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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 -
Neurobiology of Learning and Memory Jul 2022Repeated intermittent exposure to psychostimulants, such as amphetamine, leads to a progressive enhancement of the drug's ability to increase both behavioral and brain...
Repeated intermittent exposure to psychostimulants, such as amphetamine, leads to a progressive enhancement of the drug's ability to increase both behavioral and brain neurochemical responses. The expression of these enhancements, known as sensitization, can be regulated by Pavlovian conditioned stimuli. Cues that are associated with drug experience can facilitate sensitization so that it only occurs in the presence of these stimuli (context-specific sensitization). In contrast, cues that are explicitly related to the absence of drugs (conditioned inhibitors) can prevent the expression of sensitization. We hypothesized that disrupting conditioned inhibition would enable amphetamine sensitization in new contexts. Using male Sprague Dawley rats and a two-context amphetamine conditioning procedure, we found that extinguishing amphetamine experience in one environment led to the loss of conditioned inhibition in a separate context. Thus, amphetamine-induced sensitized locomotion, as well as both enhanced dopamine and glutamate neurotransmission in the nucleus accumbens, were observed in a context where the drug was never experienced before. A similar loss of contextual control of sensitization was seen after using baclofen/muscimol microinjections to transiently inhibit the medial prefrontal cortex, basolateral amygdala, or ventral subiculum of the hippocampus. In other words, compared to control infusions, these intracranial injections of GABA-receptor agonists were able to block conditioned inhibitors from preventing the expression of sensitized locomotion. Together, these findings reveal the importance of conditioned inhibitors for regulating addiction-like behavior. The results suggest that dopaminergic and glutamatergic brain circuitry controls the context-specific expression of amphetamine sensitization.
Topics: Amphetamine; Animals; Conditioning, Classical; Dopamine; Male; Nucleus Accumbens; Rats; Rats, Sprague-Dawley
PubMed: 35597434
DOI: 10.1016/j.nlm.2022.107636 -
Cell Reports. Medicine Aug 2021A promising new Phase III study of MDMA plus psychotherapy for PTSD treatment by Mitchell and colleagues that appeared in raises important new questions about the...
A promising new Phase III study of MDMA plus psychotherapy for PTSD treatment by Mitchell and colleagues that appeared in raises important new questions about the biology and optimal treatment of this disorder.
Topics: Combined Modality Therapy; Humans; Medicine; N-Methyl-3,4-methylenedioxyamphetamine; Psychotherapy; Stress Disorders, Post-Traumatic
PubMed: 34467253
DOI: 10.1016/j.xcrm.2021.100378 -
Gut Microbes 2022Colonic luminal aromatic amines have been historically considered to be derived from dietary source, especially fermented foods; however, recent studies indicate that...
Colonic luminal aromatic amines have been historically considered to be derived from dietary source, especially fermented foods; however, recent studies indicate that the gut microbiota serves as an alternative source of these amines. Herein, we show that five prominent genera of Firmicutes , and ) have the ability to abundantly produce aromatic amines through the action of aromatic amino acid decarboxylase (AADC). cultivation of human fecal samples revealed that a significant positive correlation between copy number of and phenylethylamine (PEA) production. Furthermore, using genetically engineered -colonized BALB/cCrSlc mouse model, we showed that the gut bacterial stimulates the production of colonic serotonin, which is reportedly involved in osteoporosis and irritable bowel syndrome. Finally, we showed that human AADC inhibitors carbidopa and benserazide inhibit PEA production in .
Topics: Animals; Aromatic-L-Amino-Acid Decarboxylases; Benserazide; Carbidopa; Gastrointestinal Microbiome; Humans; Mice; Phenethylamines; Serotonin
PubMed: 36217238
DOI: 10.1080/19490976.2022.2128605 -
Scientific Reports Aug 2023Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging...
Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium-high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose-response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted and may assist the development of personalized treatments.
Topics: Humans; Psilocybin; Prospective Studies; Hallucinogens; Fear; Methamphetamine
PubMed: 37608057
DOI: 10.1038/s41598-023-40856-5 -
Journal of Analytical Toxicology Aug 2022Synthetic cathinones (SCs) are currently the second largest and the second most frequently seized group of new psychoactive substances. They are sold as replacements for...
Synthetic cathinones (SCs) are currently the second largest and the second most frequently seized group of new psychoactive substances. They are sold as replacements for controlled stimulants such as amphetamine, cocaine and 3,4-methylenedioxymethamphetamine. Administration of low doses of SCs can cause euphoria and increased alertness, and administration of high doses or chronic use of cathinones can cause serious adverse effects such as hallucinations, delirium, hyperthermia and tachycardia. In the years 2013-2019 in our practice, as many as 16 different SCs were detected in biological materials. This article lists the observed concentrations in 39 fatal and 18 non-fatal cases, in which a single SC as well as an SC in combination with amphetamine or ethyl alcohol were detected and quantified in biological materials. The quantitative analyses were carried out by liquid chromatography with tandem mass spectrometry. The analyzed cases of taking SCs were associated with intoxication (2 cases), fatal intoxication (36), driving under the influence of drugs (10) and other circumstances (9) such as violence, insulting an officer and holding a hostage. Taking SCs has serious side effects that can lead to multiple organ failure and death. Screening for the presence of SCs in biological materials should be part of the routine course of treatment in intoxication cases, both at the stage of clinical diagnosis and at the stage of forensic toxicological analysis. Ethyl alcohol and amphetamine may contribute to increased SC toxicity. These data could be valuable for further interpretation of other results from toxicological analyses.
Topics: Alkaloids; Amphetamine; Chromatography, Liquid; Drug-Related Side Effects and Adverse Reactions; Ethanol; Humans
PubMed: 34592764
DOI: 10.1093/jat/bkab102 -
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 -
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