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Nature Dec 2023Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic...
Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous β-phenylethylamine (β-PEA) as well as methamphetamine, an abused substance that has posed a severe threat to human health and society. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and β-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HTR (refs. ). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.
Topics: Humans; Ligands; Methamphetamine; Nervous System Diseases; Phenethylamines; Receptors, G-Protein-Coupled; Substance-Related Disorders; Heterotrimeric GTP-Binding Proteins; Polypharmacology; Hydrogen Bonding
PubMed: 37935377
DOI: 10.1038/s41586-023-06775-1 -
The American Journal of Drug and... Sep 2023A drug concoction called tusi has emerged in Latin America and in Europe and is now beginning to acquire popularity in the United States. "Tusi" is a phonetic...
A drug concoction called tusi has emerged in Latin America and in Europe and is now beginning to acquire popularity in the United States. "Tusi" is a phonetic translation of "2C," a series of psychedelic phenethylamines. The concoction is also sometimes referred to as "pink cocaine" as it typically comes in the form of pink powder. However, despite its name, the concoction rarely contains 2C series drugs. Multiple drug checking studies have found that the majority of tusi samples contain ketamine, often combined with 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine, cocaine, opioids, and/or new psychoactive substances. The tusi phenomenon complicates the drug landscape because it has the potential to confuse both people who use it and researchers alike. People using may think the drug is 2C/2C-B, and they may also be unaware that the concoction tends to consist of ketamine and a wide variety of other drugs. Unintentional exposure to its contents can lead to increased risk of adverse effects. The tusi phenomenon also has the potential to complicate drug research as unknown exposure to drugs like ketamine and MDMA will lead to underreporting of use. A combination of self-report and toxicological testing may be needed to inform the most accurate estimates of use. Both researchers and people at risk for use need to be informed about this new concoction. Drug researchers need to be cognizant about the way they query use, and people at risk for using need to be educated about the possible contents of tusi and associated dangers.
Topics: Humans; N-Methyl-3,4-methylenedioxyamphetamine; Ketamine; Hallucinogens; Methamphetamine; Cocaine; Substance-Related Disorders
PubMed: 37162319
DOI: 10.1080/00952990.2023.2207716 -
Gut-derived bacterial LPS attenuates incubation of methamphetamine craving via modulating microglia.Brain, Behavior, and Immunity Jul 2023The microbiota-gut-brain axis plays a critical role in the pathophysiology of neuropsychiatric disorders, and the compositions of gut microbiota are altered by addictive...
BACKGROUND
The microbiota-gut-brain axis plays a critical role in the pathophysiology of neuropsychiatric disorders, and the compositions of gut microbiota are altered by addictive drugs. However, the role of gut microbiota in the incubation of methamphetamine (METH) craving remains poorly understood.
METHODS
16S rRNA gene sequencing was performed to assess the richness and diversity of gut microbiota in METH self-administration model. Hematoxylin and eosin staining was performed to evaluate the integrity of intestinal barrier. Immunofluorescence and three-dimensional reconstruction were performed to assess the morphologic changes of microglia. Serum levels of lipopolysaccharide (LPS) were determined using the rat enzyme-linked immunosorbent assay kits. Quantitative real-time PCR was performed to assess transcript levels of dopamine receptor, glutamate ionotropic AMPA receptor 3 and brain-derived neurotrophic factor.
RESULTS
METH self-administration induced gut microbiota dysbiosis, intestinal barrier damage and microglia activation in the nucleus accumbens core (NAcc), which was partially recovered after prolonged withdrawal. Microbiota depletion via antibiotic treatment increased LPS levels and induced a marked change in the microglial morphology in the NAcc, as indicated by the decreases in the lengths and numbers of microglial branches. Depleting the gut microbiota also prevented the incubation of METH craving and increased the population of Klebsiella oxytoca. Furthermore, Klebsiella oxytoca treatment or exogenous administration of the gram-negative bacterial cell wall component LPS increased serum and central LPS levels, induced microglial morphological changes and reduced the dopamine receptor transcription in the NAcc. Both treatments and NAcc microinjections of gut-derived bacterial LPS significantly decreased METH craving after prolonged withdrawal.
CONCLUSIONS
These data suggest that LPS from gut gram-negative bacteria may enter circulating blood, activate microglia in the brain and consequently decrease METH craving after withdrawal, which may have important implications for novel strategies to prevent METH addiction and relapse.
Topics: Rats; Animals; Methamphetamine; Central Nervous System Stimulants; Lipopolysaccharides; Microglia; Craving; RNA, Ribosomal, 16S
PubMed: 37004759
DOI: 10.1016/j.bbi.2023.03.027 -
NEJM Evidence Dec 2023Methamphetamine Toxicities and Clinical ManagementMethamphetamine increases the release and blocks the uptake of norepinephrine, serotonin, and dopamine. This article... (Review)
Review
Methamphetamine Toxicities and Clinical ManagementMethamphetamine increases the release and blocks the uptake of norepinephrine, serotonin, and dopamine. This article reviews the morbidity and mortality associated with methamphetamine use and discusses prevention and treatment strategies.
Topics: Methamphetamine; Dopamine; Serotonin; Biological Transport
PubMed: 38320504
DOI: 10.1056/EVIDra2300160 -
Emergency Medicine Practice Nov 2023Management of patients who are acutely intoxicated with methamphetamine (a member of the substituted amphetamine class of drugs) can be resource-intensive for most... (Review)
Review
Management of patients who are acutely intoxicated with methamphetamine (a member of the substituted amphetamine class of drugs) can be resource-intensive for most emergency departments. Clinical presentations of the methamphetamine sympathomimetic toxidrome range from mild agitation to rhabdomyolysis, acute kidney injury, seizures, and intracranial hemorrhage. High-quality evidence on how to best manage these patients is lacking, and most research focuses on symptomatic interventions to control patients' agitation and hemodynamics. This review analyzes the best available evidence on the diagnosis and management of emergency department patients with substituted amphetamine toxicity and offers best-practice recommendations on treatment and disposition.
Topics: Humans; Methamphetamine; Emergency Service, Hospital; Amphetamine
PubMed: 37877728
DOI: No ID Found -
Harm Reduction Journal Jul 2023Opioid and methamphetamine co-use is increasing across the USA with overdoses involving these drugs also rising. West Virginia (WV) has led the US in opioid overdose...
BACKGROUND
Opioid and methamphetamine co-use is increasing across the USA with overdoses involving these drugs also rising. West Virginia (WV) has led the US in opioid overdose death rates since at least 2013 and rising co-use of methamphetamine with opioids has played a greater role in deaths over the last 5 years.
METHODS
This study used rapid ethnography to examine methods and motivations behind opioids and methamphetamine co-use from the viewpoint of their consumers. Participants (n = 30) were people who injected heroin/fentanyl also using methamphetamine who participated in semi-structured interviews.
RESULTS
We found multiple methods of co-using opioids and methamphetamine, whether alternately or simultaneously and in varying order. Most prioritized opioids, with motives for using methamphetamine forming three thematic categories: 'intrinsic use', encompassing both inherent pleasure of combined use greater than using both drugs separately or for self-medication of particular conditions; 'opioid assisting use' in which methamphetamine helped people manage their existing heroin/fentanyl use; and 'reluctant or indifferent use' for social participation, reflecting methamphetamine's low cost and easy availability.
CONCLUSIONS
Methamphetamine serves multiple functions among people using opioids in WV. Beliefs persist that methamphetamine can play a role in preventing and reversing opioid overdose, including some arguments for sequential use being protective of overdose. 'Reluctant' uptake attests to methamphetamine's social use and the influence of supply. The impact on overdose risk of the many varied co-use patterns needs further investigation.
Topics: Motivation; Methamphetamine; Heroin; West Virginia; Fentanyl; Heroin Dependence; Interviews as Topic; Self Medication; Pleasure; Social Interaction; Health Knowledge, Attitudes, Practice; Humans; Male; Female; Adult
PubMed: 37438812
DOI: 10.1186/s12954-023-00816-8 -
Frontiers in Pediatrics 2023The escalation in opioid pain relief (OPR) medications, heroin and fentanyl, has led to an increased use during pregnancy and a public health crisis. Methamphetamine use... (Review)
Review
The escalation in opioid pain relief (OPR) medications, heroin and fentanyl, has led to an increased use during pregnancy and a public health crisis. Methamphetamine use in women of childbearing age has now eclipsed the use of cocaine and other stimulants globally. Recent reports have shown increases in methamphetamine are selective to opioid use, particularly in rural regions in the US. This report compares the extent of our knowledge of the perinatal outcomes of OPRs, heroin, fentanyl, two long-acting substances used in the treatment of opioid use disorders (buprenorphine and methadone), and methamphetamine. The methodological limitations of the current research are examined, and two important initiatives that will address these limitations are reviewed. Current knowledge of the perinatal effects of short-acting opioids, OPRs, heroin, and fentanyl, is scarce. Most of what we know about the perinatal effects of opioids comes from research on the long-acting opioid agonist drugs used in the treatment of OUDs, methadone and buprenorphine. Both have better perinatal outcomes for the mother and newborn than heroin, but the uptake of these opioid substitution programs is poor (<50%). Current research on perinatal outcomes of methamphetamine is limited to retrospective epidemiological studies, chart reviews, one study from a treatment center in Hawaii, and the US and NZ cross-cultural infant Development, Environment And Lifestyle IDEAL studies. Characteristics of pregnant individuals in both opioid and MA studies were associated with poor maternal health, higher rates of mental illness, trauma, and poverty. Infant outcomes that differed between opioid and MA exposure included variations in neurobehavior at birth which could complicate the diagnosis and treatment of neonatal opioid withdrawal (NOWs). Given the complexity of OUDs in pregnant individuals and the increasing co-use of these opioids with MA, large studies are needed. These studies need to address the many confounders to perinatal outcomes and employ neurodevelopmental markers at birth that can help predict long-term neurodevelopmental outcomes. Two US initiatives that can provide critical research and treatment answers to this public health crisis are the US Environmental influences on Child Health Outcomes (ECHO) program and the Medication for Opioid Use Disorder During Pregnancy Network (MAT-LINK).
PubMed: 38250592
DOI: 10.3389/fped.2023.1305508 -
Current HIV/AIDS Reports Dec 2023In the era of HIV treatment as prevention (TasP), more clarity is needed regarding whether people with HIV who use stimulants (i.e., methamphetamine, powder cocaine, and... (Review)
Review
PURPOSE OF REVIEW
In the era of HIV treatment as prevention (TasP), more clarity is needed regarding whether people with HIV who use stimulants (i.e., methamphetamine, powder cocaine, and crack cocaine) display elevated HIV viral load and greater immune dysregulation.
RECENT FINDINGS
Although rates of viral suppression have improved in the TasP era, stimulant use was independently associated with elevated viral load in 23 of 28 studies included in our review. In the 12 studies examining other HIV disease markers, there was preliminary evidence for stimulant-associated alterations in gut-immune dysfunction and cellular immunity despite effective HIV treatment. Studies generally focused on documenting the direct associations of stimulant use with biomarkers of HIV pathogenesis without placing these in the context of social determinants of health. Stimulant use is a key barrier to optimizing the effectiveness of TasP. Elucidating the microbiome-gut-brain axis pathways whereby stimulants alter neuroimmune functioning could identify viable targets for pharmacotherapies for stimulant use disorders. Examining interpersonal, neighborhood, and structural determinants that could modify the associations of stimulant use with biomarkers of HIV pathogenesis is critical to guiding the development of comprehensive, multi-level interventions.
Topics: Humans; Acquired Immunodeficiency Syndrome; Biomarkers; Central Nervous System Stimulants; Crack Cocaine; HIV Infections; Methamphetamine
PubMed: 37971597
DOI: 10.1007/s11904-023-00672-y