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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 -
Purinergic Signalling Jun 2020Exosomes, small-sized extracellular vesicles, carry components of the purinergic pathway. The production by cells of exosomes carrying this pathway remains poorly...
Exosomes, small-sized extracellular vesicles, carry components of the purinergic pathway. The production by cells of exosomes carrying this pathway remains poorly understood. Here, we asked whether type 1, 2A, or 2B adenosine receptors (ARs, ARs, and ARs, respectively) expressed by producer cells are involved in regulating exosome production. Preglomerular vascular smooth muscle cells (PGVSMCs) were isolated from wildtype, AR, AR, and AR rats, and exosome production was quantified under normal or metabolic stress conditions. Exosome production was also measured in various cancer cells treated with pharmacologic agonists/antagonists of ARs, ARs, and ARs in the presence or absence of metabolic stress or cisplatin. Functional activity of exosomes was determined in Jurkat cell apoptosis assays. In PGVSMCs, AR and AR constrained exosome production under normal conditions (p = 0.0297; p = 0.0409, respectively), and AR, AR, and AR constrained exosome production under metabolic stress conditions. Exosome production from cancer cells was reduced (p = 0.0028) by the selective AR agonist CGS 21680. These exosomes induced higher levels of Jurkat apoptosis than exosomes from untreated cells or cells treated with AR and AR agonists (p = 0.0474). The selective AR antagonist SCH 442416 stimulated exosome production under metabolic stress or cisplatin treatment, whereas the selective AR antagonist MRS 1754 reduced exosome production. Our findings indicate that ARs suppress exosome release in all cell types examined, whereas effects of ARs and ARs are dependent on cell type and conditions. Pharmacologic targeting of cancer with AR antagonists may inadvertently increase exosome production from tumor cells.
Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Exosomes; Male; Phenethylamines; Rats; Receptor, Adenosine A1; Receptor, Adenosine A2A; Tumor Cells, Cultured
PubMed: 32440820
DOI: 10.1007/s11302-020-09700-7 -
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 -
Clinical Drug Investigation May 2016Lisdexamfetamine dimesylate (LDX) is a long-acting d-amphetamine prodrug used to treat attention-deficit/hyperactivity disorder (ADHD) in children, adolescents and... (Review)
Review
Lisdexamfetamine dimesylate (LDX) is a long-acting d-amphetamine prodrug used to treat attention-deficit/hyperactivity disorder (ADHD) in children, adolescents and adults. LDX is hydrolysed in the blood to yield d-amphetamine, and the pharmacokinetic profile of d-amphetamine following oral administration of LDX has a lower maximum plasma concentration (Cmax), extended time to Cmax (Tmax) and lower inter- and intra-individual variability in exposure compared with the pharmacokinetic profile of an equivalent dose of immediate-release (IR) d-amphetamine. The therapeutic action of LDX extends to at least 13 h post-dose in children and 14 h post-dose in adults, longer than that reported for any other long-acting formulation. Drug-liking scores for LDX are lower than for an equivalent dose of IR d-amphetamine, which may result from the reduced euphorigenic potential associated with its pharmacokinetic profile. These pharmacokinetic and pharmacodynamic characteristics of LDX may be beneficial in the management of symptoms in children, adolescents and adults with ADHD.
Topics: Administration, Oral; Adolescent; Adult; Amphetamine; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Child; Drug Delivery Systems; Humans; Lisdexamfetamine Dimesylate; Male; Prodrugs; Treatment Outcome
PubMed: 27021968
DOI: 10.1007/s40261-015-0354-y -
Current Opinion in Neurobiology Oct 2015Trace amine-associated receptors (TAARs) are G Protein-Coupled Receptors that function as vertebrate olfactory receptors. Like odorant receptors, TAARs constitute an... (Review)
Review
Trace amine-associated receptors (TAARs) are G Protein-Coupled Receptors that function as vertebrate olfactory receptors. Like odorant receptors, TAARs constitute an ever-evolving sensory subsystem, with individual TAARs recognizing particular chemicals and some evoking stereotyped behaviors. Several TAARs mediate aversion or attraction towards volatile amines that include the mouse odor trimethylamine, the predator odor 2-phenylethylamine, and the death-associated odor cadaverine. TAAR-expressing sensory neurons achieve monoallelic receptor expression, use canonical olfactory signaling molecules, and target a dedicated olfactory bulb region. In mouse, TAAR4 and TAAR5 are encoded by adjacent genes and localize to adjacent glomeruli, yet mediate opposing behaviors. Future studies are needed to understand how TAAR-expressing sensory neurons engage higher-order neural circuits to encode odor valence.
Topics: Animals; Behavior; Cadaverine; Humans; Ligands; Olfactory Receptor Neurons; Phenethylamines; Receptors, G-Protein-Coupled
PubMed: 25616211
DOI: 10.1016/j.conb.2015.01.001 -
Phytotherapy Research : PTR Aug 2020Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p-synephrine and p-octopamine relative to ephedrine and... (Review)
Review
Confusion and misunderstanding exist regarding the lack of cardiovascular and other adverse health effects of p-synephrine and p-octopamine relative to ephedrine and m-synephrine (phenylephrine) which are known for their effects on the cardiovascular system. These four molecules have some structural similarities. However, the structural and stereochemical differences of p-synephrine and p-octopamine as related to ephedrine and m-synephrine result in markedly different adrenergic receptor binding characteristics as well as other mechanistic differences which are reviewed. p-Synephrine and p-octopamine exhibit little binding to α-1, α-2, β-1 and β-2 adrenergic receptors, nor are they known to exhibit indirect actions leading to an increase in available levels of endogenous norepinephrine and epinephrine at commonly used doses. The relative absence of these mechanistic actions provides an explanation for their lack of production of cardiovascular effects at commonly used oral doses as compared to ephedrine and m-synephrine. As a consequence, the effects of ephedrine and m-synephrine cannot be directly extrapolated to p-synephrine and p-octopamine which exhibit significantly different pharmacokinetic, and physiological/pharmacological properties. These conclusions are supported by human, animal and in vitro studies that are discussed.
Topics: Animals; Ephedrine; Humans; Octopamine; Rats; Synephrine
PubMed: 32101364
DOI: 10.1002/ptr.6649 -
Biomedicine & Pharmacotherapy =... Nov 2018Nature is the most abundant source for novel drug discovery. Lycorine is a natural alkaloid with immense therapeutic potential. Lycorine is active in a very low... (Review)
Review
Nature is the most abundant source for novel drug discovery. Lycorine is a natural alkaloid with immense therapeutic potential. Lycorine is active in a very low concentration and with high specificity against a number of cancers both in vivo and in vitro and against various drug-resistant cancer cells. This review summarized the therapeutic effect and the anticancer mechanisms of lycorine. At the same time, we have discussed the pharmacology and comparative structure-activity relationship for the anticancer activity of this compound. The researches outlined in this paper serve as a foundation to explain lycorine as an important lead compound for new generation anticancer drug design and provide the principle for the development of biological strategies to utilize lycorine in the treatment of cancers.
Topics: Amaryllidaceae Alkaloids; Antineoplastic Agents; Biological Products; Drug Discovery; Humans; Models, Biological; Phenanthridines; Structure-Activity Relationship
PubMed: 30114645
DOI: 10.1016/j.biopha.2018.07.147 -
JAMA Psychiatry Jan 2023Psychedelic drugs are becoming accessible in the US through a patchwork of state legislative reforms. This shift necessitates consensus on treatment models, education...
IMPORTANCE
Psychedelic drugs are becoming accessible in the US through a patchwork of state legislative reforms. This shift necessitates consensus on treatment models, education and guidance for health care professionals, and planning for implementation and regulation.
OBJECTIVE
To assess trends in psychedelics legislative reform and legalization in the US to provide guidance to health care professionals, policy makers, and the public.
EVIDENCE REVIEW
Data were compiled from legislative databases (BillTrack50, LexisNexis, and Ballotpedia) from January 1, 2019, to September 28, 2022. Legislation was identified by searching for terms related to psychedelics (eg, psilocybin, MDMA, peyote, mescaline, ibogaine, LSD, ayahuasca, and DMT). Bills were coded by an attorney along 2 axes: which psychedelic drugs would be affected and in what ways (eg, decriminalization, funding for medical research, and right to try). To explore drivers and rates of legislative reform, data were compared with other state indices including 2020 presidential voting margins and marijuana legislative reform.
FINDINGS
Twenty-five states have considered 74 bills (69 legislative initiatives, 5 ballot measures); 10 bills were enacted, and 32 were still active. The number of psychedelic reform bills introduced during each calendar year increased steadily from 5 in 2019 to 6 in 2020, 27 in 2021, and 36 in 2022. Nearly all bills specified psilocybin (67 [90%]), and many also included MDMA (3,4-methylenedioxy-methamphetamine; 27 [36%]). While bills varied in their framework, most (43 [58%]) proposed decriminalization, of which few delineated medical oversight (10 of 43 [23%]) or training and/or licensure requirements (15 of 43 [35%]). In general, bills contained less regulatory guidance than the enacted Oregon Measure 109. While early legislative efforts occurred in liberal states, the margin between liberal and conservative states has decreased over time (although the difference was not significant), suggesting that psychedelic drug reform is becoming a bipartisan issue. In addition, an analytic model based on marijuana legalization projected that a majority of states will legalize psychedelics by 2034 to 2037.
CONCLUSIONS AND RELEVANCE
Legislative reform for psychedelic drugs has been proceeding in a rapid, patchwork fashion in the US. Further consideration should be given to key health care issues such as establishing (1) standards for drugs procured outside the medical establishment, (2) licensure criteria for prescribers and therapists, (3) clinical and billing infrastructure, (4) potential contraindications, and (5) use in special populations like youths, older adults, and pregnant individuals.
Topics: Pregnancy; Female; Adolescent; Humans; Aged; Hallucinogens; Psilocybin; N-Methyl-3,4-methylenedioxyamphetamine; Mescaline; Educational Status
PubMed: 36477830
DOI: 10.1001/jamapsychiatry.2022.4101 -
Microbial Cell Factories Oct 2015Hydroxycinnamic acids (HCAs) including cinnamic acid, p-coumaric acid, caffeic acid, and ferulic acid, are C6-C3 phenolic compounds that are synthesized via the...
BACKGROUND
Hydroxycinnamic acids (HCAs) including cinnamic acid, p-coumaric acid, caffeic acid, and ferulic acid, are C6-C3 phenolic compounds that are synthesized via the phenylpropanoid pathway. HCAs serve as precursors for the synthesis of lignins, flavonoids, anthocyanins, stilbenes and other phenolic compounds. HCAs can also be conjugated with diverse compounds including quinic acid, hydroxyl acids, and amines. Hydroxycinnamoyl (HC) amine conjugates such as N-HC tyramines and N-HC phenethylamines have been considered as potential starting materials to develop antiviral and anticancer drugs.
RESULTS
We synthesized N-HC tyramines and N-HC phenethylamines using three different approaches in Escherichia coli. Five N-HC phenethylamines and eight N-HC tyramines were synthesized by feeding HCAs and phenethylamine or tyramine to E. coli harboring 4CL (encoding 4-coumarate CoA:ligase) and either SHT (encoding phenethylamine N-HC transferase) or THT (encoding tyramine N-HC transferase). Also, N-(p-coumaroyl) phenethylamine and N-(p-coumaroyl) tyramine were synthesized from p-coumaric acid using E. coli harboring an additional gene, PDC (encoding phenylalanine decarboxylase) or TDC (encoding tyrosine decarboxylase). Finally, we synthesized N-(p-coumaroyl) phenethylamine and N-(p-coumaroyl) tyramine from glucose by reconstructing the metabolic pathways for their synthesis in E. coli. Productivity was maximized by optimizing the cell concentration and incubation temperature.
CONCLUSIONS
We reconstructed the metabolic pathways for synthesis of N-HC tyramines and N-HC phenethylamines by expressing several genes including 4CL, TST or SHT, PDC or TDC, and TAL (encoding tyrosine ammonia lyase) and engineering the shikimate metabolic pathway to increase endogenous tyrosine concentration in E. coli. Approximately 101.9 mg/L N-(p-coumaroyl) phenethylamine and 495.4 mg/L N-(p-coumaroyl) tyramine were synthesized from p-coumaric acid. Furthermore, 152.5 mg/L N-(p-coumaroyl) phenethylamine and 94.7 mg/L N-(p-coumaroyl) tyramine were synthesized from glucose.
Topics: Coenzyme A Ligases; Coumaric Acids; Escherichia coli; Escherichia coli Proteins; Mass Spectrometry; Metabolic Engineering; Phenethylamines; Plasmids; Transferases; Tyramine
PubMed: 26463041
DOI: 10.1186/s12934-015-0353-y