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Brain, Behavior and Evolution 2020Phenethylamines (e.g., methamphetamine) are a common source of drug toxicity. Phenethylamine-induced hyperthermia (PIH) can activate a cascade of events that may result... (Review)
Review
Phenethylamines (e.g., methamphetamine) are a common source of drug toxicity. Phenethylamine-induced hyperthermia (PIH) can activate a cascade of events that may result in rhabdomyolysis, coagulopathy, and even death. Here, we review recent evidence that suggests a potential link between the gut-brain axis and PIH. Within the preoptic area of the hypothalamus, phenethylamines lead to changes in catecholamine levels, that activate the sympathetic nervous system (SNS) and increase the peripheral levels of norepinephrine (NE), resulting in: (1) the loss of heat dissipation through α1 adrenergic receptor (α1-AR)-mediated vasoconstriction, (2) heat generation through β-AR activation and subsequent free fatty acid (FFA) activation of uncoupling proteins (UCPs) in brown and white adipose tissue, and (3) alteration of the gut microbiome and its link to the gut-brain axis. Recent studies have shown that phenethylamine derivatives can influence the composition of the gut microbiome and thus its metabolic potential. Phenethylamines increase the relative level of Proteuswhich has been linked to enhanced NE turnover. Bidirectional fecal microbial transplants (FMT) between PIH-tolerant and PIH-naïve rats demonstrated that the transplantation of gut microbiome can confer phenotypic hyperthermic and tolerant responses to phenethylamines. These phenethylamine-mediated changes in the gut microbiome were also associated with epigenetic changes in the mediators of thermogenesis. Given the significant role that the microbiome has been shown to play in the maintenance of body temperature, we outline current studies demonstrating the effects of phenethylamines on the gut microbiome and how these microbiome changes may mechanistically contribute to alterations in body temperature.
Topics: Animals; Gastrointestinal Microbiome; Hyperthermia; Phenethylamines; Rats; Thermogenesis
PubMed: 33472193
DOI: 10.1159/000512098 -
Journal of Pharmaceutical and... Oct 2023The hypolipidemic and hypoglycemic drug benfluorex was widely applied to treat type 2 diabetes mellitus and metabolic syndrome in overweight patients since 1976....
The hypolipidemic and hypoglycemic drug benfluorex was widely applied to treat type 2 diabetes mellitus and metabolic syndrome in overweight patients since 1976. However, benfluorex was connected to multiple cases of valvular heart disease and pulmonary arterial hypertension later on. Similar adverse drug reactions were previously found to be associated to the structurally related drug fenfluramine, which was attributed to the formation of its N-deethylated metabolite norfenfluramine. Even though norfenfluramine was known to be a common metabolite of fenfluramine and benfluorex, only fenfluramine was withdrawn from European and United States markets in 1997 while benfluorex remained available until 2009. In this work, the metabolism of benfluorex is simulated by an online hyphenation of electrochemistry and mass spectrometry and the observed transformation products are further characterized using liquid chromatography and high-resolution tandem mass spectrometry. Using this approach, norfenfluramine is found to be the main electrochemical transformation product of benfluorex. Considering the knowledge about norfenfluramine toxicity, rapid metabolite screening using electrochemistry hyphenated to mass spectrometry could have been used to predict the potential of benfluorex for adverse drug reactions early on, showcasing the value of electrochemical metabolism mimicry for rapid drug safety evaluation.
Topics: Humans; Norfenfluramine; Diabetes Mellitus, Type 2; Electrochemistry; Fenfluramine; Tandem Mass Spectrometry
PubMed: 37542830
DOI: 10.1016/j.jpba.2023.115626 -
International Journal of Environmental... Nov 2019Contamination of residential homes with methamphetamine is an emerging issue of significant concern to public health. Cooking or smoking methamphetamine in a residential... (Review)
Review
Contamination of residential homes with methamphetamine is an emerging issue of significant concern to public health. Cooking or smoking methamphetamine in a residential property contaminates the house, furnishings and personal possessions within it, with subsequent exposure through ingestion, dermal absorption and/or inhalation causing adverse health effects. Current guidelines identifying levels of methamphetamine contamination that require remediation vary between countries. There is also no international standard protocol for measuring levels of contamination and research has shown that different materials give rise to different recovery rates of methamphetamine. There are a number of currently used remediation methods; however, they have varying levels of success with limited studies comparing their long-term efficacies. Most importantly, there are few guidelines available that are based on a transparent, health risk-based approach, and there are many uncertainties on exposures and health effects, making it difficult to ensure the health of people residing in homes that have been used to cook or smoke methamphetamine are sufficiently protected. This manuscript presents the current state of knowledge regarding the contamination of residential homes with methamphetamine and identifies the current gaps in knowledge and priority areas for future research. The current regulatory approach to public health protection associated with exposure to residential premises contaminated with methamphetamine in Australia, New Zealand and the USA is also discussed.
Topics: Environmental Pollutants; Humans; Methamphetamine; Public Health; Substance-Related Disorders
PubMed: 31771211
DOI: 10.3390/ijerph16234676 -
Forensic Toxicology Jan 2023The present review aims to provide an overview of methods for the quantification of 2,5-dimethoxy-amphetamines and -phenethylamines in different biological matrices,... (Review)
Review
PURPOSE
The present review aims to provide an overview of methods for the quantification of 2,5-dimethoxy-amphetamines and -phenethylamines in different biological matrices, both traditional and alternative ones.
METHODS
A complete literature search was carried out with PubMed, Scopus and the World Wide Web using relevant keywords, e.g., designer drugs, amphetamines, phenethylamines, and biological matrices.
RESULTS
Synthetic phenethylamines represent one of the largest classes of "designer drugs", obtained through chemical structure modifications of psychoactive substances to increase their pharmacological activities. This practice is also favored by the fact that every new synthetic compound is not considered illegal by existing legislation. Generally, in a toxicological laboratory, the first monitoring of drugs of abuse is made by rapid screening tests that sometimes can occur in false positive or false negative results. To reduce evaluation errors, it is mandatory to submit the positive samples to confirmatory methods, such as gas chromatography or liquid chromatography combined to mass spectrometry, for a more specific qualitative and quantitative analysis.
CONCLUSIONS
This review highlights the great need for updated comprehensive analytical methods, particularly when analyzing biological matrices, both traditional and alternative ones, for the search of newly emerging designer drugs.
Topics: Phenethylamines; Gas Chromatography-Mass Spectrometry; Amphetamines; Mass Spectrometry; Chromatography, Liquid
PubMed: 36652064
DOI: 10.1007/s11419-022-00638-6 -
European Neuropsychopharmacology : the... Aug 2021Psychedelics alter the perception of reality through agonist or partial agonist interaction with the 2A serotoninergic receptor. They are classified as phenethylamines,...
Psychedelics alter the perception of reality through agonist or partial agonist interaction with the 2A serotoninergic receptor. They are classified as phenethylamines, tryptamines and lysergamides. These classes, according to the United Nations Office on Drugs and Crime (UNODC) and European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), account for an important percentage of the new psychoactive substances (NPS) current scenario.The paper aimed at: a) identifying and categorising psychedelic molecules from a list of psychonaut websites and NPS online resources; and b) comparing the NPSfinder results with those from the European and United Nations databases. A crawling software (i.e. 'NPSfinder') was created to automatically scan, 24/7, a list of URLs and to extract a range of information (chemical/street names, chemical formulae, etc.) to facilitate NPS identification. Data collected were manually analysed and compared with the EMCDDA and UNODC databases.The overall number of psychedelic NPS detected by NPSfinder (November 2017-February 2020) was 1344, almost ten-times higher than that reported by the UNODC and EMCDDA combined. Of these, 994 previously unknown molecules were identified as (potential) novel psychedelics, suggesting a strong discrepancy between online and real-world NPS scenarios. The results show the interest of psychonauts, and maybe of the much larger community of 'recreational' drug users, towards psychedelics. Moreover, examining online scenario may help in assessing the availability in the real world of psychedelic NPS; understanding drug trends; and in possibly predicting future drug scenarios.
Topics: Hallucinogens; Humans; Illicit Drugs; Phenethylamines; Psychotropic Drugs; Substance-Related Disorders
PubMed: 33857740
DOI: 10.1016/j.euroneuro.2021.03.006 -
Drug and Alcohol Dependence Jul 2020Synthetic phenethylamines are widely abused drugs, comprising new psychoactive substances such as synthetic cathinones, but also well-known amphetamines such as... (Review)
Review
Synthetic phenethylamines are widely abused drugs, comprising new psychoactive substances such as synthetic cathinones, but also well-known amphetamines such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Cathinones and amphetamines share many toxicodynamic mechanisms. One of their potentially life-threatening consequences, particularly of MDMA, is serotonin-mediated hyponatraemia. Herein, we review the state of the art on phenethylamine-induced hyponatremia; discuss the mechanisms involved; and present the preventive and therapeutic measures. Hyponatraemia mediated by phenethylamines results from increased secretion of antidiuretic hormone (ADH) and consequent kidney water reabsorption, additionally involving diaphoresis and polydipsia. Data for MDMA suggest that acute hyponatraemia elicited by cathinones may also be a consequence of metabolic activation. The literature often reveals hyponatraemia-associated complications such as cerebral oedema, cerebellar tonsillar herniation and coma that may evolve to a fatal outcome, particularly in women. Ready availability of fluids and the recommendation to drink copiously at the rave scene to counteract hyperthermia, often precipitate water intoxication. Users should be advised about the importance of controlling fluid intake while using phenethylamines. At early signs of adverse effects, medical assistance should be promptly sought. Severe hyponatraemia (<130 mmol sodium/L plasma) may be corrected with hypertonic saline or suppression of fluid intake. Also, clinicians should be made aware of the hyponatraemic potential of these drugs and encouraged to report future cases of toxicity to increase knowledge on this potentially lethal outcome.
Topics: Alcohol Drinking; Alkaloids; Amphetamine; Drinking; Humans; Hyponatremia; Illicit Drugs; N-Methyl-3,4-methylenedioxyamphetamine; Neurophysins; Phenethylamines; Protein Precursors; Vasopressins
PubMed: 32460203
DOI: 10.1016/j.drugalcdep.2020.108045 -
Scientific Reports Feb 20224-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a new psychoactive substance with strong hallucinogenic properties. Our previous data reported...
4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a new psychoactive substance with strong hallucinogenic properties. Our previous data reported increased release of dopamine, serotonin, and glutamate after acute injections and a tolerance development in the neurotransmitters release and rats' behavior after chronic treatment with 25I-NBOMe. The recreational use of 25I-NBOMe is associated with severe intoxication and deaths in humans. There is no data about 25I-NBOMe in vivo toxicity towards the brain tissue. In this article 25I-NBOMe-crossing through the blood-brain barrier (BBB), the impact on DNA damage, apoptosis induction, and changes in the number of cortical and hippocampal cells were studied. The presence of 25I-NBOMe in several brain regions shortly after the drug administration and its accumulation after multiple injections was found. The DNA damage was detected 72 h after the chronic treatment. On the contrary, at the same time point apoptotic signal was not identified. A decrease in the number of glial but not in neural cells in the frontal (FC) and medial prefrontal cortex (mPFC) was observed. The obtained data indicate that 25I-NBOMe passes easily across the BBB and accumulates in the brain tissue. Observed oxidative DNA damage may lead to the glial cells' death.
Topics: Animals; Apoptosis; Blood-Brain Barrier; Brain; DNA Damage; Dimethoxyphenylethylamine; Dopamine; Glutamic Acid; Hallucinogens; Humans; Injections; Neuroglia; Oxidative Stress; Rats; Serotonin
PubMed: 35190675
DOI: 10.1038/s41598-022-07069-8 -
Experimental Neurology Jan 20223,4 Methylenedioxymethamphetamine generally referred to as MDMA or 'ecstasy' is a ring-substituted phenethylamine stimulant which produces powerful empathogenic effects.... (Review)
Review
3,4 Methylenedioxymethamphetamine generally referred to as MDMA or 'ecstasy' is a ring-substituted phenethylamine stimulant which produces powerful empathogenic effects. Use of MDMA remains popular despite prohibition, and potential long-term negative consequences of repeated use. MDMA produces its acute subjective effects primarily by stimulating the release of serotonin via action at the serotonin transporter (SERT). There is evidence that MDMA administration may lead to long lasting neurotoxic effects on serotonin neurons in primates, and reductions in markers of central serotonin axons, and axon terminals in animals. In humans, demonstration of serotonergic neurotoxicity is much more difficult to identify, and much of the research is complicated by confounding issues of polysubstance use, genetic and environmental factors and reliance on self-reports of previous drug use. We do not review the mechanisms for neurotoxicity in detail as they are covered elsewhere in this special issue. There is a large body of literature, however, which has investigated potential cognitive and neurocognitive consequences of repeated MDMA use. Here we review the literature on cognition, and neuroimaging studies that have investigated structural and functional brain changes associated with ecstasy use.
Topics: Brain; Cognition; Hallucinogens; Humans; N-Methyl-3,4-methylenedioxyamphetamine
PubMed: 34624331
DOI: 10.1016/j.expneurol.2021.113888 -
International Journal of Molecular... Dec 2020Psychedelic and stimulating phenethylamines belong to the family of new psychoactive substances (NPS). The acute toxicity framework has begun to be investigated, while...
Psychedelic and stimulating phenethylamines belong to the family of new psychoactive substances (NPS). The acute toxicity framework has begun to be investigated, while studies showing genotoxic potential are very limited or not available. Therefore, in order to fill this gap, the aim of the present work was to evaluate the genotoxicity by treating TK6 cells with 2C-H, 2C-I, 2C-B, 25B-NBOMe, and the popular 3,4-Methylenedioxymethylamphetamine (MDMA). On the basis of cytotoxicity and cytostasis results, we selected the concentrations (6.25-35 µM) to be used in genotoxicity analysis. We used the micronucleus (MN) as indicator of genetic damage and analyzed the MNi frequency fold increase by an automated flow cytometric protocol. All substances, except MDMA, resulted genotoxic; therefore, we evaluated reactive oxygen species (ROS) induction as a possible mechanism at the basis of the demonstrated genotoxicity. The obtained results showed a statistically significant increase in ROS levels for all genotoxic phenethylamines confirming this hypothesis. Our results highlight the importance of genotoxicity evaluation for a complete assessment of the risk associated also with NPS exposure. Indeed, the subjects who do not have hazardous behaviors or require hospitalization by using active but still "safe" doses could run into genotoxicity and in the well-known long-term effects associated.
Topics: Anisoles; Apoptosis; Cell Line; Cell Survival; Dimethoxyphenylethylamine; Flow Cytometry; Genes; Hallucinogens; Humans; Micronuclei, Chromosome-Defective; Micronucleus Tests; N-Methyl-3,4-methylenedioxyamphetamine; Phenethylamines; Psychotropic Drugs; Reactive Oxygen Species
PubMed: 33348640
DOI: 10.3390/ijms21249616 -
The Journal of Neuroscience : the... Oct 2023Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the...
Prevailing frameworks propose that a key feature of attention-deficit/hyperactivity disorder (ADHD) is lower motivation. An important component of motivation is the willingness to engage in cognitively or physically effortful behavior. However, the degree to which effort sensitivity is impaired in ADHD has rarely been tested, and the efficacy of stimulant medication in ameliorating any such impairments is unclear. Here, we tested 20 individuals with ADHD (11 males, 9 females) who were managed with amphetamine-based medication (dexamfetamine, lisdexamfetamine), and 24 controls (8 males, 16 females). Individuals with ADHD were tested over two counterbalanced sessions, ON and OFF their usual amphetamine-based medication. In each session, participants performed an effort-based decision-making task, in which they were required to choose how much cognitive or physical effort they were willing to engage in return for reward. Our results revealed three main findings. First, individuals with ADHD had lower motivation relative to controls to invest effort in both the cognitive and physical domains. Second, amphetamine increased motivation uniformly across both domains. Finally, the net effect of amphetamine treatment was to mostly restore motivation across both domains of effort relative to healthy controls. These data provide clear evidence for a heightened sensitivity to both cognitive and physical effort in ADHD, and reveal the efficacy of amphetamine-based drugs in restoring effort sensitivity to levels similar to controls. These findings confirm the existence of reduced motivational drive in ADHD, and more broadly provide direct causal evidence for a domain-general role of catecholamines in motivating effortful behavior. A core feature of attention-deficit/hyperactivity disorder (ADHD) is thought to be a heightened aversion to effort. Surprisingly, however, the degree to which effort sensitivity is impaired in ADHD has rarely been tested. More broadly, the relative efficacy of catecholamines in motivating the investment of cognitive and physical effort is unclear. We tested 20 individuals with ADHD ON and OFF amphetamines, and compared their behavior on an effort-based decision-making task to 24 controls. When tested OFF medication, the ADHD group was less cognitively and physically motivated than controls. However, amphetamines led to a comparable increase in motivation across both domains. This demonstrates the efficacy of catecholamines in facilitating domain-general effort, and highlights the broader potential of such drugs to treat disorders of motivation.
Topics: Male; Female; Humans; Attention Deficit Disorder with Hyperactivity; Motivation; Amphetamines; Lisdexamfetamine Dimesylate; Catecholamines; Central Nervous System Stimulants
PubMed: 37666665
DOI: 10.1523/JNEUROSCI.0982-23.2023