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Structures of ephedrine (A), pseudoephedrine (B), phenylephrine (C), 1,3-dimethylamylamine (D), tuaminoheptane (E), phentermine (F), Methamphetamine (G), MDMA (H), Amphetamine (I).
Source publication
Sympathomimetic amine compounds are often pooled together and incorrectly assumed to be interchangeable with respect to potential adverse effects. A brief and specific review of sympathomimetic compounds and one instance (i.e., hepatotoxicity) where these compounds have been improperly grouped together is covered. A review of the proposed mechanism...
Contexts in source publication
Context 1
... contrast to amphetamine, compounds such as tuaminoheptane and 1,3-dimethylamylamine obviously lack the necessary aromatic ring for aromatic hydroxylation to occur (Fig. 1), while also lacking the aromatic ring necessary for catechol formation as demonstrated in the case of MDMA [6][7][8]. Pseudoephedrine, while possessing an aromatic ring and basic phenethylamine skeleton undergoes N-demethylation to form norpseudoephedrine as a minor (i.e. less than 1%) metabolite [9], while it does not appear to ...
Context 2
... the case of MDMA [6][7][8]. Pseudoephedrine, while possessing an aromatic ring and basic phenethylamine skeleton undergoes N-demethylation to form norpseudoephedrine as a minor (i.e. less than 1%) metabolite [9], while it does not appear to undergo aromatic hydroxylation in man, calling into question the potential for increased oxidative stress (Fig. 1). Similarly, ephedrine also undergoes N-demethylation to form nor- ephedrine but does not appear to undergo aromatic hydroxylation in man ...
Context 3
... pseudoephedrine and ephedrine also show a pharmacological profile which indicates a mechanism of selective modulation of norepinephrine [72,71]. Such distinctions at least in the case of 1,3-dimethylamylamine and tuaminoheptane may be at least partially due to the lack of the aromatic ring [73,74] (Fig.1). As neurotransmitter efflux is related to locomotor stimulating effects in animal models, it is also worth noting that 1,3-dimethylamylamine demonstrates distinct (i.e., no stimulation of locomotor activity) effects as compared to amphetamine and me- thamphetamine, which significantly increase locomotor activity [75,76]. ...
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Citations
... The most significant risk associated with sibutramine is its ability to increase blood pressure and heart rate; consequently, a large proportion of obese patients also have cardiovascular morbidity. These cautions prohibit the use of SHCl in obese individuals (Furman, 2007;Nelson and Gehlert, 2007;Willson, 2019;Wooltorton, 2002). All 12 patients developed acute liver injury characterized by a significant increase in serum liver chemistry values (mean alanine aminotransferase level, 1978 U/L [range, 283 to 4074 U/L]) after ingesting the Japanese-marketed Chinese herbal weight loss supplements Chaso and Onshido. ...
Context: Weight-loss supplements are typically natural or herbal supplements that promote weight loss and enhance health. However, the increase in consumption results in the fraudulent adulteration of conventional pharmaceutical drugs, such as sibutramine hydrochloride (SHCl). Aims: To determine the toxicity of weight loss supplements adulterated with SHCl in rats. Methods: Five samples (J1-J5) of weight loss supplements adulterated with SHCl were collected from an online market. The toxicity of the samples was evaluated using 42 male Wistar rats for 35 days. The rats were divided into seven groups: control, J1, J2, J3, J4, J5, and SHCl. Results: The J1 supplement resulted in the most rapid weight loss in rats compared to the other supplements tested. The kidney and liver weights of rats administered weight loss supplements adulterated with SHCl were greater than those of control rats. J1 indicated the supplement with the highest level of toxicity. The group administered J1 exhibited the highest levels of toxicity across all evaluated parameters. Conclusions: This study confirmed the toxicity of weight loss supplements adulterated with SHCl in rats, contributing to the understanding and treatment of adulterated weight loss supplements. Dietary supplements for weight loss should be thoroughly screened for undeclared sibutramine hydrochloride adulteration to protect public health and strengthen legal provisions.
... The fact that 1,3-DMAA is a sympathomimetic amine leads it to be grouped together with other sympathomimetic amines and it assumed to have the same potential adverse effects, such as hepatotoxicity [76]. There are case reports that link 1,3-DMAA to hepatotoxicity, with one example being a series of cases of seven members of the US military who developed hepatoxicity after taking OxyELITE Pro ® [11]. ...
... In a study that evaluated the different known pathways by which sympathomimetic amines are known to cause hepatotoxicity, such as: the "production of reactive metabolites, hyperthermia, increased neurotransmitter efflux, oxidation of biogenic amines, mitochondrial impairment and apoptosis", no evidence was found that 1,3-DMAA could cause hepatotoxicity by those same pathways [76]. ...
1,3-dimethylamylamine (1,3-DMAA) is a simple straight-chain aliphatic sympathomimetic amine, which was used as a nasal decongestant between 1948 and 1983. It reappeared in both dietary supplements as a substitute for ephedrine, and in party pills as an alternative to 3,4-methylenedioxymethamphetamine and/or 1-benzylpiperazine, after these substances were banned. Following its introduction to the market, it became one of the most widely used stimulants, and several case reports started to raise concerns about the safety and adverse effects of 1,3-DMAA. As a result, many countries banned or restricted the sale of 1,3-DMAA. Nevertheless, despite the efforts of regulating agencies, it has been reported that 1,3-DMAA is still found in dietary supplements and has been identified in doping controls. Therefore, the objective of this work is to review both the clinical and forensic aspects of 1,3-DMAA.
... Data are expressed as mean ± SEM. *Significant difference from control values (p < 0.05) Those treatments focus on the primary toxicities known to be involved in acute METH overdose based on readily observable symptoms such as high blood pressure and hyperthermia. METH is well-known from clinical reports of METH overdose to produce neural, cardiac, renal, and hepatic toxicity (Isoardi et al. 2019;Richards et al. 1999;Willson 2019). Nonetheless, few preclinical studies have focused on the mechanisms underlying METH overdose or lethal toxicity, although in vitro studies have examined METH-induced hepatotoxicity (for review, see Carvalho et al. (2012)). ...
Rationale
The use of novel psychoactive substances has been steadily increasing in recent years. Given the rapid emergence of new substances and their constantly changing chemical structure, it is necessary to develop an efficient and expeditious approach to examine the mechanisms underlying their pharmacological and toxicological effects. Zebrafish (Danio rerio) have become a popular experimental subject for drug screening due to their amenability to high-throughput approaches.
Objectives
In this study, we used methamphetamine (METH) as an exemplary psychoactive substance to investigate its acute toxicity and possible underlying mechanisms in 5-day post-fertilization (5 dpf) zebrafish larvae.
Methods
Lethality and toxicity of different concentrations of METH were examined in 5-dpf zebrafish larvae using a 96-well plate format.
Results
METH induced lethality in zebrafish larvae in a dose-dependent manner, which was associated with initial sympathomimetic activation, followed by cardiotoxicity. This was evidenced by significant heart rate increases at low doses, followed by decreased cardiac function at high doses and later time points. Levels of ammonia in the excreted water were increased but decreased internally. There was also evidence of seizures. Co-administration of the glutamate AMPA receptor antagonist GYKI-52466 and the dopamine D2 receptor antagonist raclopride significantly attenuated METH-induced lethality, suggesting that this lethality may be mediated synergistically or independently by glutamatergic and dopaminergic systems.
Conclusions
These experiments provide a baseline for the study of the toxicity of related amphetamine compounds in 5-dpf zebrafish as well as a new high-throughput approach for investigating the toxicities of rapidly emerging new psychoactive substances.
... The mechanism of cannabis hepatotoxicity has been postulated to be through action on CB1R found in hepatic cells [21]. Methamphetamine is considered a hepatotoxic synthetic amine [28]. The proposed mechanism of methamphetamine hepatotoxic action is through increased neurotransmitter efflux, generation of reactive metabolites, oxidation of biogenic amines, mitochondrial impairment, apoptosis, and hyperthermia [28,29]. ...
... Methamphetamine is considered a hepatotoxic synthetic amine [28]. The proposed mechanism of methamphetamine hepatotoxic action is through increased neurotransmitter efflux, generation of reactive metabolites, oxidation of biogenic amines, mitochondrial impairment, apoptosis, and hyperthermia [28,29]. ...
We present the case of a 51-year-old male admitted for cardiovascular complications in the face of concomitant chronic methamphetamine and cannabis use. Upon further assessment, the patient exhibited cardiotoxicity, including acute to chronic congestive heart failure (CHF) exacerbation, hypercoagulable state, and electrolyte abnormalities. Cardiotoxicity secondary to chronic methamphetamine use has been established. However, marijuana's cardiovascular effects have not been well established. Even less information exists about the simultaneous use of methamphetamine and cannabis. With increasing interest in the use of marijuana for medical purposes, it is imperative to study any corresponding toxicity and adverse effect profile. The worldwide pattern of drug co-administration also brings the importance of this topic to light. This case report serves to provide insight into this information gap.
... 61-64 METH-induced hepatotoxicity involves a variety of mechanisms, including the induction of hepatic metabolic disorder, the stimulation of oxidative stress, the promotion of hyperthermia, and the impairment of mitochondrial function. 65 It also has been shown to induce hepatic damage by suppressing cell division and the cell cycle which possibly accelerates liver apoptosis. 66 An RNAsequencing analysis indicated that LUT might have a hepatoprotective effect on METH-induced liver injury by restoring metabolic balance and by modulation of oxidative phosphorylation and cytochrome P450 regulation. ...
Humans are continuously exposed to environmental, occupational, consumer and household products, food, and pharmaceutical substances. Luteolin, a flavone from the flavonoids family of compounds, is found in different fruits and vegetables. LUT is a strong anti-inflammatory (via inhibition of NF-κB, ERK1/2, MAPK, JNK, IL-6, IL-8, and TNF-α) and antioxidant agent (reducing ROS and enhancement of endogenous antioxidants). LUT can chelate transition metal ions responsible for ROS generation and consequently repress lipoxygenase. Some studies have suggested that LUT also suppresses the nontransition metal-dependent oxidation. This review summarizes the available literature discussing luteolin and its potential protective role against pharmaceuticals-, metals-, and environmental compounds-induced toxicities.
... In addition, it is reported that synephrine may act as a biomarker [49]. Compared with other phenylethanolamines and catecholamines, synephrine has the advantage of fewer adverse reactions [50] and lower hepatotoxicity [51]. In a previous review article, Stohs et al. summarized the reported adverse reactions and concluded that there are no evidences showing that synephrine has side effects at common doses [2]. ...
Synephrine, a natural product also known as deoxyepinephrine, exists in Rutaceae plants and is widely distributed in China. In addition to natural sources, synephrine may also be obtained by means of chemical synthesis and genetic engineering methods. In recent years, extensive studies on the biological activity of synephrine have shown that this compound has significant anti-cancer, anti-depressant, anti-Parkinson and other effects. In addition, synephrine exhibits good metabolic regulatory activity and thereby is widely used in weight loss. As a foodborne compound, synephrine has the outstanding features of low toxicity and side effects. In this review, we will elaborate the pharmacological activity and toxic side effects of synephrine, as well as its new applications in the field of biomedicine.
... METH use causes systemic toxicity, affecting immune function [10] and impairing the function of multiple organs [2]. A variety of medical complications have been related to METH use, such as tooth decay ('meth mouth') [11], pulmonary hypertension [12], hepatotoxicity [13], cardiovascular diseases and strokes [14,15], and blood-borne and sexually transmitted infections [16]. These complications may indicate physiological characteristics of premature aging process in METH users. ...
Methamphetamine (METH) use, most prevalent in young adults, has been associated with high rates of morbidity and mortality. The relationship between METH use and accelerated biological aging, which can be measured using leukocyte telomere length (LTL), remains unclear. We examined whether young adult METH users have shorter LTL and explored the relationship between characteristics of METH use and LTL by using Mendelian randomization (MR) analysis. We compared the LTL for 187 METH users and 159 healthy individuals aged between 25 and 34 years and examined the relationship of LTL with METH use variables (onset age, duration, and maximum frequency of METH use) by using regression analyses. In addition, 2-stage-least-squares (2SLS) MR was also performed to possibly avoid uncontrolled confounding between characteristics of METH use and LTL. We found METH users had significantly shorter LTL compared to controls. Multivariate regression analysis showed METH use was negatively associated with LTL (β = −0.36, P < .001). Among METH users, duration of METH use was negatively associated with LTL after adjustment (β = −0.002, P = .01). We identified a single nucleotide polymorphism (SNP) rs6585206 genome-wide associated with duration of METH use. This SNP was used as an instrumental variable to avoid uncontrolled confounding for the relationship between the use duration and LTL shortening. In conclusion, we show that young adult METH users may have shorter LTL compared with controls and longer duration of METH use was significantly associated with telomere shortening. These observations suggest that METH use may accelerate biological senescence.
... The time to onset ranged from a few weeks to more than 6 months, but averaged 12 weeks, associated with symptoms of fatigue, nausea and abdominal discomfort followed by jaundice 125 Willson in his review discussed the reports that investigated the extent and mechanism of hepatotoxicity induced by sympathomimetic amines. The review concluded that sympathomimetic agents such as ephedrine, pseudoephedrine, phenylephrine, and 1,3dimethylamylamine fail to provide enough evidence of production of hyperthermia, reactive metabolites, oxidation of biogenic amines, increased neurotransmitter efflux, mitochondrial impairment and apoptosis compared to known hepatotoxic agents such as amphetamine, methamphetamine, and 3, 4-methylenedioxymethamphetamine (MDMA) 127 . The co-administration of commercial products containing p-synephrine along with caffeine, salicin and ephedrine led to an acute toxicity and a number of adverse events i.e. reduction in locomotor activity, ptosis, seizures, salivation, agitation and eventually deaths due to cardiopulmonary hemorrhage as revealed by animal study. ...
Ephedrine, a sympathomimetic amine that exhibits several of adrenaline actions, is a plant alkaloid
that is a common ingredient in several cold, asthma and narcolepsy treatment preparations, and in
obesity management, and sport medicine. Its principal action mechanism relies on its direct
adrenergic actions as well as indirect role that involves the release of epinephrine and
norepinephrine, thus increasing the activity of epinephrine and norepinephrine at the postsynaptic
α and β receptors. Nevertheless, its serious side effects including stroke, heart attack, drug abuse
and interactions have never been comprehensively reviewed. We conducted a systematic review
of data on ephedrine including its occurrence in functional foods, pharmacological aspects,
metabolism, pharmaco/toxicokinetics and clinical features. Further, a review of ephedrine natural
structural analogues with regards to their differential adrenergic receptor binding affinities, food
interaction and their impact on the pharmacokinetics and effects relative to ephedrine are presented
for the first time, and in comparison to its action when present in herbs
... METH also causes multiple organ damage in abusers, and the liver is a significant target of METH damage. The main mechanisms of METH-induced hepatotoxicity are production of reactive metabolites, hyperthermia, increased neurotransmitter efflux, oxidation of biogenic amines, mitochondrial impairment, apoptosis and indirectly, genetic polymorphisms (Willson, 2019). Recently, our group focused on the hepatotoxicity caused by METH and also demonstrated that METH could cause liver injury in an experiment on rats (Wang et al., 2017a). ...
In this study, RNA-sequencing (RNA-seq) was utilized to investigate the effects of luteolin on hepatotoxicity caused by methamphetamine (METH). The rats in METH group were administrated with METH (15 mg/kg, two times per day) via intraperitoneal (i.p.) injections for four consecutive days. The rats in luteolin + METH group were firstly administrated with luteolin (100 mg/kg, once a day) by oral gavage for 3 days before METH treatment. Lueolin attenuated the hepatotoxicity induced by METH via histopathological and biochemical analysis. The results of RNA-seq showed that luteolin could regulate 497 differentially expressed genes (DEGs), and the selected DEGs were mainly enriched in eight pathways, according to KEGG analysis. Furthermore, qRT-PCR was utilized to verify the results of RNA-seq. Six genes were selected as follows: liver enriched antimicrobial peptide 2 (Leap2), fatty acid synthase (Fasn), fatty acid binding protein 5 (Fabp5), patatin like phospholipase domain containing 3 (Pnpla3), myelin basic protein (Mbp) and calmodulin 3 (Calm3). Though because of the design flaws, the luteolin group has not been included, this study demonstrated that luteolin might exert hepato-protective effects from METH via modulation of oxidative phosphorylation, cytochrome P450 and certain signaling pathways.
Methamphetamine (Meth), an addictive psychostimulant of abuse worldwide, has been a common cause of acute toxic hepatitis in adults. Gut microbiota has emerged as a modulator of host immunity via metabolic pathways. However, the microbial mechanism of Meth-induced hepatic inflammation and effective therapeutic strategies remain unknown. Here, mice were intraperitoneally (i.p.) injected with Meth to induce hepatotoxicity. Cecal microbiome and bile acids (BAs) composition were analysed after Meth administration. Fecal microbiota transplantation (FMT) technology was utilized to investigate the role of microbiota. Additionally, the protective effects of obeticholic acid (OCA), an agonist of farnesoid X receptor (FXR), were evaluated. Results indicated that Meth administration induced hepatic cholestasis, dysfunction and aroused hepatic inflammation by stimulating the TLR4/MyD88/NF-κB pathway in mice. Meanwhile, Meth disturbed the cecal microbiome and impaired the homeostasis of BAs. Interestingly, FMT from Meth administered mice resulted in serum and hepatic BA accumulation and transferred similar phenotypic changes into the healthy recipient mice. Finally, OCA normalized Meth-induced BA accumulation in both serum and the liver, and effectively protected against Meth-induced hepatic dysfunction and inflammation by suppressing the TLR4/MyD88/NF-κB pathway. This study established the importance of microbial mechanism and its inhibition as a potential therapeutic target to treat Meth-related hepatotoxicity.
