Well, no. That's just an effect common to many drugs classed as ADs. One could argue that something like buprenorphine would be an effective antidepressant, and I don't think it does anything to BDNF directly. Tianeptine's close cousin amineptine is a dopamine reuptake inhibitor, too. I'm willing to bet that makes you feel good but probably doesn't exactly encourage neuronal growth.but it really also has to be a bdnf/neurotrophin enhancer in the hippocampus to be a true ad
It was never clearly established what the mechanism of a SSRE would be, and given that tianeptine is basically the only one that was described as such, I concur that it's pretty much bullshit... there are a few problems with the theory, like tianrptine having no affinity for SERT.How do you enhance reuptake of a neurotransmitter? Does it bind allosterically with the transporter in order to pry open its doors (so to speak)?
Really, people throw the term around as a stand in for "antidepressant, mechanism not otherwise specified".Wiki - Reuptake enhancers said:
more and more it turns out that paracetamol isn't quite benign as believed. i've recently read something that when given to children it increases the risk for developing neurodermitis or asthma.Associations between Acetaminophen Use during Pregnancy and ADHD Symptoms Measured at Ages 7 and 11 Years
Thanks mom for taking tylenol and ruining my brain... (but thank you for giving birth to me, and raising me)
Nothing like getting picked up off the street by paramedics while all dissociated out.Introduction. Methoxphenidine is a novel dissociative designer drug of the diarylethylamine class which shares structural features with phencyclidine (PCP), and is not at present subject to restrictive regulations. There is very limited information about the acute toxicity profile of methoxphenidine and the only sources are anonymous internet sites and a 1989 patent of the Searle Company. We report a case of analytically confirmed oral methoxphenidine toxicity. Case details. A 53-year-old man was found on the street in a somnolent and confusional state. Observed signs and symptoms such as tachycardia (112 bpm), hypertension (220/125 mmHg), echolalia, confusion, agitation, opisthotonus, nystagmus and amnesia were consistent with phencyclidine-induced adverse effects. Temperature (99.1°F (37.3°C)) and peripheral oxygen saturation while breathing room air (99 were normal. Laboratory analysis revealed an increase of creatine kinase (max 865 U/L), alanine aminotransferase (72 U/L) and gamma-glutamyl transpeptidase (123 U/L). Methoxphenidine was identified by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction in plasma and urine samples collected on admission. The clinical course was favourable and signs and symptoms resolved with symptomatic treatment. Conclusion. Based on this case report and users’ web reports, and compatible with the chemical structure, methoxphenidine produces effects similar to those of the arylcyclohexylamines, as PCP.
The trick is not OD'ing on dissociatives.Acute toxicity associated with the recreational use of the novel dissociative psychoactive substance methoxphenidine
K. E. Hofer, C. Degrandi, D. M. Müller, U. Zürrer-Härdi, S. Wahl, C. Rauber-Lüthy, and A. Ceschi
Nothing like getting picked up off the street by paramedics while all dissociated out.
Dave Nichols made a bunch N-benzyl tryptamines and compared them to N-benzyl phenethylaminesaRATIONALE:2-([2-(4-cyano-2,5-dimethoxyphenyl)ethylamino]methyl)phenol (25CN-NBOH) is structurally similar to N-benzyl substituted phenethylamine hallucinogens currently emerging as drugs of abuse. 25CN-NBOH exhibits dramatic selectivity for 5-HT2A receptors in vitro, but has not been behaviorally characterized.OBJECTIVE: 25CN-NBOH was compared to the traditional phenethylamine hallucinogen R(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) using mouse models of drug-elicited head twitch behavior and drug discrimination. METHODS: Drug-elicited head twitches were quantified for 10 min following administration of various doses of either DOI or 25CN-NBOH, with and without pretreatments of 0.01 mg/kg 5-HT2A antagonist M100907 or 3.0 mg/kg 5-HT2C antagonist RS102221. The capacity of 25CN-NBOH to attenuate DOI-elicited head twitch was also investigated. Mice were trained to discriminate DOI or M100907 from saline, and 25CN-NBOH was tested for generalization. RESULTS: 25CN-NBOH induced a head twitch response in the mouse that was lower in magnitude than that of DOI, blocked by M100907, but not altered by RS102221. DOI-elicited head twitch was dose-dependently attenuated by 25CN-NBOH pretreatment. 25CN-NBOH produced an intermediate degree of generalization (55 for the DOI training dose, and these interoceptive effects were attenuated by M100907. Finally, 25CN-NBOH did not generalize to M100907 at any dose, but ketanserin fully substituted in these animals. CONCLUSIONS: 25CN-NBOH was behaviorally active, but less effective than DOI in two mouse models of hallucinogenic effects. The effectiveness with which M100907 antagonized the behavioral actions of 25CN-NBOH strongly suggests that the 5-HT2A receptor is an important site of agonist action for this compound in vivo.
Martin Hansen made a bunch of new N-heterocyclic phenethylaminesA series of N-benzylated-5-methoxytryptamine analogs was prepared and investigated, with special emphasis on substituents in the meta position of the benzyl group. A parallel series of several N-benzylated analogs of 2,5-dimethoxy-4-iodophenethylamine (2C-I) also was included for comparison of the two major templates (i.e., tryptamine and phenethylamine). A broad affinity screen at serotonin receptors showed that most of the compounds had highest affinity at the 5-HT2 family receptors. Substitution at the para-position of the benzyl group resulted in reduced affinity, whereas substitution in either the ortho or meta position enhanced affinity. In general, introduction of a large lipophilic group improved affinity, whereas functional activity often followed the opposite trend. Tests of the compounds for functional activity utilized intracellular Ca2+ mobilization. Function was measured at the human 5-HT2A, 5-HT2B, and 5-HT2C receptors, as well as at the rat 5-HT2A and 5-HT2C receptors. There was no general correlation between affinity and function. Several of the tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM), but most were partial agonists. Tests in the mouse head twitch assay revealed that many of the compounds induced the head twitch, and there was a significant correlation between this behavior and functional potency at the rat 5-HT2A receptor.
N-benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2’ and 3’-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2’-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2’-benzylsubstituent was also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.
http://www.sciencedaily.com/releases/2014/12/141215094147.htmThe organismal performance assay detects subtle toxic effects by subjecting mice to a relentless, Darwinian competition for food, shelter and mates. If there is a defect in any physiological system, it is more likely to stand out if test animals have to compete for resources, scientists say.
Paroxetine is a selective serotonin reuptake inhibitor (SSRI) that is currently available on the market and is suspected of causing congenital malformations in babies born to mothers who take the drug during the first trimester of pregnancy. We utilized organismal performance assays (OPAs), a novel toxicity assessment method, to assess the safety of paroxetine during pregnancy in a rodent model. OPAs utilize genetically diverse wild mice (Mus musculus) to evaluate competitive performance between experimental and control animals as they compete among each other for limited resources in semi-natural enclosures. Performance measures included reproductive success, male competitive ability and survivorship. Paroxetine-exposed males weighed 13% less, had 44% fewer offspring, dominated 53% fewer territories and experienced a 2.5-fold increased trend in mortality, when compared with controls. Paroxetine-exposed females had 65% fewer offspring early in the study, but rebounded at later time points, presumably, because they were no longer exposed to paroxetine. In cages, paroxetine-exposed breeders took 2.3 times longer to produce their first litter and pups of both sexes experienced reduced weight when compared with controls. Low-dose paroxetine-induced health declines detected in this study that were undetected in preclinical trials with doses 2.5–8 times higher than human therapeutic doses. These data indicate that OPAs detect phenotypic adversity and provide unique information that could be useful towards safety testing during pharmaceutical development.
The therapeutic effects induced by serotonin-selective reuptake inhibitor (SSRI) antidepressants are initially triggered by blocking the serotonin transporter and rely on long-term adaptations of pre- and post-synaptic receptors. We show here that long-term behavioral and neurogenic SSRI effects are abolished after either genetic or pharmacological inactivation of 5-HT(2B) receptors. Conversely, direct agonist stimulation of 5-HT(2B) receptors induces an SSRI-like response in behavioral and neurogenic assays. Moreover, the observation that (i) this receptor is expressed by raphe serotonergic neurons, (ii) the SSRI-induced increase in hippocampal extracellular serotonin concentration is strongly reduced in the absence of functional 5-HT(2B) receptors and (iii) a selective 5-HT(2B) agonist mimics SSRI responses, supports a positive regulation of serotonergic neurons by 5-HT(2B) receptors. The 5-HT(2B) receptor appears, therefore, to positively modulate serotonergic activity and to be required for the therapeutic actions of SSRIs. Consequently, the 5-HT(2B) receptor should be considered as a new tractable target in the combat against depression.
Fluoxetine and other serotonin-specific re-uptake inhibitors (SSRIs) are generally thought to owe their therapeutic potency to inhibition of the serotonin transporter (SERT). However, research in our laboratory showed that it affects, with relatively high affinity the 5-HT2B receptor in cultured astrocytes; this finding was confirmed by independent observations showing that fluoxetine loses its ability to elicit SSRI-like responses in behavioral assays in mice in which the 5-HT2B receptor was knocked-out genetically or inhibited pharmacologically. All clinically used SSRIs are approximately equipotent towards 5-HT2B receptors and exert their effect on cultured astrocytes at concentrations similar to those used clinically, a substantial difference from their effect on SERT. We have demonstrated up-regulation and editing of astrocytic genes for ADAR2, the kainate receptor GluK2, cPLA2 and the 5-HT2B receptor itself after chronic treatment of cultures, which do not express SERT and after treatment of mice (expressing SERT) for 2 weeks with fluoxetine, followed by isolation of astrocytic and neuronal cell fractionation. Affected genes were identical in both experimental paradigms. Fluoxetine treatment also altered Ca(2+) homeostatic cascades, in a specific way that differs from that seen after treatment with the anti-bipolar drugs carbamazepine, lithium, or valproic acid. All changes occurred after a lag period similar to what is seen for fluoxetine's clinical effects, and some of the genes were altered in the opposite direction by mild chronic inescapable stress, known to cause anhedonia, a component of major depression. In the anhedonic mice these changes were reversed by treatment with SSRIs.
Good read. I would presume being 'placated' gives less drive and similarly being even contented (by recreational or therapeutic drug use) would intuitively put a life-form 'evolved', or even "designed" (it's all the same for me), for struggle at a social- or ecological- -Darwinistic disadvantage. This was nothing where a study had to be made for me to come to that assumption. Of course, I've been using prescribed and self-sought psychoactive substances for approaching a decade now, and I know my capacity to persist in the competitive stratosphere of excelling at facets of life has been blunted. So it is of concern to me on some level. Though the over-domestication and abstracted machinery of civilization of the human species negates a lot of the pertinence had of true instincts & their pull for many kinds of ingrained feelings for accomplishments, though certainly never to the full degree of any one out of all of them.'Darwinian' test uncovers an antidepressant's hidden toxicity
How many reports on our website come from "drug testers" with links to RC selling websites? I know that I won't place as much faith in trip reports I read online from now on.The subject was seen by one of the authors (LT) to prepare a pre-trial psychiatric report. He had been charged with the attempted murder of his father. Mr X had a history of regular recreational use of a wide range of illicit drugs between the ages of 14 and 20. In his early twenties he became dependant on heroin, and was prescribed methadone which led to a reduction in his use of illicit drugs. He continued to use illicit drugs periodically, and also started using novel psychoactive substances regularly, which he obtained over the internet. He was a self-described “drug tester” for websites who sold novel psychoactive substances (NPS). He reported that the websites provided him with free samples of new drugs in exchange for him reporting on his drug experiences on internet forums for users of these drugs.