1.
Mouth
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It is also the cavity lying at the upper end of the alimentary canal, bounded on the outside by the lips and inside by the pharynx and containing in higher vertebrates the tongue and teeth. This cavity is known as the buccal cavity, from the Latin bucca. Some animal phyla, including vertebrates, have a digestive system, with a mouth at one end. Which end forms first in ontogeny is a used to classify animals into protostome and deuterostome. In the first multicellular animals there was probably no mouth or gut, the particles became enclosed in vacuoles into which enzymes were secreted and digestion took place intracellularly. The digestive products were absorbed into the cytoplasm and diffused into other cells, the vast majority of other multicellular organisms have a mouth and a gut, the lining of which is continuous with the epithelial cells on the surface of the body. A few animals which live parasitically originally had guts but have secondarily lost these structures, the original gut of multicellular organisms probably consisted of a simple sac with a single opening, the mouth. Indigestible waste is ejected through the mouth, in animals at least as complex as an earthworm, the embryo forms a dent on one side, the blastopore, which deepens to become the archenteron, the first phase in the formation of the gut. In deuterostomes, the blastopore becomes the anus while the gut tunnels through to make another opening. In the protostomes, it used to be thought that the formed the mouth while the anus formed later as an opening made by the other end of the gut. More recent research, however, shows that in protostomes the edges of the slit-like blastopore close up in the middle, apart from sponges and placozoans, almost all animals have an internal gut cavity which is lined with gastrodermal cells. In less advanced invertebrates such as the sea anemone, the mouth also acts as an anus, circular muscles around the mouth are able to relax or contract in order to open or close it. A fringe of tentacles thrusts food into the cavity and it can gape widely enough to large prey items. Food passes first into a pharynx and digestion occurs extracellularly in the gastrovascular cavity, annelids have simple tube-like gets and the possession of an anus allows them to separate the digestion of their foodstuffs from the absorption of the nutrients. Many molluscs have a radula which is used to scrape microscopic particles off surfaces, in invertebrates with hard exoskeletons, various mouthparts may be involved in feeding behaviour. Insects have a range of mouthparts suited to their mode of feeding and these include mandibles, maxillae and labium and can be modified into suitable appendages for chewing, cutting, piercing, sponging and sucking. Decapods have six pairs of appendages, one pair of mandibles. Sea urchins have a set of five sharp calcareous plates which are used as jaws and are known as Aristotles lantern, in vertebrates, the first part of the digestive system is the buccal cavity, commonly known as the mouth
2.
Regulation of therapeutic goods
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The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the level by a single agency. In other jurisdictions they are regulated at the level, or at both state and national levels by various bodies, as is the case in Australia. The role of therapeutic goods regulation is designed mainly to protect the health, regulation is aimed at ensuring the safety, quality, and efficacy of the therapeutic goods which are covered under the scope of the regulation. In most jurisdictions, therapeutic goods must be registered before they are allowed to be marketed, there is usually some degree of restriction of the availability of certain therapeutic goods depending on their risk to consumers. Therapeutic goods in Australia are regulated by the Therapeutic Goods Administration, there are 5 main categories, Normal Medicines - Cough, cold and fever medicines, antiseptics, vitamins and others. Sold freely in pharmacies and some large supermarkets, red Stripe Medicines - These medicines are sold only with medical prescription. Antibiotics, Anti allergenics, Anti inflammatories, and other medicines, in Brazil, governmental control is loose on this type, it is not uncommon to buy this type of prescription medicine over the counter without a prescription. Red Stripe Psychoactive Medicines - These medicines are only with a Special Control white medical prescription with carbon copy. The original must be retained by the pharmacist after the sale, Drugs include anti-depressants, anti-convulsants, some sleep aids, anti-psychotics and other non-habit-inducing controlled medicines. Though some consider them habit inducing, anabolic steroids are also regulated under this category, black Stripe Medicines - These medicines are sold only with the Blue B Form medical prescription, which is valid for 30 days and must be retained by the pharmacist after the sale. Includes sedatives, some anorexic inducers and other habit-inducing controlled medicines, includes amphetamines and other stimulants, opioids and other strong habit-forming controlled medicines. In Canada, regulation of goods are governed by the Food and Drug Act. In addition, the Controlled Drugs and Substances Act requires additional regulatory requirements for controlled drugs, the regulation of drugs in Burma is governed by the Food and Drug Administration and Food and Drug Board of Authority. The regulation of drugs in China is governed by the China Food, Medicines for Human Use in the United Kingdom are regulated by the Medicines and Healthcare products Regulatory Agency. The availability of drugs is regulated by classification by the MHRA as part of marketing authorisation of a product, Medicines in the Republic of Ireland are regulated according to the Misuse of Drugs Regulations 1988. Controlled drugs are divided into five categories based on their potential for misuse, cD1, cannabis, lysergamide, coca leaf, etc. Use prohibited except in limited circumstances where a license has been granted, CD2, amphetamine, methadone, morphine, fentanyl, oxycodone, tapentadol, etc
3.
Federal Analogue Act
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The Federal Analogue Act,21 U. S. C. These similar substances are often called designer drugs, united States v. Forbes,806 F. Supp. 232, a Colorado district court case, considered the question of whether the drug alphaethyltryptamine was a controlled substance analogue in the USA, the controlled drugs to which it was alleged that AET was substantially similar were the tryptamine analogues dimethyltryptamine and diethyltryptamine. However, despite this ruling the Federal Analogue Act was not revised, as a district court decision, this case is no binding precedent. The controlled drug which it was alleged 1, 4-B was substantially similar to was gamma-hydroxybutyrate. ”The court in Washam construed the Analogue Act to require parts A and either A or A, and concluded the Act was constitutionally permissible upon this construction. As a result of Washam, the Federal Analogue Act has been upheld, DEA list of chemicals, aka the DEA Watchlist Operation Web Tryp Section 813. Drug Enforcement Administration Appendix A - Controlled Substance Analogue Enforcement Act of 1986 - P. L. 99-570, subtitle E, Title I. on Erowid
4.
United States
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Forty-eight of the fifty states and the federal district are contiguous and located in North America between Canada and Mexico. The state of Alaska is in the northwest corner of North America, bordered by Canada to the east, the state of Hawaii is an archipelago in the mid-Pacific Ocean. The U. S. territories are scattered about the Pacific Ocean, the geography, climate and wildlife of the country are extremely diverse. At 3.8 million square miles and with over 324 million people, the United States is the worlds third- or fourth-largest country by area, third-largest by land area. It is one of the worlds most ethnically diverse and multicultural nations, paleo-Indians migrated from Asia to the North American mainland at least 15,000 years ago. European colonization began in the 16th century, the United States emerged from 13 British colonies along the East Coast. Numerous disputes between Great Britain and the following the Seven Years War led to the American Revolution. On July 4,1776, during the course of the American Revolutionary War, the war ended in 1783 with recognition of the independence of the United States by Great Britain, representing the first successful war of independence against a European power. The current constitution was adopted in 1788, after the Articles of Confederation, the first ten amendments, collectively named the Bill of Rights, were ratified in 1791 and designed to guarantee many fundamental civil liberties. During the second half of the 19th century, the American Civil War led to the end of slavery in the country. By the end of century, the United States extended into the Pacific Ocean. The Spanish–American War and World War I confirmed the status as a global military power. The end of the Cold War and the dissolution of the Soviet Union in 1991 left the United States as the sole superpower. The U. S. is a member of the United Nations, World Bank, International Monetary Fund, Organization of American States. The United States is a developed country, with the worlds largest economy by nominal GDP. It ranks highly in several measures of performance, including average wage, human development, per capita GDP. While the U. S. economy is considered post-industrial, characterized by the dominance of services and knowledge economy, the United States is a prominent political and cultural force internationally, and a leader in scientific research and technological innovations. In 1507, the German cartographer Martin Waldseemüller produced a map on which he named the lands of the Western Hemisphere America after the Italian explorer and cartographer Amerigo Vespucci
5.
PubChem
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PubChem is a database of chemical molecules and their activities against biological assays. The system is maintained by the National Center for Biotechnology Information, a component of the National Library of Medicine, PubChem can be accessed for free through a web user interface. Millions of compound structures and descriptive datasets can be downloaded via FTP. PubChem contains substance descriptions and small molecules with fewer than 1000 atoms and 1000 bonds, more than 80 database vendors contribute to the growing PubChem database. PubChem consists of three dynamically growing primary databases, as of 28 January 2016, Compounds,82.6 million entries, contains pure and characterized chemical compounds. Substances,198 million entries, contains also mixtures, extracts, complexes, bioAssay, bioactivity results from 1.1 million high-throughput screening programs with several million values. PubChem contains its own online molecule editor with SMILES/SMARTS and InChI support that allows the import and export of all common chemical file formats to search for structures and fragments. In the text search form the database fields can be searched by adding the name in square brackets to the search term. A numeric range is represented by two separated by a colon. The search terms and field names are case-insensitive, parentheses and the logical operators AND, OR, and NOT can be used. AND is assumed if no operator is used, example,0,5000,50,10 -5,5 PubChem was released in 2004. The American Chemical Society has raised concerns about the publicly supported PubChem database and they have a strong interest in the issue since the Chemical Abstracts Service generates a large percentage of the societys revenue. To advocate their position against the PubChem database, ACS has actively lobbied the US Congress, soon after PubChems creation, the American Chemical Society lobbied U. S. Congress to restrict the operation of PubChem, which they asserted competes with their Chemical Abstracts Service
6.
ChemSpider
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ChemSpider is a database of chemicals. ChemSpider is owned by the Royal Society of Chemistry, the database contains information on more than 50 million molecules from over 500 data sources including, Each chemical is given a unique identifier, which forms part of a corresponding URL. This is an approach to develop an online chemistry database. The search can be used to widen or restrict already found results, structure searching on mobile devices can be done using free apps for iOS and for the Android. The ChemSpider database has been used in combination with text mining as the basis of document markup. The result is a system between chemistry documents and information look-up via ChemSpider into over 150 data sources. ChemSpider was acquired by the Royal Society of Chemistry in May,2009, prior to the acquisition by RSC, ChemSpider was controlled by a private corporation, ChemZoo Inc. The system was first launched in March 2007 in a release form. ChemSpider has expanded the generic support of a database to include support of the Wikipedia chemical structure collection via their WiChempedia implementation. A number of services are available online. SyntheticPages is an interactive database of synthetic chemistry procedures operated by the Royal Society of Chemistry. Users submit synthetic procedures which they have conducted themselves for publication on the site and these procedures may be original works, but they are more often based on literature reactions. Citations to the published procedure are made where appropriate. They are checked by an editor before posting. The pages do not undergo formal peer-review like a journal article. The comments are moderated by scientific editors. The intention is to collect practical experience of how to conduct useful chemical synthesis in the lab, while experimental methods published in an ordinary academic journal are listed formally and concisely, the procedures in ChemSpider SyntheticPages are given with more practical detail. Comments by submitters are included as well, other publications with comparable amounts of detail include Organic Syntheses and Inorganic Syntheses
7.
ChEMBL
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ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug-like properties. It is maintained by the European Bioinformatics Institute, of the European Molecular Biology Laboratory, based at the Wellcome Trust Genome Campus, Hinxton, the database, originally known as StARlite, was developed by a biotechnology company called Inpharmatica Ltd. later acquired by Galapagos NV. The data was acquired for EMBL in 2008 with an award from The Wellcome Trust, resulting in the creation of the ChEMBL chemogenomics group at EMBL-EBI, the ChEMBL database contains compound bioactivity data against drug targets. Bioactivity is reported in Ki, Kd, IC50, and EC50, data can be filtered and analyzed to develop compound screening libraries for lead identification during drug discovery. ChEMBL version 2 was launched in January 2010, including 2.4 million bioassay measurements covering 622,824 compounds and this was obtained from curating over 34,000 publications across twelve medicinal chemistry journals. ChEMBLs coverage of available bioactivity data has grown to become the most comprehensive ever seen in a public database, in October 2010 ChEMBL version 8 was launched, with over 2.97 million bioassay measurements covering 636,269 compounds. ChEMBL_10 saw the addition of the PubChem confirmatory assays, in order to integrate data that is comparable to the type, ChEMBLdb can be accessed via a web interface or downloaded by File Transfer Protocol. It is formatted in a manner amenable to computerized data mining, ChEMBL is also integrated into other large-scale chemistry resources, including PubChem and the ChemSpider system of the Royal Society of Chemistry. In addition to the database, the ChEMBL group have developed tools and these include Kinase SARfari, an integrated chemogenomics workbench focussed on kinases. The system incorporates and links sequence, structure, compounds and screening data, the primary purpose of ChEMBL-NTD is to provide a freely accessible and permanent archive and distribution centre for deposited data. July 2012 saw the release of a new data service, sponsored by the Medicines for Malaria Venture. The data in this service includes compounds from the Malaria Box screening set, myChEMBL, the ChEMBL virtual machine, was released in October 2013 to allow users to access a complete and free, easy-to-install cheminformatics infrastructure. In December 2013, the operations of the SureChem patent informatics database were transferred to EMBL-EBI, in a portmanteau, SureChem was renamed SureChEMBL. 2014 saw the introduction of the new resource ADME SARfari - a tool for predicting and comparing cross-species ADME targets
8.
Chemical formula
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These are limited to a single typographic line of symbols, which may include subscripts and superscripts. A chemical formula is not a name, and it contains no words. Although a chemical formula may imply certain simple chemical structures, it is not the same as a full chemical structural formula. Chemical formulas can fully specify the structure of only the simplest of molecules and chemical substances, the simplest types of chemical formulas are called empirical formulas, which use letters and numbers indicating the numerical proportions of atoms of each type. Molecular formulas indicate the numbers of each type of atom in a molecule. For example, the formula for glucose is CH2O, while its molecular formula is C6H12O6. This is possible if the relevant bonding is easy to show in one dimension, an example is the condensed molecular/chemical formula for ethanol, which is CH3-CH2-OH or CH3CH2OH. For reasons of structural complexity, there is no condensed chemical formula that specifies glucose, chemical formulas may be used in chemical equations to describe chemical reactions and other chemical transformations, such as the dissolving of ionic compounds into solution. A chemical formula identifies each constituent element by its chemical symbol, in empirical formulas, these proportions begin with a key element and then assign numbers of atoms of the other elements in the compound, as ratios to the key element. For molecular compounds, these numbers can all be expressed as whole numbers. For example, the formula of ethanol may be written C2H6O because the molecules of ethanol all contain two carbon atoms, six hydrogen atoms, and one oxygen atom. Some types of compounds, however, cannot be written with entirely whole-number empirical formulas. An example is boron carbide, whose formula of CBn is a variable non-whole number ratio with n ranging from over 4 to more than 6.5. When the chemical compound of the consists of simple molecules. These types of formulas are known as molecular formulas and condensed formulas. A molecular formula enumerates the number of atoms to reflect those in the molecule, so that the formula for glucose is C6H12O6 rather than the glucose empirical formula. However, except for very simple substances, molecular chemical formulas lack needed structural information, for simple molecules, a condensed formula is a type of chemical formula that may fully imply a correct structural formula. For example, ethanol may be represented by the chemical formula CH3CH2OH
9.
Jmol
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Jmol is computer software for molecular modelling chemical structures in 3-dimensions. Jmol returns a 3D representation of a molecule that may be used as a teaching tool and it is written in the programming language Java, so it can run on the operating systems Windows, macOS, Linux, and Unix, if Java is installed. It is free and open-source software released under a GNU Lesser General Public License version 2.0, a standalone application and a software development kit exist that can be integrated into other Java applications, such as Bioclipse and Taverna. A popular feature is an applet that can be integrated into web pages to display molecules in a variety of ways, for example, molecules can be displayed as ball-and-stick models, space-filling models, ribbon diagrams, etc. Jmol supports a range of chemical file formats, including Protein Data Bank, Crystallographic Information File, MDL Molfile. There is also a JavaScript-only version, JSmol, that can be used on computers with no Java, the Jmol applet, among other abilities, offers an alternative to the Chime plug-in, which is no longer under active development. While Jmol has many features that Chime lacks, it does not claim to reproduce all Chime functions, most notably, Chime requires plug-in installation and Internet Explorer 6.0 or Firefox 2.0 on Microsoft Windows, or Netscape Communicator 4.8 on Mac OS9. Jmol requires Java installation and operates on a variety of platforms. For example, Jmol is fully functional in Mozilla Firefox, Internet Explorer, Opera, Google Chrome, fast and Scriptable Molecular Graphics in Web Browsers without Java3D
10.
Simplified molecular-input line-entry system
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The simplified molecular-input line-entry system is a specification in form of a line notation for describing the structure of chemical species using short ASCII strings. SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules, the original SMILES specification was initiated in the 1980s. It has since modified and extended. In 2007, a standard called OpenSMILES was developed in the open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, the original SMILES specification was initiated by David Weininger at the USEPA Mid-Continent Ecology Division Laboratory in Duluth in the 1980s. The Environmental Protection Agency funded the project to develop SMILES. It has since modified and extended by others, most notably by Daylight Chemical Information Systems. In 2007, a standard called OpenSMILES was developed by the Blue Obelisk open-source chemistry community. Other linear notations include the Wiswesser Line Notation, ROSDAL and SLN, in July 2006, the IUPAC introduced the InChI as a standard for formula representation. SMILES is generally considered to have the advantage of being slightly more human-readable than InChI, the term SMILES refers to a line notation for encoding molecular structures and specific instances should strictly be called SMILES strings. However, the term SMILES is also used to refer to both a single SMILES string and a number of SMILES strings, the exact meaning is usually apparent from the context. The terms canonical and isomeric can lead to confusion when applied to SMILES. The terms describe different attributes of SMILES strings and are not mutually exclusive, typically, a number of equally valid SMILES strings can be written for a molecule. For example, CCO, OCC and CC all specify the structure of ethanol, algorithms have been developed to generate the same SMILES string for a given molecule, of the many possible strings, these algorithms choose only one of them. This SMILES is unique for each structure, although dependent on the algorithm used to generate it. These algorithms first convert the SMILES to a representation of the molecular structure. A common application of canonical SMILES is indexing and ensuring uniqueness of molecules in a database, there is currently no systematic comparison across commercial software to test if such flaws exist in those packages. SMILES notation allows the specification of configuration at tetrahedral centers, and these are structural features that cannot be specified by connectivity alone and SMILES which encode this information are termed isomeric SMILES
11.
International Chemical Identifier
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Initially developed by IUPAC and NIST from 2000 to 2005, the format and algorithms are non-proprietary. The continuing development of the standard has supported since 2010 by the not-for-profit InChI Trust. The current version is 1.04 and was released in September 2011, prior to 1.04, the software was freely available under the open source LGPL license, but it now uses a custom license called IUPAC-InChI Trust License. Not all layers have to be provided, for instance, the layer can be omitted if that type of information is not relevant to the particular application. InChIs can thus be seen as akin to a general and extremely formalized version of IUPAC names and they can express more information than the simpler SMILES notation and differ in that every structure has a unique InChI string, which is important in database applications. Information about the 3-dimensional coordinates of atoms is not represented in InChI, the InChI algorithm converts input structural information into a unique InChI identifier in a three-step process, normalization, canonicalization, and serialization. The InChIKey, sometimes referred to as a hashed InChI, is a fixed length condensed digital representation of the InChI that is not human-understandable. The InChIKey specification was released in September 2007 in order to facilitate web searches for chemical compounds and it should be noted that, unlike the InChI, the InChIKey is not unique, though collisions can be calculated to be very rare, they happen. In January 2009 the final 1.02 version of the InChI software was released and this provided a means to generate so called standard InChI, which does not allow for user selectable options in dealing with the stereochemistry and tautomeric layers of the InChI string. The standard InChIKey is then the hashed version of the standard InChI string, the standard InChI will simplify comparison of InChI strings and keys generated by different groups, and subsequently accessed via diverse sources such as databases and web resources. Every InChI starts with the string InChI= followed by the version number and this is followed by the letter S for standard InChIs. The remaining information is structured as a sequence of layers and sub-layers, the layers and sub-layers are separated by the delimiter / and start with a characteristic prefix letter. The six layers with important sublayers are, Main layer Chemical formula and this is the only sublayer that must occur in every InChI. The atoms in the formula are numbered in sequence, this sublayer describes which atoms are connected by bonds to which other ones. Describes how many hydrogen atoms are connected to each of the other atoms, the condensed,27 character standard InChIKey is a hashed version of the full standard InChI, designed to allow for easy web searches of chemical compounds. Most chemical structures on the Web up to 2007 have been represented as GIF files, the full InChI turned out to be too lengthy for easy searching, and therefore the InChIKey was developed. With all databases currently having below 50 million structures, such duplication appears unlikely at present, a recent study more extensively studies the collision rate finding that the experimental collision rate is in agreement with the theoretical expectations. Example, Morphine has the structure shown on the right, as the InChI cannot be reconstructed from the InChIKey, an InChIKey always needs to be linked to the original InChI to get back to the original structure
12.
Drug
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A drug is any substance that, when inhaled, injected, smoked, consumed, absorbed via a patch on the skin, or dissolved under the tongue, causes a physiological change in the body. In pharmacology, a drug, also called a medication or medicine, is a chemical substance used to treat, cure, prevent. Traditionally drugs were obtained through extraction from plants, but more recently also by organic synthesis. Pharmaceutical drugs may be used for a duration, or on a regular basis for chronic disorders. Another major classification system is the Biopharmaceutics Classification System and this classifies drugs according to their solubility and permeability or absorption properties. Psychoactive drugs are chemical substances that affect the function of the nervous system, altering perception. They include alcohol, a depressant, and the nicotine and caffeine. These three are the most widely consumed psychoactive drugs worldwide and are also considered recreational drugs since they are used for rather than medicinal purposes. Other recreational drugs include hallucinogens, opiates and amphetamines and some of these are used in spiritual or religious settings. Some drugs can cause addiction and all drugs can have side effects, excessive use of stimulants can promote stimulant psychosis. Many recreational drugs are illicit and international such as the Single Convention on Narcotic Drugs exist for the purpose of their prohibition. The transitive verb to drug arose later and invokes the psychoactive rather than properties of a substance. A medication or medicine is a drug taken to cure or ameliorate any symptoms of an illness or medical condition, the use may also be as preventive medicine that has future benefits but does not treat any existing or pre-existing diseases or symptoms. In the United Kingdom, behind-the-counter medicines are called pharmacy medicines which can only be sold in registered pharmacies and these medications are designated by the letter P on the label. The range of medicines available without a prescription varies from country to country, medications are typically produced by pharmaceutical companies and are often patented to give the developer exclusive rights to produce them. Those that are not patented are called generic drugs since they can be produced by other companies without restrictions or licenses from the patent holder, pharmaceutical drugs are usually categorised into drug classes. A group of drugs will share a chemical structure, or have the same mechanism of action. Another major classification system is the Biopharmaceutics Classification System and this groups drugs according to their solubility and permeability or absorption properties
13.
Substituted amphetamine
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The compounds in this class span a variety of pharmacological subclasses, including stimulants, empathogens, and hallucinogens, among others. Some of amphetamines substituted derivatives occur in nature, for example in the leaves of Ephedra and these have been used since antiquity for their pharmacological effects. Amphetamine was first produced at the end of the 19th century, by the 1930s, amphetamine and some of its derivative compounds found use as decongestants in the symptomatic treatment of colds and also occasionally as psychoactive agents. Their effects on the nervous system are diverse, but can be summarized by three overlapping types of activity, psychoanaleptic, hallucinogenic and empathogenic. Various substituted amphetamines may cause these actions either separately or in combination, amphetamines are a subgroup of the substituted phenethylamine class of compounds. Substitution of hydrogen results in a large class of compounds. Natives of Yemen and Ethiopia have a tradition of chewing khat leaves to achieve a stimulating effect. The active substances of khat are cathinone and, to a lesser extent, amphetamine was first synthesized in 1887 by Romanian chemist Lazăr Edeleanu, although its pharmacological effects remained unknown until the 1930s. MDMA was produced in 1912 as an intermediate product, however, this synthesis also went largely unnoticed. In the 1920s, both methamphetamine and the dextrorotatory optical isomer of amphetamine, dextroamphetamine, were synthesized and this synthesis was a by-product of a search for ephedrine, a bronchodilator used to treat asthma extracted exclusively from natural sources. Over-the-counter use of substituted amphetamines was initiated in the early 1930s by the pharmaceutical company Smith, Kline & French, as a medicine for colds and nasal congestion. Subsequently, amphetamine was used in the treatment of narcolepsy, obesity, hay fever, orthostatic hypotension, epilepsy, Parkinsons disease, alcoholism, the reinforcing effects of substituted amphetamines were quickly discovered, and the misuse of substituted amphetamines had been noted as far back as 1936. During World War II, amphetamines were used by the German military to keep their tank crews awake for long periods and it was noticed that extended rest was required after such artificially induced activity. The widespread use of substituted amphetamines began in postwar Japan and quickly spread to other countries, modified designer amphetamines gained popularity since the 1960s, such as MDA and PMA. In 1970, the United States adopted the Controlled Substances Act that limited non-medical use of substituted amphetamines, street use of PMA was noted in 1972. MDMA emerged as a substitute to MDA in the early 1970s, american chemist Alexander Shulgin first synthesized the drug in 1976 and through him the drug was briefly introduced into psychotherapy. Recreational use grew and in 1985 MDMA was banned by the US authorities in an emergency scheduling initiated by the Drug Enforcement Administration, since the mid-1990s, MDMA has become a popular entactogenic drug among the youth and quite often non-MDMA substances were sold as ecstasy. Ongoing trials are investigating its efficacy as an adjunct to psychotherapy in the management of treatment-resistant post-traumatic stress disorder
14.
Selective serotonin releasing agent
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A serotonin releasing agent is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent is an SRA with less significant or no efficacy in producing neurotransmitter efflux at other types of monoamine neurons, a closely related type of drug is a serotonin reuptake inhibitor. Amphetamines like MDMA, MDEA, MDA, and MBDB, among other relatives, are recreational drugs termed entactogens and they act as serotonin-norepinephrine-dopamine releasing agents and also agonize serotonin receptors such as those in the 5-HT2 subfamily. Fenfluramine, chlorphentermine, and aminorex, which are also amphetamines and relatives, were used as appetite suppressants but were discontinued due to concerns of cardiac valvulopathy. This side effect has been attributed to their action of potent agonism of the 5-HT2B receptor. The designer drug 4-methylaminorex, which is an SNDRA and 5-HT2B agonist, has reported to cause this effect as well. Many tryptamines, such as DMT, αMT, 5MeO-NMT, NMT, NETP, Dimethyl-Serotonin and these drugs are serotonergic psychedelics, which is a consequence of their ability to activate the 5-HT2A receptor. αET and αMT, also tryptamines, are SNDRAs and non-selective serotonin receptor agonists that were used as antidepressants. They have since discontinued and are now encountered solely as recreational drugs. Tramadol, in addition to its actions as an opioid and norepinephrine reuptake inhibitor, is an SRA and is used as an analgesic and it is also under investigation as an antidepressant. Indeloxazine is an SRA and norepinephrine reuptake inhibitor that was used as an antidepressant, nootropic
15.
IC50
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The half maximal inhibitory concentration is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. This quantitative measure indicates how much of a drug or other substance is needed to inhibit a given biological process by half. The values are expressed as molar concentration. It is commonly used as a measure of antagonist drug potency in pharmacological research, according to the FDA, IC50 represents the concentration of a drug that is required for 50% inhibition in vitro. It is comparable to an EC50 for agonist drugs, EC50 also represents the plasma concentration required for obtaining 50% of a maximum effect in vivo. The IC50 of a drug can be determined by constructing a dose-response curve, IC50 values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist. IC50 values can be used to compare the potency of two antagonists, IC50 values are very dependent on conditions under which they are measured. In general, the higher the concentration of inhibitor, the more agonist activity will be lowered, IC50 value increases as agonist concentration increases. In this type of assay, a concentration of radioligand is used in every assay tube. The ligand is used at a low concentration, usually at or below its Kd value, competition curves may also be computer-fitted to a logistic function as described under direct fit. In this situation the IC50 is the concentration of competing ligand which displaces 50% of the binding of the radioligand. The IC50 value is converted to an absolute inhibition constant Ki using the Cheng-Prusoff equation formulated by Yung-Chi Cheng, IC50 is not a direct indicator of affinity although the two can be related at least for competitive agonists and antagonists by the Cheng-Prusoff equation. Whereas the IC50 value for a compound may vary between experiments depending on conditions, the Ki is an absolute value. Ki is the constant for a drug, the concentration of competing ligand in a competition assay which would occupy 50% of the receptors if no ligand were present. The Cheng-Prusoff equation produces good estimates at high agonist concentrations, in these conditions, other analyses have been recommended. Sometimes, IC50 values are converted to the pIC50 scale, PIC50 = − log 10 Note the minus sign, which means that higher values of pIC50 indicate exponentially greater potency. PIC50 is usually given in terms of molar concentration, therefore, to obtain a pIC50, an IC50 should be specified in units of M. When IC50 is expressed in μM or nM, it will need to be converted to M before conversion to pIC50, the IC50 terminology is also used for some behavioral measures in vivo, such as a two bottle fluid consumption test
16.
Reuptake inhibitor
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Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants. Most known reuptake inhibitors affect the monoamine neurotransmitters serotonin, norepinephrine, standard reuptake inhibitors are believed to act simply as competitive substrates that work by binding directly to the plasmalemma transporter of the neurotransmitter in question. They occupy the transporter in place of the respective neurotransmitter and competitively block it from being transported from the terminal or synapse into the pre-synaptic neuron. With high enough doses, occupation becomes as much as 80–90%, alternatively, some reuptake inhibitors bind to allosteric sites and inhibit reuptake indirectly and noncompetitively. Phencyclidine and related such as benocyclidine, tenocyclidine, ketamine. They appear to exert their reuptake inhibition by binding to vaguely characterized allosteric sites on each of the monoamine transporters. Benztropine, mazindol, and vanoxerine also bind to sites and have similar properties. A few of the selective reuptake inhibitors such as the dextro-enantiomer of citalopram appear to be allosteric reuptake inhibitors of serotonin. As a result, escitalopram has been marketed as a serotonin reuptake inhibitor. Notably, this site may be directly related to the above-mentioned PCP binding sites. A second type of reuptake inhibition affects vesicular transport, and blocks the intracellular repackaging of neurotransmitters into cytoplasmic vesicles, with vesicular transport blocked, neurotransmitter stores quickly become depleted. Reserpine is an inhibitor of the vesicular monoamine transporter 2. Two of the active constituents of the medicinal herb Hypericum perforatum are hyperforin and adhyperforin. Activation of TRPC6 induces the entry of calcium and sodium into the cell, which causes the effect through unknown mechanism
17.
Reuptake
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Reuptake, or re-uptake, is the reabsorption of a neurotransmitter by a neurotransmitter transporter of a pre-synaptic neuron after it has performed its function of transmitting a neural impulse. Because neurotransmitters are too large and hydrophilic to diffuse through the membrane, much research, both biochemical and structural, has been performed to obtain clues about the mechanism of reuptake. The first primary sequence of a protein was published in 1990. After separation, it was realized that there were similarities between the two DNA sequences. The members of new family include transporters for dopamine, norepinephrine, serotonin, glycine, proline. They were called Na+/Cl− dependent neurotransmitter transporters, Sodium and Chloride ion dependence will be discussed later in the mechanism of action. Using the commonalities among sequences and hydropathy plot analyses, it was predicted that there are 12 hydrophobic membrane spanning regions in the ‘Classical’ transporter family, in addition to this, the N- and C-termini exist in the intracellular space. These proteins also all have an extracellular loop between the third and fourth transmembrane sequences. Site-directed chemical labeling experiments verified the predicted topological organization of the serotonin transporter, in addition to neurotransmitter transporters, many other proteins in both animals and prokaryotes were found with similar sequences, indicating a larger family of Neurotransmitter, Sodium Symporters. They found that the transmembrane helices 1 and 6 contained unwound segments in the middle of the membrane, along with these two helices, TM helices 3 and 8 and the areas surrounding the unwound sections of 1 and 6 formed the substrate and sodium ion binding sites. The crystal structure revealed pseudo-symmetry in LeuT, in which the structure of TM helices 1-5 is reflected in the structure of helices 6-10, there is an extracellular cavity in the protein, into which protrudes a helical hairpin formed by extracellular loop EL4. In TM1, an aspartate distinguishes monoamine NSS transporters from amino acid transporters which contain a glycine at the same position, external and internal “gates” were assigned to pairs of negatively and positively charged residues in the extracellular cavity and near the cytoplasmic ends of TM helices 1 and 8. The classic transporter proteins use transmembrane ion gradients and electrical potential to transport neurotransmitter across the membrane of the presynaptic neuron, typical neurotransmitter sodium symport transporters, which are Na+ and Cl− ion dependent, take advantage of both Na+ and Cl− gradients, inwardly directed across the membrane. The ions flow down their concentration gradients, in many cases leading to transmembrane charge movement that is enhanced by the membrane potential and these forces pull the neurotransmitter substrate into the cell, even against its own concentration gradient. At a molecular level, Na+ ions stabilize amino acid binding at the substrate site, the role of the Cl− ion in the symport mechanism has been proposed to be for stabilizing the charge of the symported Na+. After ion and substrate binding have taken place, some conformational change must occur and this increases neurotransmitter binding to pre- and postsynaptic neurotransmitter receptors. Depending on the system in question, a reuptake inhibitor can have drastic effects on cognition. Non-competitive inhibition of the bacterial homologue LeuT by tricyclic antidepressants resulted from binding of inhibitors in the extracellular permeation pathway
18.
Serotonin
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Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is found in the gastrointestinal tract, blood platelets. It is popularly thought to be a contributor to feelings of well-being, approximately 90% of the human bodys total serotonin is located in the enterochromaffin cells in the GI tract, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions and these include the regulation of mood, appetite, and sleep. Serotonin also has some functions, including memory and learning. Modulation of serotonin at synapses is thought to be an action of several classes of pharmacological antidepressants. Serotonin secreted from the cells eventually finds its way out of tissues into the blood. There, it is taken up by blood platelets, which store it. When the platelets bind to a clot, they release serotonin, Serotonin is also a growth factor for some types of cells, which may give it a role in wound healing. Serotonin is metabolized mainly to 5-HIAA, chiefly by the liver, metabolism involves first oxidation by monoamine oxidase to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the acetic acid derivative. The latter is then excreted by the kidneys, in addition to animals, serotonin is found in fungi and plants. Serotonins presence in insect venoms and plant spines serves to cause pain, Serotonin is produced by pathogenic amoebae, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds, Serotonin is a neurotransmitter and is found in all bilateral animals, where it mediates gut movements and the animals perceptions of resource availability. In less complex animals, such as invertebrates, resources simply mean food availability. In more complex animals, such as arthropods and vertebrates, resources also can mean social dominance, in response to the perceived abundance or scarcity of resources, an animals growth, reproduction or mood may be elevated or lowered. This may somewhat depend on how much serotonin the organism has at its disposal, except for the 5-HT3 receptor, a ligand-gated ion channel, all other 5-HT receptors are G-protein-coupled receptors that activate an intracellular second messenger cascade. Serotonergic action is terminated primarily via uptake of 5-HT from the synapse and this is accomplished through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron
19.
Dopamine
–
Dopamine is an organic chemical of the catecholamine and phenethylamine families that plays several important roles in the brain and body. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, dopamine is also synthesized in plants and most multicellular animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to nerve cells. The brain includes several distinct dopamine pathways, one of plays a major role in reward-motivated behavior. Most types of rewards increase the level of dopamine in the brain, other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a system which is neuromodulatory. Outside the central system, dopamine functions primarily as a local chemical messenger. With the exception of the vessels, dopamine in each of these peripheral systems is synthesized locally. Several important diseases of the system are associated with dysfunctions of the dopamine system. Parkinsons disease, a condition causing tremor and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra. Its metabolic precursor L-DOPA can be manufactured, and in its pure form marketed as Levodopa is the most widely used treatment for the condition. There is evidence that schizophrenia involves altered levels of dopamine activity, similar dopamine antagonist drugs are also some of the most effective anti-nausea agents. Restless legs syndrome and attention deficit hyperactivity disorder are associated with decreased dopamine activity, dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. A dopamine molecule consists of a structure with one amine group attached via an ethyl chain. As such, dopamine is the simplest possible catecholamine, a family that includes the neurotransmitters norepinephrine and epinephrine. The presence of a ring with this amine attachment makes it a substituted phenethylamine. Like most amines, dopamine is an organic base, as a base, it is generally protonated in acidic environments. The protonated form is highly water-soluble and relatively stable, but can become oxidized if exposed to oxygen or other oxidants, in basic environments, dopamine is not protonated
20.
Norepinephrine
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Norepinephrine, also called noradrenaline or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone and neurotransmitter. Norepinephrine is also the international nonproprietary name given to the drug, regardless of which name is used for the substance itself, parts of the body that produce or are affected by it are referred to as noradrenergic. In the brain, norepinephrine is produced in closely packed brain cell neurons or nuclei that are small yet exert powerful effects on brain areas. The most important of these nuclei is the locus coeruleus, located in the pons, regardless of how and where it is released, norepinephrine acts on target cells by binding to and activating noradrenergic receptors located on the cell surface. The general function of norepinephrine is to mobilize the brain and body for action, norepinephrine release is lowest during sleep, rises during wakefulness, and reaches much higher levels during situations of stress or danger, in the so-called fight-or-flight response. In the brain, norepinephrine increases arousal and alertness, promotes vigilance, enhances formation and retrieval of memory, a variety of medically important drugs work by altering the actions of norepinephrine systems. Norepinephrine itself is used as an injectable drug for the treatment of critically low blood pressure. Beta blockers, which some of the effects of norepinephrine, are frequently used to treat glaucoma, migraine. Alpha blockers, which counter a different set of effects, are used to treat several cardiovascular. Alpha-2 agonists often have an effect, and are commonly used as anesthesia-enhancers in surgery. Many important psychiatric drugs exert strong effects on systems in the brain. Norepinephrine is a catecholamine and a phenethylamine and its structure differs from that of epinephrine only in that epinephrine has a methyl group attached to its nitrogen, whereas the methyl group is replaced by a hydrogen atom in norepinephrine. The prefix nor- is derived as an abbreviation of the word normal, norepinephrine is synthesized from the amino acid tyrosine by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of the sympathetic nervous system. These amino acids are found in nearly every protein and, as such, are provided by ingestion of protein-containing food, phenylalanine is converted into tyrosine by the enzyme phenylalanine hydroxylase, with molecular oxygen and tetrahydrobiopterin as cofactors. Tyrosine is converted into L-DOPA by the tyrosine hydroxylase, with tetrahydrobiopterin, O2. L-DOPA is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase, dopamine is then converted into norepinephrine by the enzyme dopamine β-monooxygenase, with O2 and ascorbic acid as cofactors. Norepinephrine itself can further be converted into epinephrine by the enzyme phenylethanolamine N-methyltransferase with S-adenosyl-L-methionine as cofactor, in mammals, norepinephrine is rapidly degraded to various metabolites. The initial step in the breakdown can be catalyzed by either of the monoamine oxidase or COMT
21.
In vitro
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In vitro studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. In contrast, in studies are those conducted in animals, including humans. In vitro studies are conducted using components of an organism that have been isolated from their biological surroundings, such as microorganisms, cells. For example, microrganisms or cells can be studied in artificial culture media, colloquially called test-tube experiments, these studies in biology, medicine, and their subdisciplines are traditionally done in test tubes, flasks, Petri dishes, etc. They now involve the range of techniques used in molecular biology. In contrast, studies conducted in living beings are called in vivo, polymerase chain reaction is a method for selective replication of specific DNA and RNA sequences in the test tube. Protein purification involves the isolation of a protein of interest from a complex mixture of proteins. In vitro fertilization is used to allow spermatozoa to fertilize eggs in a culture dish before implanting the resulting embryo or embryos into the uterus of the prospective mother and these ADME process parameters can then be integrated into so called physiologically based pharmacokinetic models or PBPK. In vitro studies permit a species-specific, simpler, more convenient, just as studies in whole animals more and more replace human trials, so are in vitro studies replacing studies in whole animals. This complexity makes it difficult to identify the interactions between individual components and to explore their basic biological functions, in vitro work simplifies the system under study, so the investigator can focus on a small number of components. Another advantage of in vitro methods is that cells can be studied without extrapolation from an experimental animals cellular response. Investigators doing in vitro work must be careful to avoid over-interpretation of their results, for example, scientists developing a new viral drug to treat an infection with a pathogenic virus may find that a candidate drug functions to prevent viral replication in an in vitro setting. However, before this drug is used in the clinic, it must progress through a series of in vivo trials to determine if it is safe and effective in intact organisms. Results obtained from in vitro experiments cannot usually be transposed, as is, building a consistent and reliable extrapolation procedure from in vitro results to in vivo is therefore extremely important. However, increasingly sophisticated in vitro experiments collect increasingly numerous, complex, mathematical models, such as systems biology models, are much needed here. In pharmacology, IVIVE can be used to approximate pharmacokinetics or pharmacodynamics and that indicates that extrapolating effects observed in vitro needs a quantitative model of in vivo PK. Physiologically based PK models are generally accepted to be central to the extrapolations, in these conditions, developing a simple PD model of the dose–response relationship observed in vitro, and transposing it without changes to predict in vivo effects is not enough
22.
Amphetamine
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Amphetamine is a potent central nervous system stimulant that is used in the treatment of attention deficit hyperactivity disorder, narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers, levoamphetamine and dextroamphetamine, amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. The term is used informally to refer to any combination of the enantiomers. Historically, it has used to treat nasal congestion and depression. Amphetamine is also used as a performance enhancer and cognitive enhancer. The first amphetamine pharmaceutical was Benzedrine, a brand which was used to treat a variety of conditions, currently, pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall, dextroamphetamine, or the inactive prodrug lisdexamfetamine. At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria, change in desire for sex, increased wakefulness and it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown, drug addiction is a serious risk with large recreational doses but is unlikely to arise from typical long-term medical use at therapeutic doses. Very high doses can result in psychosis which rarely occurs at therapeutic doses even during long-term use, recreational doses are generally much larger than prescribed therapeutic doses and carry a far greater risk of serious side effects. Amphetamine belongs to the phenethylamine class and it is also the parent compound of its own structural class, the substituted amphetamines, which includes prominent substances such as bupropion, cathinone, MDMA, and methamphetamine. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is an isomer of amphetamine that differs only in the placement of the methyl group. Amphetamine is used to attention deficit hyperactivity disorder, narcolepsy, and obesity. Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD, randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning two years have demonstrated treatment effectiveness and safety. Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems, approximately 80% of those who use these stimulants see improvements in ADHD symptoms. A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. Amphetamine and other ADHD stimulants also improve task saliency and increase arousal, stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid. However, high doses that are above the therapeutic range can interfere with working memory. Amphetamine improves endurance and reaction time primarily through reuptake inhibition and effluxion of dopamine in the nervous system
23.
MBDB
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1, 3-Benzodioxolyl-N-methylbutanamine is an entactogen of the phenethylamine chemical class. It is known by the street names Eden and Methyl-J, MBDB is a closely related chemical analogue of MDMA, with the only difference between the two molecules being an ethyl group instead of a methyl group attached to the alpha carbon. It has IC50 values of 784 nM against 5-HT,7825 nM against dopamine and its metabolism has been described in scientific literature. MBDB was first synthesized by pharmacologist and medicinal chemist David E. Nichols and later tested by Alexander Shulgin and described in his book, PiHKAL, mBDBs dosage, according to PiHKAL, is 180–210 mg, the proper dosage relative to body mass seems unknown. Its duration is 4–6 hours, with noticeable after-effects lasting for 1–3 hours, MBDB was initially developed as a non-psychedelic entactogen. MBDB tends to produce euphoria, psychedelia, and stimulation in comparison. Unlike MDMA, MBDB is not internationally scheduled under the United Nations Convention on Psychotropic Substances, the thirty-second meeting of the WHO Expert Committee on Drug Dependence evaluated MBDB and recommended against scheduling. There have been no reports of adverse or toxic effects of MBDB in humans, law enforcement data on illicit trafficking of MBDB in Europe suggest that its availability and abuse may now be declining after reaching a peak during the latter half of the 1990s. For these reasons, the Committee did not consider the abuse liability of MBDB would constitute a significant risk to public health, scheduling of MBDB was therefore not recommended. MBDB is considered a Schedule 9 Prohibited substance in Australia under the Poisons Standard, ethylbenzodioxolylbutanamine Methylbenzodioxolylpentanamine UWA-101 PiHKAL entry METHYL-J entry in PiHKAL • info Erowid MBDB vault
24.
Alexander Shulgin
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Alexander Theodore Sasha Shulgin was an American medicinal chemist, biochemist, organic chemist, pharmacologist, psychopharmacologist, and author. In 1991 and 1997, he and his wife Ann Shulgin authored the books PIHKAL and TIHKAL, Shulgin performed seminal work into the descriptive synthesis of many of these compounds. Some of Shulgins noteworthy discoveries include compounds of the 2C* family, due in part to Shulgins extensive work in the field of psychedelic research and the rational drug design of psychedelic drugs, he has since been dubbed the godfather of psychedelics. Shulgin was born in Berkeley, California to Theodore Stevens Shulgin and his father was born in Russia, while his mother was born in Illinois. Both Theodore and Henrietta were public school teachers in Alameda County, Shulgin began studying organic chemistry as a Harvard University scholarship student at the age of 16. In 1943 he dropped out of school to join the U. S. Navy, while serving on USS Pope in the Navy during World War II, Shulgin was given a glass of orange juice by a nurse prior to surgery for a thumb infection. Shulgin drank the juice and, assuming that the powder at the bottom of the glass was a sedative, upon waking he learned that the powder was undissolved sugar. The experience made him aware of the influence of placebos over the human mind, after serving in the Navy, Shulgin returned to Berkeley, California, and in 1954 earned his Ph. D. in biochemistry from the University of California, Berkeley. Through the late 1950s Shulgin completed post-doctoral work in the fields of psychiatry and pharmacology at University of California, after working at Bio-Rad Laboratories as a research director for a brief period, he began work at Dow Chemical Company as a senior research chemist. At this time he had a series of experiences that helped to shape his further goals and research. I first explored mescaline in the late 50s, I learned there was a great deal inside me. I understood that our universe is contained in the mind. We may choose not to access to it, we may even deny its existence, but it is indeed there inside us. Shulgins professional activities continued to lean in the direction of psychopharmacology, but during this period he was unable to do much independent research. His opportunity for further research came in 1961 after his development of Zectran, the first biodegradable pesticide, in his book PIHKAL, Shulgin limits his pesticide days at Dow Chemical to one sentence in 978 pages. Dow Chemical Company, in return for Zectrans valuable patent, gave Shulgin great freedom, during this time, he created and patented drugs when Dow asked, and published findings on other drugs in journals such as Nature and the Journal of Organic Chemistry. Eventually, Dow Chemical requested that he no longer use their name on his publications, in late 1966, Shulgin left Dow in order to pursue his own interests. He first spent two years studying neurology at the University of California, San Francisco School of Medicine, leaving to work on a consulting project and he set up a home-based lab on his property, known as the Farm, and became a private consultant
25.
EDMA
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3, 4-Ethylenedioxy-N-methylamphetamine is an entactogen drug of the amphetamine class. It is an analogue of MDMA where the ring has been replaced by an ethylenedioxy ring. EDMA was first synthesized by Alexander Shulgin, in his book PiHKAL, the dosage is listed as 150–250 mg, and the duration listed as 3–5 hours. According to Shulgin, EDMA produces a bare threshold consisting of paresthesia, nystagmus, scientific research has demonstrated that EDMA acts as a non-neurotoxic serotonin releasing agent with moderately diminished potency relative to MDMA, and with negligible effects on dopamine release. Based on Shulgins reports of essential inactivity at 150–250 mg, it may be active at higher doses. EDMA entry in PiHKAL MDMC entry in PiHKAL • info
26.
Structural analog
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It can differ in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. A structural analog can be imagined to be formed, at least theoretically, despite a high chemical similarity, structural analogs are not necessarily functional analogs and can have very different physical, chemical, biochemical, or pharmacological properties. Chemical analogues of illegal drugs are developed and sold in order to circumvent laws, such substances are often called designer drugs. Because of this, the United States passed the Federal Analog Act in 1986 and this bill banned the production of any chemical analogue of a Schedule I or Schedule II substance that has substantially similar pharmacological effects, with the intent of human consumption
27.
Pharmacokinetics
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Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. The substances of interest include any chemical xenobiotic such as, pharmaceutical drugs, pesticides, food additives, cosmetic ingredients, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is eliminated from the body. Pharmacokinetics is the study of how an organism affects a drug, both together influence dosing, benefit, and adverse effects, as seen in PK/PD models. Pharmacokinetic properties of chemicals are affected by the route of administration and these may affect the absorption rate. Models have been developed to simplify conceptualization of the processes that take place in the interaction between an organism and a chemical substance. The various compartments that the model is divided into are commonly referred to as the ADME scheme, absorption - the process of a substance entering the blood circulation. Distribution - the dispersion or dissemination of substances throughout the fluids, metabolism – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites. Excretion - the removal of the substances from the body, in rare cases, some drugs irreversibly accumulate in body tissue. The two phases of metabolism and excretion can also be grouped together under the title elimination, the study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. All these concepts can be represented through mathematical formulas that have a graphical representation. The model outputs for a drug can be used in industry or in the application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals, in practice, it is generally considered that steady state is reached when a time of 4 to 5 times the half-life for a drug after regular dosing is started. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph, compartmental methods estimate the concentration-time graph using kinetic models. Noncompartmental methods are more versatile in that they do not assume any specific compartmental model. The final outcome of the transformations that a drug undergoes in an organism, a number of functional models have been developed in order to simplify the study of pharmacokinetics. These models are based on a consideration of an organism as a number of related compartments, the simplest idea is to think of an organism as only one homogenous compartment. However, these models do not always reflect the real situation within an organism
28.
2-Aminotetralin
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2-Aminotetralin, also known as 1,2,3, 4-tetrahydronaphthalen-2-amine, is a stimulant drug with a chemical structure consisting of a tetralin group combined with an amine. 2-AT is a analogue of phenylisobutylamine and fully substitutes for d-amphetamine in rat discrimination tests. It has been shown to inhibit the reuptake of serotonin and norepinephrine and it is also likely to act on dopamine on account of its full substitution of d-amphetamine in rodent studies. A number of derivatives of 2-aminotetralin exist, including, 2-Aminodilin 2-Aminoindane
29.
PubMed Identifier
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PubMed is a free search engine accessing primarily the MEDLINE database of references and abstracts on life sciences and biomedical topics. The United States National Library of Medicine at the National Institutes of Health maintains the database as part of the Entrez system of information retrieval, from 1971 to 1997, MEDLINE online access to the MEDLARS Online computerized database primarily had been through institutional facilities, such as university libraries. PubMed, first released in January 1996, ushered in the era of private, free, home-, the PubMed system was offered free to the public in June 1997, when MEDLINE searches via the Web were demonstrated, in a ceremony, by Vice President Al Gore. Information about the journals indexed in MEDLINE, and available through PubMed, is found in the NLM Catalog. As of 5 January 2017, PubMed has more than 26.8 million records going back to 1966, selectively to the year 1865, and very selectively to 1809, about 500,000 new records are added each year. As of the date,13.1 million of PubMeds records are listed with their abstracts. In 2016, NLM changed the system so that publishers will be able to directly correct typos. Simple searches on PubMed can be carried out by entering key aspects of a subject into PubMeds search window, when a journal article is indexed, numerous article parameters are extracted and stored as structured information. Such parameters are, Article Type, Secondary identifiers, Language, publication type parameter enables many special features. As these clinical girish can generate small sets of robust studies with considerable precision, since July 2005, the MEDLINE article indexing process extracts important identifiers from the article abstract and puts those in a field called Secondary Identifier. The secondary identifier field is to store numbers to various databases of molecular sequence data, gene expression or chemical compounds. For clinical trials, PubMed extracts trial IDs for the two largest trial registries, ClinicalTrials. gov and the International Standard Randomized Controlled Trial Number Register, a reference which is judged particularly relevant can be marked and related articles can be identified. If relevant, several studies can be selected and related articles to all of them can be generated using the Find related data option, the related articles are then listed in order of relatedness. To create these lists of related articles, PubMed compares words from the title and abstract of each citation, as well as the MeSH headings assigned, using a powerful word-weighted algorithm. The related articles function has been judged to be so precise that some researchers suggest it can be used instead of a full search, a strong feature of PubMed is its ability to automatically link to MeSH terms and subheadings. Examples would be, bad breath links to halitosis, heart attack to myocardial infarction, where appropriate, these MeSH terms are automatically expanded, that is, include more specific terms. Terms like nursing are automatically linked to Nursing or Nursing and this important feature makes PubMed searches automatically more sensitive and avoids false-negative hits by compensating for the diversity of medical terminology. The My NCBI area can be accessed from any computer with web-access, an earlier version of My NCBI was called PubMed Cubby
30.
International Standard Book Number
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The International Standard Book Number is a unique numeric commercial book identifier. An ISBN is assigned to each edition and variation of a book, for example, an e-book, a paperback and a hardcover edition of the same book would each have a different ISBN. The ISBN is 13 digits long if assigned on or after 1 January 2007, the method of assigning an ISBN is nation-based and varies from country to country, often depending on how large the publishing industry is within a country. The initial ISBN configuration of recognition was generated in 1967 based upon the 9-digit Standard Book Numbering created in 1966, the 10-digit ISBN format was developed by the International Organization for Standardization and was published in 1970 as international standard ISO2108. Occasionally, a book may appear without a printed ISBN if it is printed privately or the author does not follow the usual ISBN procedure, however, this can be rectified later. Another identifier, the International Standard Serial Number, identifies periodical publications such as magazines, the ISBN configuration of recognition was generated in 1967 in the United Kingdom by David Whitaker and in 1968 in the US by Emery Koltay. The 10-digit ISBN format was developed by the International Organization for Standardization and was published in 1970 as international standard ISO2108, the United Kingdom continued to use the 9-digit SBN code until 1974. The ISO on-line facility only refers back to 1978, an SBN may be converted to an ISBN by prefixing the digit 0. For example, the edition of Mr. J. G. Reeder Returns, published by Hodder in 1965, has SBN340013818 -340 indicating the publisher,01381 their serial number. This can be converted to ISBN 0-340-01381-8, the check digit does not need to be re-calculated, since 1 January 2007, ISBNs have contained 13 digits, a format that is compatible with Bookland European Article Number EAN-13s. An ISBN is assigned to each edition and variation of a book, for example, an ebook, a paperback, and a hardcover edition of the same book would each have a different ISBN. The ISBN is 13 digits long if assigned on or after 1 January 2007, a 13-digit ISBN can be separated into its parts, and when this is done it is customary to separate the parts with hyphens or spaces. Separating the parts of a 10-digit ISBN is also done with either hyphens or spaces, figuring out how to correctly separate a given ISBN number is complicated, because most of the parts do not use a fixed number of digits. ISBN issuance is country-specific, in that ISBNs are issued by the ISBN registration agency that is responsible for country or territory regardless of the publication language. Some ISBN registration agencies are based in national libraries or within ministries of culture, in other cases, the ISBN registration service is provided by organisations such as bibliographic data providers that are not government funded. In Canada, ISBNs are issued at no cost with the purpose of encouraging Canadian culture. In the United Kingdom, United States, and some countries, where the service is provided by non-government-funded organisations. Australia, ISBNs are issued by the library services agency Thorpe-Bowker
31.
Substituted phenethylamine
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The structural formula of any substituted phenethylamine contains a phenyl ring that is joined to an amino group via an ethyl sidechain. Hence, any substituted phenethylamine can be classified according to the substitution of hydrogen atoms on phenethylamines phenyl ring, sidechain, numerous endogenous compounds – including hormones, monoamine neurotransmitters, and many trace amines – are substituted phenethylamines. Several notable recreational drugs, such as MDMA, methamphetamine, all of the substituted amphetamines and substituted methylenedioxyphenethylamines are substituted phenethylamines as well. Substituted amphetamines Substituted methylenedioxyphenethylamines Substituted cathinones Substituted phenylmorpholines 2Cs and DOx Substituted tryptamines
32.
4-Chlorophenylisobutylamine
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4-Chlorophenylisobutylamine, also known as 4-chloro-α-ethylphenethylamine, is an entactogen and stimulant drug of the phenethylamine class. It is an analogue of para-chloroamphetamine where the alpha position methyl has been replaced with an ethyl group, though its dopaminergic activity is significantly attenuated compared to PCA, unlike the case of MBDB, it is not abolished, and is actually similar to that of MDMA. Relative to PCA, 4-CAB is also substantially less effective as a serotonergic neurotoxin, a single 10 mg/kg administration of PCA to rats produces an approximate 80% decrease in serotonin markers as observed 1 week later. In contrast,11 mg/kg and 22 mg/kg doses of 4-CAB result in only 20% and 50% decreases and this is once again similar to MDMA which causes a 40-60% reduction with a single 20 mg/kg dose
33.
4-Fluoroamphetamine
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4-Fluoroamphetamine, also known as para-fluoroamphetamine is a psychoactive research chemical of the phenethylamine and substituted amphetamine chemical classes. It produces stimulant and entactogenic effects, and is described subjectively as being between amphetamine and MDMA, as a recreational drug, 4-FA is sometimes sold along with related compounds such as 2-fluoroamphetamine and 4-fluoromethamphetamine. 4-FA is popular in the Netherlands where it is used for its specific effects rather than its legal status. The general course of effects involves primarily empathogenic effects for the first few hours, the dopamine reuptake inhibition produced by 4-FA is stronger than that of either 4-CA or 4-IA. 4-FA also produces less hyperthermia than similar compounds such as PMA, 3-MTA, common acute side effects are nausea, headaches, increased heart rate and insomnia. 4-FA reacts with reagent tests to give an array of colors which can be used to aid its identification. 4-Fluoroamphetamine is an agent and reuptake inhibitor of dopamine, serotonin. The respective EC50 values are 2.0 x 10−7 M,7.3 x 10−7 M, and 0.37 x 10−7 M, while the IC50 values are 7.7 x 10−7 M,68 x 10−7 M, and 4.2 x 10−7 M. Regarding the metabolic fate of 4-FA, the C-F bond at the 4-position on the phenyl ring likely resists deactivation in the liver by cytochrome P450 oxidase, 4-FA does not cause long-lasting depletion of brain serotonin, unlike its analogs 4-CA and 4-BA. This is thought to reflect the inability of the fluoro-compound to be metabolized in the way as the other haloamphetamines. Neurotoxicity does not increase down the series of para-halogenated amphetamine derivatives, for example, 4-iodoamphetamine is less toxic than is 4-chloroamphetamine. Hence, this property is not related to serotonin releasing potency as such and it is unclear where 4-methylamphetamine fits in on the neurotoxicity scale. Exceptions include 4-MTA, a para-substituted, non-neurotoxic amphetamine, the LD50 of 4-FA is 46 mg/kg. 4-FA has only involved in one death worldwide, where it was combined with amphetamine, methadone. As of October 2015, 4-FA is a substance in China. 4-FA is banned in the Czech Republic, as of April 1,2017 4-FA is a controlled substance in the Netherlands. 4-FA is also controlled in Belgium, UK, Germany, Israel, Slovakia, Chile, Brazil, Canada, Croatia, Sweden, USA, New Zealand, 2-Fluoroamphetamine 3-Fluoroamphetamine 4-Fluoromethamphetamine 4-Fluoromethcathinone para-Bromoamphetamine Erowid, 4-Fluoroamphetamine
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4-Fluoromethamphetamine
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4-Fluoromethamphetamine is a stimulant drug related to methamphetamine and 4-fluoroamphetamine. It has been reported to be sold on the market as a controlled substance analogue. It was first detected from legal highs sold in Japan in 2006 and it reduces the metabolism of methamphetamine, which has the effect of increasing its potency, duration and systemic toxicity while also reducing its cellular toxicity. As of October 2015 4-FMA is a substance in China. 4-FMA is considered a Schedule 9 substance in Australia under the Poisons Standard
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4-Methylthioamphetamine
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4-Methylthioamphetamine is a designer drug developed in the 1990s by a team led by David E. Nichols at Purdue University. It acts as a highly selective serotonin releasing agent in animals. It is distantly related to several other SSRAs, including MMAI, MDAI, 4-MTA is a strong serotonin releaser similar to paramethoxyamphetamine, which can cause pronounced hyperthermia potentially resulting in organ failure and death. The subjective effects of 4-MTA include prolonged stimulation, which, in contrast to other amphetamines, is accompanied by little sense of euphoria. 4-MTA is also an MAO-A inhibitor, which may explain its tendency to cause adverse effects. It was also sold on the black market as MDMA during the late 1990s, mainly in the USA. 4-MTA is currently a Class A drug in the United Kingdom although it has suggested it be rescheduled as a Class B drug. It is also a controlled substance in Argentina
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4,4'-Dimethylaminorex
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4, 4-Dimethylaminorex, sometimes referred to by the street name Serotoni, is a psychostimulant and entactogen designer drug related to aminorex, 4-methylaminorex and pemoline. It was first detected in the Netherlands in December 2012, and has sold as a designer drug around Europe since mid-2013. 4, 4-DMAR had been linked to at least 31 deaths in Hungary, Poland, nineteen deaths linked to 4, 4-DMAR were reported in Northern Ireland in the same time period. The UK Home Office expressed intent to ban 4, 4-DMAR following advice from the Advisory Council on the Misuse of Drugs,4, 4-DMAR is an Anlage II controlled substance in Germany as of May 2015. Swedens public health agency suggested to classify 4, 4-DMAR as hazardous substance on November 10,2014,4, 4-DMAR is also banned in the Czech Republic
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Ariadne (psychedelic)
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Ariadne, 4C-D, α-Et-2C-D, BL-3912 or Dimoxamine is a lesser-known psychedelic drug. It is a homologue of 2C-D and DOM, Ariadne was first synthesized by Alexander Shulgin. In his book PiHKAL, Shulgin reported testing Ariadne up to a dose of 32 mg, very little data exists about the pharmacological properties, metabolism, and toxicity of Ariadne in humans apart from Shulgins limited testing
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Metaescaline
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Metaescaline, or 3, 4-dimethoxy-5-ethoxyphenethylamine, is a lesser-known psychedelic drug. It is an analog of mescaline, Metaescaline was first synthesized by Alexander Shulgin. In his book PiHKAL, the range is listed as 200–350 mg. Metaescaline produces mental insights, entactogenic, MDMA-like effects, and TOMSO-like activation, very little data exists about the pharmacological properties, metabolism, and toxicity of metaescaline. Substituted phenethylamine Phenethylamine Psychedelics, dissociatives and deliriants Metaescaline entry in PiHKAL Metaescaline entry in PiHKAL • info
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3-Methoxy-4-methylamphetamine
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3-Methoxy-4-methylamphetamine is an entactogen and psychedelic drug of the phenethylamine and amphetamine classes. It was first synthesized in 1970 and was encountered as a drug in Italy in the same decade. MMA was largely forgotten until being reassayed by David E. Nichols as a non-neurotoxic MDMA analogue in 1991, in animal studies, MMA fully substitutes for MDMA and MBDB, partially substitutes for LSD, and does not substitute for amphetamine. Additionally, it has shown to potently inhibit the reuptake of serotonin. These data appear to confer a profile of MMA as a serotonin releasing agent. At high doses, such as 120 mg, the effects are psychedelic
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Para-Methoxyamphetamine
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Para-Methoxyamphetamine, also known as 4-methoxyamphetamine, is a designer drug of the amphetamine class with serotonergic effects. PMA has been found in tablets touted as MDMA although its effects are different compared to those of MDMA. The consequences of such deception has often been hospitalizations and deaths among unwitting users, PMA has been associated with numerous adverse reactions including death. At high doses unpleasant effects such as nausea and vomiting, severe hyperthermia, while PMA alone may cause significant toxicity, the combination of PMA with MDMA has a synergistic effect that seems to be particularly hazardous. PMA overdose can be a medical emergency that may occur at only slightly above the usual recreational dose range. Characteristic symptoms are pronounced hyperthermia, tachycardia, and hypertension, along with agitation, confusion, PMA overdose also tends to cause hypoglycaemia and hyperkalaemia, which can help to distinguish it from MDMA overdose. Complications can sometimes include more serious symptoms such as rhabdomyolysis and cerebral hemorrhage, there is no specific antidote, so treatment is symptomatic, and usually includes both external cooling, and internal cooling via IV infusion of cooled saline. Benzodiazepines are used initially to control convulsions, with stronger anticonvulsants such as phenytoin or thiopental used if convulsions continue, blood pressure can be lowered either with a combination of alpha blockers and beta blockers, or with other drugs such as nifedipine or nitroprusside. Serotonin antagonists and dantrolene may be used as required, PMA acts as a selective serotonin releasing agent with weak effects on dopamine and norepinephrine transporters. However, relative to MDMA, it is less effective as a releaser of serotonin with properties more akin to a reuptake inhibitor in comparison. It evokes robust hyperthermia in rodents while producing only modest hyperactivity and serotonergic neurotoxicity, substantially lower than that caused by MDMA, and only at very high doses. Accordingly, it is not self-administered by rodents unlike amphetamine and MDMA, amphetamines, especially serotonergic analogues such as MDMA, are strongly contraindicated to take with MAOIs. Many people taking PMA try to get rid of the heat by taking off their clothes, taking cold showers or wrapping themselves in wet towels, PMA first came into circulation in the early 1970s, where it was used intentionally as a substitute for the hallucinogenic properties of LSD. It went by the names of Chicken Powder and Chicken Yellow and was found to be the cause of a number of drug overdose deaths in the United States. Between 1974 and the mid-1990s, there appear to have no known fatalities from PMA. Several deaths reported as MDMA-induced in Australia in the mid-1990s are now considered to have been caused by PMA, there have been a number of PMA-induced deaths around the world since then. In July 2013, seven deaths in Scotland were linked to tablets containing PMA that had been mis-sold as ecstasy, several deaths in Northern Ireland, Particularly East Belfast were also linked to Green Rolex pills during that month. In 2014,2015 and early 2016, PMA sold as ecstasy was attributed for more deaths in the United States, United Kingdom, Netherlands, the pills containing the drug were reported to be red triangular tablets with a Superman logo
