rats subjected to an animal mania model induced by daily administration of LDX (10 mg/Kg), did not demonstrate that LDX influences neither IL‐10 (anti‐inflammatory cytokine), TNF‐α, nor IL‐1β (pro‐inflammatory cytokines) [59]. On the other hand, the inhibition of MAO_A and the activation of TAAR₁ by LDX can influence the activation of MAPK₃, which induces the expression of some anti‐inflammatory cytokines that are negatively regulated in patients with ADHD, through the activation of NFκB, which is crucial for the downstream modulation of a large number of proteins involved in many biological processes, such as neuroinflammation [60]. This suggested a potential immunomodulatory role for LDX, reducing the inflammatory response. Nevertheless, more studies are needed to elucidate the inflammatory activity of LDX.

LDX causes oxidative imbalance through increased lipid peroxidation, protein oxidation and changes in the activity of antioxidant enzymes in some brain areas [61]. Two studies in male Wistar rats that received LDX orally for 7 days demonstrated that LDX decreased antioxidant enzymes, such as catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), revealing a potential mechanism of action related to oxidative stress [61, 62].

LDX is also helpful for the treatment of BED, as it reduces both symptoms and body weight in patients with the disorder. Evidence suggests that LDX may reduce binge eating through effects on appetite/satiety, reward and cognitive processes, including attention and impulsivity, which are mediated by the brain's catecholamine and serotonin neuronal pathways [63].

7. Clinical Efficacy

A randomized, double‐blind, placebo‐controlled study compared the efficacy, safety and tolerability of LDX and the oral osmotic release system of MPH (OROS‐methylphenidate) in adolescents with ADHD [64]. For this purpose, they divided their sample into three groups with flexible [LDX 30–70 mg/day (n = 186 randomized); OROS‐methylphenidate 18–72 mg/day (n = 185 randomized); placebo (n = 93 randomized)] or forced doses [LDX 70 mg/day (n = 219 randomized); OROS‐methylphenidate 72 mg/day (n = 220 randomized); placebo (n = 110 randomized)]. The study occurred for eight and six weeks of the trial for flexible and forced doses, respectively. LDX was superior to OROS‐methylphenidate for improving ADHD symptoms in a forced‐dose study but not in a flexible‐dose study. As previously reported in other studies [65, 66, 67], LDX and OROS‐methylphenidate showed greater efficacy than placebo, demonstrating their therapeutic potential.

The results of a meta‐analysis [68], which aimed to compare the different treatments used for ADHD and their effectiveness, concluded that treatment with LDX, when compared with atomoxetine, methylphenidate long‐acting and methylphenidate short‐acting, resulted in a positive response in a larger number of patients. In a systematic review [69], the authors collected information from 32 studies, of which 24 adopted an optimized dosing method and the remaining eight used forced dosing; they used two instruments to understand the response to treatment with LDX (i.e., the ADHD‐ Rating Scale and the Clinical Global Impressions‐Improvement). By the ADHD‐Rating Scale evaluation method, LDX resulted in 41%, 22% and 32% more positive responses than atomoxetine, methylphenidate long‐acting and methylphenidate short‐acting, respectively. By the second evaluation method, LDX had 55%, 23%, 95% and 61% more responses than atomoxetine, methylphenidate long‐acting, methylphenidate intermediate release and methylphenidate short‐acting, respectively. LDX treatment showed the most significant response and efficacy regardless of the scale used.

It is equally important to note that individuals with ADHD commonly have other comorbid psychiatric conditions. There are a few studies that have evaluated the effect and influence of LDX on other psychiatric disorders. In one cohort study (n = 221 714; aged 16 to 65 years old) of patients diagnosed with ADHD, 125 164 (56.5%) had some psychiatric comorbidity, with anxiety or stress‐related disorders (53 314 individuals [24.0%]) and depression and/or bipolar disorders (43 344 individuals [19.5%]) being the most common, demonstrated a decreased risk of suicidal behaviour associated with LDX when compared to other pharmaceutical products, as well as not being associated with an increased risk of non‐psychiatric hospitalization [70]. It was even observed that there was a reduction in the risk of non‐psychiatric hospitalization. Overall, these results support a higher efficacy of LDX for ADHD treatment in children and adolescents compared to other currently available therapies.

Regarding BED, this pathology was studied by assessing the effect of LDX on food intake over 36 weeks in female Wistar rats divided into three groups with different food exposure conditions [71]. The results demonstrated that LDX affected food intake and food‐enhanced operant behaviour, with more significant effects observed in the chocolate‐exposed group. A multinational, phase III, double‐blind, placebo‐controlled, randomized study by Hudson et al. [72], including 418 adults (18–55 years) with moderate to severe BED, evaluated the maintenance of treatment efficacy with LDX. The study included a 12‐week open‐label phase [dose optimization: 4 weeks (LDX, 50 or 70 mg); dose maintenance: 8 weeks] and a 26‐week double‐blind randomized withdrawal phase. Participants were randomized to receive a placebo or LDX during this last phase. Of the 275 randomized participants (placebo, n = 138; LDX, n = 137), the observed proportions of participants meeting relapse criteria were 3.7% for LDX and 32.1% for placebo. After the initial response to LDX, continued treatment was associated with a longer time to relaxation from cravings by six months than the placebo. The estimated risk of relapse with LDX was 11 times lower than with placebo. Overall, these findings indicate that LDX was associated with a clinically meaningful reduction in the likelihood of BE relapses and extend the short‐term findings from the LDX efficacy study in adults with protocol‐defined moderate to severe BED.

Guerdjikova et al. [73] proposed to evaluate LDX in the treatment of BED in 50 participants (18–55 years of age) who received LDX (20–70 mg/day) (n = 25) or placebo (n = 25) for 12 weeks in a single‐centre, randomized, double‐blind, flexible‐dose study. The trial consisted of three phases: a two‐week screening period during which participants had to experience ≥ three BEs days/week to be randomized, a 12‐week double‐blind treatment period, and a treatment discontinuation period of 1 week. Participants were assessed at least twice during the screening period: after 1, 2, 3, 4, 6, 8, 10 and 12 weeks during the treatment period and 1 week after discontinuation of study medication. At the last visit of the screening period, participants who continued to meet entry criteria were enrolled into the treatment period and randomly assigned in a 1:1 ratio to LDX therapy or placebo. The intention of treating the population for the primary longitudinal analysis was to include all randomized participants. For the secondary outcome analysis, all participants had at least one post‐baseline visit. In the primary longitudinal analysis, LDX did not demonstrate a significantly greater reduction compared to placebo in BE days per week, BE episodes per week or scores on the CGI‐Severity and Yale‐Brown Obsessive‐Compulsive Scale modified for BE. However, LDX was associated with significant reductions in weight, body mass index (BMI) and fasting triglyceride levels. In secondary analyses, LDX was linked to statistically significant decreases in BE days per week, BE episodes per week, weight and BMI, as well as significantly higher rates of categorical response and overall clinical improvement. Several studies evaluated the impact of LDX in individuals with ADHD and other comorbidities such as anxiety, bipolar disorder and depression, among others [74, 75, 76]. There are also clinical trials that have attempted to evaluate the effectiveness of LDX in pathologies such as bulimia nervosa [77], major depressive disorder [78] and bipolar depression [79]. Additionally, pilot studies have investigated LDX as a treatment for cocaine [80, 81] and methamphetamine addiction [82].

8. Adverse Effects

Table 1 summarizes five studies that evaluated the main treatment‐emergent adverse events (TEAEs) of LDX in the treatment of ADHD and three trials that observed the main TEAEs inherent to LDX consumption in the treatment of BED.

TABLE 1.

—Treatment‐emergent adverse events (TEAEs) reported in five studies with lisdexamfetamine dimesylate (LDX) for the treatment of attention deficit hyperactivity disorder (ADHD) and three studies with LDX for the treatment of binge eating disorder (BED).

	ADHD												BED
	Children (6–12 y) [83]		Children and adolescents (6–17 y) [84]		Children and adolescents (6–17 y) [85]			Adolescents (13–17 y) [65]		Adults (18–55 y) [86]			Adults (18–55 y) [87]		Adults (18–55 y) [72]			Adults (18–55 y) [73]
Treatment	LDX	PBO	LDX	ATX	LDX	OROS‐MPH	PBO	LDX	PBO	LDX	LDX	PBO	LDX	LDX + TPM	LDX	LDX	PBO	LDX	PBO
N	218	72	128	134	111	111	110	233	77	142 a	115 b	117 b	48	45	411	136	134	25	25
Trial duration (weeks)	4		9		7			4		4	2		12		12 (4 + 8)	26		12
Study design	Forced‐dose titration		Dose optimization		Dose optimization			Forced‐dose titration		Dose optimization	Crossover phase		Dose optimization		Dose optimization + dose maintenance	Dose optimization		Dose optimization
TEAEs (%)
Abdominal pain	—	—	2.3	6	5.4	3.6	5.5	—	—	—	—	—	—	—	—	—	—	—	—
Anorexia	—	—	—	—	10.8	5.4	1.8	—	—	—	—	—	—	—	—	—	—	—	—
Anxiety	—	—	—	—	—	—	—	—	—	5.6	1.7	0	25	15.9	7.1	1.5	1.5	8	0
Ataxia	—	—	—	—	—	—	—	—	—	—	—	—	0	13.3	—	—	—	—	—
Back pain	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	4	4
Bruxism	—	—	—	—	—	—	—	—	—	—	—	—	20.8	20	—	—	—	—	—
Confusion	—	—	—	—	—	—	—	—	—	—	—	—	0	8.9	—	—	—	—	—
Constipation	—	—	6.3	1.5	—	—	—	—	—	—	—	—	—	—	6.8	2.9	0.7	0	8
Cough	1.4	5.6	—	—	2.7	7.2	0	—	—	—	—	—	—	—	—	—	—	—	—
Decreased appetite	39	4.2	25.8	10.4	25.2	15.3	2.7	33.9	2.6	36.6	3.5	1.7	—	—	9.2	0	0	—	—
Decreased memory	—	—	—	—	—	—	—	—	—	—	—	—	0	6.7	—	—	—	—	—
Diarrhoea	—	—	—	—	—	—	—	—	—	—	—	—	—	—	5.1	1.5	2.2	16	4
Disturbance in attention	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	12	0
Dizziness	5	0	—	—	—	—	—	4.3	3.9	—	—	—	10.4	13.3	—	—	—	12	0
Dry mouth	4.6	0	6.3	3	—	—	—	4.3	1.3	30.3	3.5	0.9	81.3	84.4	33.8	5.1	1.5	48	0
Emotional lability	—	—	—	—	—	—	—	—	—	—	—	—	10.4	4.4	—	—	—	—	—
Fatigue	—	—	9.4	10.4	—	—	—	4.3	2.6	4.9	0.9	12.9	4.2	13.3	4.4	2.9	5.2	8	16
Feeling jittery	—	—	—	—	—	—	—	—	—	5.6	0	0	—	—	5.1	0	0	28	0
Gastrointestinal disturbance	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	8	4
Hand tremor	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	8	4
Headache	11.9	9.7	13.3	16.4	14.4	19.8	20	14.6	13	19.7	1.7	2.6	25	11.1	16.1	8.8	6.7	20	20
Hyperhidrosis	—	—	—	—	—	—	—	—	—	—	—	—	—	—	5.6	2.2	0	—	—
Increased talkativeness	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	12	0
Increase in systolic blood pressure	—	—	—	—	—	—	—	—	—	—	—	—	10.4	11.1	—	—	—	—	—
Increased dreaming	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	4	12
Influenza‐like illness	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	8	16
Insomnia	18.8	2.8	11.7	6	14.4	8.1	0	11.2	3.9	18.3	2.6	1.7	56.3	20	11.2	0.7	1.5	44	8
Irritability	9.6	0	6.3	2.2	—	—	—	6.9	3.9	8.5	0	0.9	18.8	6.7	—	—	—	4	4
Nasal congestion	1.4	5.6	—	—	—	—	—	2.6	1.3	—	—	—	—	—	—	—	—	—	—
Nasopharyngitis	5	5.6	6.3	6	7.2	12.6	7.3	3	1.3	—	—	—	—	—	4.9	9.6	6.7	—	—
Nausea	6	2.8	12.5	15.7	10.8	7.2	2.7	3.9	2.6	7.7	1.7	0	10.4	4.4	8.5	4.4	2.2	8	12
Palpitation	—	—	—	—	—	—	—	—	—	—	—	—	16.7	15.6	—	—	—	4	4
Paresthesia	—	—	—	—	—	—	—	—	—	—	—	—	0	22.2	—	—	—	4	4
Respiratory disorder	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	20	8
Sedation	—	—	3.9	6	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Sinus problems	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—	8	4
Sleep disorder	—	—	—	—	5.4	1.8	0.9	—	—	—	—	—	—	—	—	—	—	—	—
Somnolence	—	—	3.1	11.9	—	—	—	—	—	—	—	—	—	—	—	—	—	—	—
Upper abdominal pain	11.9	5.6	2.3	7.5	7.2	8.1	5.5	—	—	—	—	—	—	—	—	—	—	—	—
Upper respiratory tract infection	—	—	2.3	6	—	—	—	4.3	7.8	9.9	1.7	7.7	—	—	2.7	8.1	3.7	—	—
Vomiting	8.7	4.2	4.7	9.7	—	—	—	1.3	5.3	—	—	—	—	—	—	—	—	—	—
Weight decreased	9.2	1.4	21.9	6.7	13.5	4.5	0	9.4	0	—	—	—	—	—	—	—	—	—	—
Any TEAE (%)	74.3	47.2	71.9	70.9	72.1	64.9	57.3	68.7	58.4	79.6	27.8	35.9	—	—	82.2	60.3	46.3	—	—

Abbreviations: ATM, atomoxetine; OROS‐MPH, oral osmotic release system of methylphenidate; PBO, placebo; TPM, topiramate.

^a Percentages are based on the number of subjects who received each dose at any point during the dose‐optimization phase.

^b Percentages are based on the number of subjects who received each dose at any point during the crossover phase.

The first study is a multicenter, randomized, double‐blind, forced‐dose, parallel‐group study conducted at 40 centers in the USA [83]. Children aged six to 12 years with ADHD were randomly assigned to receive LDX 30, 50 or 70 mg or placebo for 4 weeks. The second study took place over 9 weeks and was a randomized, double‐blind, active‐controlled trial [84]. It included children and adolescents aged six to 17 years with moderate ADHD and an inadequate response to previous methylphenidate therapy. Patients were randomized (1:1) to an optimized daily dose of LDX or atomoxetine. The third study evaluated the efficacy and safety of LDX compared to placebo in children and adolescents aged six to 17 years with ADHD in Europe [85]. Participants were randomized (1:1:1) to dose‐optimized LDX (30, 50 or 70 mg/day), OROS‐methylphenidate (18, 36 or 54 mg/day) or placebo for 7 weeks. The fourth study involved adolescents aged 13–17 years with moderately symptomatic ADHD who were randomized to receive a placebo or LDX (30, 50 or 70 mg/day) for 4 weeks [65]. The latest study on ADHD was divided into a dose‐optimization phase with LDX, 30–70 mg/day (4 weeks), and a randomized, double‐blind, placebo‐controlled crossover phase (2 weeks) [86]. Adults aged between 18 and 55 participated in this trial. Regarding the trials where the main TEAEs of LDX in BED were observed, the studies [72, 73] had already been previously described in the clinical efficacy section. The other study evaluated the efficacy of LDX therapy alone or in combination with topiramate for treating BED in adults aged 18–55 years [87]. Participants received LDX (n = 48), an average dose of 37.5 mg/day or LDX, an average dose of 38 mg/day plus TPM, an average dose of 77.7 mg/day (n = 45).

In addition to the common, non‐specific effects such as dizziness, drowsiness, decreased appetite, insomnia, headaches, nausea, fatigue and dry mouth [88], concerns have been raised about LDX's potential efects on weight and growth rate [89]. As for other stimulants, it is recommended that children's weight be monitored, as reductions in weight and height have been reported [14]. A 3‐year follow‐up study by the U.S. National Institute of Mental Health revealed that children treated with stimulants were, on average, 2.0 cm shorter and 2.7 kg lighter after three years of treatment compared with unmedicated children [90]. However, reductions in growth velocity were most significant in the first year of treatment, then decreased in the second year and were absent in the third year [90]. Growth was more affected in heavier and taller children, in those who had not previously received treatment with stimulants, and in those with a higher cumulative exposure to LDX [91]. Slight increases in blood pressure and heart rate have also been reported [89]. As such, it is recommended to avoid LDX administration in patients with cardiac abnormalities, cardiomyopathy, severe cardiac arrhythmia or coronary artery disease, despite studies demonstrating that there is no link between these abnormalities and LDX consumption [92, 93].

Some observations also suggest that caution is necessary when prescribing this substance during the peripubertal phase. Indeed, Roustaee et al. [94] analysed semen in 24 adult male albino rats administered with LDX by gavage for 4 weeks at a dose of 30 mg/kg and found a significant decrease in motility and significantly higher sperm DNA fragmentation t the control group. There was also a reduction in blood testosterone levels and the number of Leydig cells. It was suggested that this decrease in Leydig cells may be due to d‐amphetamine‐induced cell death. A stereological analysis of the testicular tissue revealed a significant reduction in the number of spermatogonia, spermatids and the length density of the testicular seminiferous tubules. The high levels of TNF‐α and caspase‐3 indicate that chronic administration of this drug may trigger an inflammatory response, leading to an increase in caspase‐dependent cell death of spermatogenic cells. Another in vivo study in Wistar male rats orally administered with LDX (5.2, 8.6 and 12.1 mg/kg/day) by gavage was carried out for 31 consecutive days, from the 23rd to the 53rd postnatal day, which corresponds to the juvenile and peripubertal period [95]. On postnatal day 54, half of the animals were sacrificed for an immediate assessment of reproductive parameters, and the other half were maintained until sexual maturation, when they were evaluated regarding sexual behaviour at postnatal day 90. This study found that regarding sperm parameters, animals exposed to 5.2 and 8.6 mg/kg of LDX showed an increase in immobile spermatozoa and a reduction in the relative number of mature spermatids in the testicles. Furthermore, animals exposed to the highest dose had a decrease in the relative number of sperm counts in the cauda epididymis compared to the control. Immediately after treatment, increased expression of CAT and SOD, as well as malondialdehyde levels, were registered. These findings support concerns regarding the prescription and administration of LDX during the prepubertal period due to its toxic effects on the male reproductive system. LDX was found to impair reproductive maturation, leading to significant and lasting disruptions in testicular function, even after exposure had ceased. This effect may be attributed to oxidative stress imbalance in the testes, as suggested by alterations in antioxidant enzyme activity.

A recent case report demonstrated that LDX, administered within the therapeutic range (with dose escalation over time: 30, 50 and 70 mg), caused delusional parasitosis (Ekbom syndrome) in a 53‐year‐old man with a history of depression, anxiety, heterozygous MTHFR mutation, Type 1 diabetes treated with insulin, sleep apnea and mild cognitive impairment. Notably, he had previously tolerated mixed amphetamine salts and armodafinil without side effects [96]. This rare condition is defined as having a fixed, false belief that one is infected with insects, parasites or organisms and that one experiences cutaneous sensations without any clinical evidence of infestation [97]. Awake bruxism, a commonly reported adverse effect of psychostimulants, has also been recently observed for LDX ([98] #34288). Moreover, there was an unexpected LDX‐induced paralytic ileus in a 55‐year‐old man [99].

9. Concerns About the Genotoxicity of MESYLATE Formation

Mesylate formation has been associated with mutagenic, carcinogenic and teratogenic effects, raising concerns about its safety [100]. For instance, the anti‐HIV drug nelfinavir mesylate (Viracept) was withdrawn from the European market owing to increased levels of ethyl methanesulfonate impurity. Indeed, alkyl mesylates such as methyl methanesulfonate have been shown to be genotoxic both in vitro and in vivo, and there is considered sufficient evidence in experimental animals of carcinogenicity (IARC Group 2A) [101]. In the typical synthesis of a mesylate salt, the process begins with the drug in its free base form, which is the most basic (proton‐accepting) component. Then, this free base reacts with an equimolar amount of methanesulfonic acid to form the mesylate salt. The reaction primarily involves protonation of the free base by the acid, leading to salt formation. Under standard reaction conditions used for mesylate salt formation, the likelihood of forming impurities such as methyl methanesulfonate is considered negligible and only occurs if residues of short‐chain alcohol are present. This is because the formation of alkyl mesylates would require a chemical reaction known as nucleophilic substitution, where a mesylate ion acts as a nucleophile (electron donor) and displaces a hydroxide ion from an alcohol to form the alkyl mesylate. In this case, both the reactants involved in such a side reaction are chemically unsuited for it to occur efficiently: (i) the hydroxide ion is a very poor leaving group, meaning it does not easily detach from molecules; and (ii) the mesylate ion is a very weak nucleophile due to its negative charge being delocalized over three oxygen atoms, making it less reactive. Furthermore, the presence of short‐chain alcohols (which could potentially lead to alkyl mesylates) is typically minimal or controlled in the synthesis process. As a result, the expected risk of significant alkyl mesylate formation under these conditions is extremely low. Therefore, mesylate salts should not require additional regulatory scrutiny solely based on concerns about potential genotoxicity, unless there is evidence of actual formation of such impurities under specific process conditions [16].

10. Forensic Aspects

Abuse of stimulants often involves intranasal or intravenous (i.v.) administration to shorten the drug blood plasma t _max of the compound and increase the C _max, thus maximizing ‘rush’ effects [20, 102, 103]. Particularly for LDX, pharmacological studies exploring these administration routes have been reported. A randomized, two‐period, crossover study involving 18 healthy male participants showed that intranasal administration of 50 mg LDX led to lower plasma levels and reduced systemic exposure to d‐amphetamine compared to oral use of an equivalent dose, with similar tolerability [28]. Another double‐blind trial in stimulant abusers found that i.v. administration of LDX (25–50 mg) produced significantly lower abuse‐related effects than d‐amphetamine (10–20 mg), despite comparable plasma levels (d‐amphetamine reached a C _max of 38.9 ± 8.1 ng/mL following administration of the pure drug (20 mg) and 105 ± 91.4 ng/mL after administration of LDX (50 mg); the t _max of d‐amphetamine was 2.51 h for a 50 mg dose of LDX, compared to 0.82 h for a 20 mg dose of d‐amphetamine). Overall, these findings suggest that non‐oral routes of LDX administration (i.v. or intranasal) are unlikely to enhance the psychoactive effects and are not favoured for abuse [7, 20]. This is further supported by the lack of reports on LDX misuse via intranasal or i.v. administration. It is worth noting that the available pharmaceutical preparation of LDX is a powder, which is physically compatible with intranasal use, potentially presenting a misuse risk. However, the presence of water‐insoluble excipients in the formulation makes i.v. administration very unlikely.

The fact that it is only metabolised to d‐amphetamine in erythrocytes at a rate‐limited extent, LDX has a lower potential for abuse compared to other substances [28]. Although many studies show a lower reinforcing effect of LDX than d‐amphetamine [7, 20, 104], other studies have found similar effects, mainly when the doses consumed are higher than the authorized dose [28, 41, 105].

Even though LDX does not appear to be metabolised by CYP450, amphetamine is metabolised by CYP2D6, and inhibitors of this isoform can increase the concentration of the drug, leading to a more significant and prolonged effect. LDX could consequently increase the risk of serotonin syndrome in patients on multiple serotonergic treatments [106].

This dose‐dependent effect is also concerning in cases of overdose since LDX has a toxicity profile similar to that of amphetamines. However, the risk is limited by the fact that the lethal dose (LD) is five times higher than that of amphetamines in Sprague–Dawley rats orally administered LDX [107]. The LD₅₀ for single oral doses of LDX in rats appears greater than 1000 mg/kg, which is equivalent to 548 mg/kg of d‐amphetamine sulphate. In turn, the LD₅₀ of oral d‐amphetamine sulphate reported in rats is 32 mg/kg. This finding supports a putative protective effect (i.e., a broader therapeutic index) through hydrolysis of LDX to d‐amphetamine and lysine. This results from the fact that it has a prolonged effect, where the active metabolite is released progressively without attaining a significant plasma peak, and the route of consumption does not alter the onset of action. Therefore, its pharmacokinetic properties limit the potential for misuse and abuse.

It is essential to differentiate the origin of d‐amphetamine, i.e., whether it is derived from a pharmaceutical source (which yields enantiopure d‐amphetamine) or a clandestine product (racemic mixture) [108]. A case report of a forensic autopsy of a man with a history of ADHD, depression and panic attacks explored this hypothesis using LDX quantification by LC–MS/MS [109]. Forty days after the autopsy, police discovered that the deceased had been prescribed Vyvanse, validating the possibility that he was consuming LDX. Besides LDX, alprazolam, amphetamine, atomoxetine, bromazepam, caffeine, sulpiride and venlafaxine were detected by LC–MS/MS in cardiac blood and urine samples. The amphetamine isomer detected in the samples from this case was identified only as d‐amphetamine. The cause of death was thermal burns due to a fire in his living room.

A recent study aimed to characterise the elimination kinetics of lisdexamphetamine, dexamphetamine and methylphenidate in oral fluid after controlled therapeutic dosing, demonstrating that it was possible to achieve comparable detection windows in oral fluid and urine for the three drugs by choosing appropriate cut‐offs and to assess therapeutic adherence of ADHD patients [110].

Deaths due to LDX have been rarely described. Recently, 64 deaths in which ADHD medications were implicated (41 due to methylphenidate and 23 due to LDX) were reported in a retrospective observational study of deaths in Australia of people aged 15 years or older. Nevertheless, 78% of cases involved ingestion of more than one drug, and 70% had known substance‐use problems [111].

11. Conclusions and Future Perspectives

LDX is rapidly absorbed and eliminated mainly via the urinary route. Its action is limited by metabolism since it is a prodrug that needs to be cleaved to d‐amphetamine in erythrocytes by a still‐unknown enzyme. As such, LDX activity depends on its active metabolite, d‐amphetamine, which mainly increases dopamine levels in the synaptic cleft, influencing attention, irritability and appetite and regulating emotional and cognitive functioning. It also has immunomodulatory, anti‐inflammatory and oxidative potential. LDX has been used to treat ADHD in children and adults. It also shows the benefits of BED. LDX's TEAEs include nausea, dizziness, xerostomia, diarrhoea and irregular heartbeat, although these are less frequent than with other CNS stimulants. In the recreational context, LDX shows a lower potential for abuse and misuse when compared to other drugs, mainly due to its pharmacokinetic characteristics.

LDX has excellent efficacy for ADHD treatment, showing higher levels of efficacy than other pharmaceuticals. Considering all the available data on LDX, we can envision its use not only for the treatment of ADHD but also for other conditions. Indeed, the potential for LDX to revolutionize neuropsychiatric care becomes increasingly evident. By pushing the boundaries of knowledge, exploring innovative applications and embracing patient‐centred approaches, the future of LDX research holds the promise of transforming the landscape of neuropsychiatric therapeutics. Some pilot studies examined the effect of LDX in the treatment of various addictions, such as cocaine and methamphetamine [80]. Indeed, amphetamine has also been shown in human laboratory studies to reduce cocaine self‐administration in humans [112]. There is also an approach to LDX for the treatment of other pathologies and diseases, such as bulimia nervosa, bipolar depression and major depressive disorder. For depression, LDX is only recommended as a second or third‐line treatment when conventional treatments do not have the desired effect [113].

Despite the increasing use of LDX for conditions such as ADHD, several scientific gaps in knowledge remain that require further investigation, particularly regarding its pharmacology, long‐term safety and forensic implications.

Although LDX is recognized as a prodrug of d‐amphetamine, more research is needed to fully understand the metabolic pathway(s) responsible for its activation, especially across different populations. Factors such as age, sex and gene variants may influence the conversion rate and, consequently, the efficacy or toxicity of the drug. Moreover, while the pharmacodynamic effects of LDX primarily involve increased dopaminergic and noradrenergic activity, its impact on other neurotransmitter systems and the downstream effects on brain function remain poorly characterised. Studies in this area would provide a more comprehensive understanding of its neurological and behavioural effects. Investigating dose–response relationships in specific patient populations (e.g., children, the elderly, individuals with comorbidities) is also essential to optimize therapeutic regimens and minimize risks.

From a safety perspective, significant uncertainties remain about the long‐term cardiovascular, neurological and psychiatric effects of LDX, especially in individuals exposed from an early age. Longitudinal studies are needed to assess the cumulative effects of prolonged use. Although the abuse potential of LDX is considered lower than that of other amphetamine formulations, this area also warrants extensive investigation. Comparative studies examining the pharmacological and behavioural effects of LDX with other stimulants could help clarify its risk for dependence.

In addition to evaluating formulation improvements, such as incorporating more lipophilic excipients to cause less painful i.v. administration or larger powder particles in the marketed pharmaceutical preparations to prevent intranasal administration, the exploration of novel prodrug strategies may further reduce abuse potential while maintaining therapeutic efficacy. For example, while LDX remains the only approved amphetamine prodrug, other conjugated molecules, including pegylated derivatives, have been investigated [114]. These novel approaches could help optimize the balance between efficacy and safety, especially in populations at higher risk for stimulant misuse.

On the other hand, there is a lack of comprehensive data on drug interactions involving LDX, particularly with commonly used medications, nutritional supplements and psychotropic drugs. Such studies are particularly important in ethnically diverse clinical populations. In forensic medicine and forensic toxicology, the development of sensitive and specific methods to detect LDX and its metabolites in biological samples, including blood, urine or hair, is increasingly critical. These methods are essential for clinical diagnosis, therapeutic interventions and investigations of abuse or poisoning.

Additionally, establishing biomarkers or metabolic patterns that can differentiate LDX use from other amphetamines is essential for both legal and clinical contexts. Finally, research to define correlations between plasma levels of LDX/d‐amphetamine and the severity of functional impairment could guide safety regulations, particularly regarding workplace performance and operating vehicles.

Author Contributions

M.S‐C. and R.J.D‐O. conceived of the presented manuscript and were responsible for methodology, formal analysis, investigation, resources, writing – original draft preparation, writing, reviewing, editing and visualization. M.S‐C., D.J.B., D.D.S. and R.J.D‐O. were responsible for writing, reviewing and editing. All authors have read and agreed to the published version of the manuscript.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Silva‐Carvalho M., Barbosa D., Dias da Silva D., and Dinis‐Oliveira R., “Multidimensional Evaluation of Lisdexamfetamine: Pharmacology, Therapeutic Use, Toxicity and Forensic Implications,” Basic & Clinical Pharmacology & Toxicology 137, no. 5 (2025): e70111, 10.1111/bcpt.70111.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.