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Article ID: WMC004459 ISSN 2046-1690

Beta-phenylethylamine, a small molecule with a large impact

Peer review status: Yes

Corresponding Author: Ms. Meredith Irsfeld, Fargo, North Dakota State University - United States of America

Submitting Author: Dr. Birgit Pruess, Associate Professor, North Dakota State University, Fargo ND 58108, 58108 - United States of America

Other Authors: Mr. Matthew Spadafore, Fargo, North Dakota State University - United States of America

Previous Article Reference: http://www.webmedcentral.com/article_view/4409 Article ID: WMC004459 Article Type: Review articles Submitted on:12-Dec-2013, 07:13:25 PM GMT Published on: 13-Dec-2013, 06:22:50 AM GMT Article URL: http://www.webmedcentral.com/article_view/4459 Subject Categories:BIOCHEMISTRY Keywords:, , food spoilage How to cite the article:Irsfeld M, Spadafore M, Pruess B. Beta-phenylethylamine, a small molecule with a large impact. WebmedCentral BIOCHEMISTRY 2013;4(12):WMC004459 Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source(s) of Funding: 1R15AI089403 from NIH/NIAID

Competing Interests: The authors declare no competing interets.

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Beta-phenylethylamine, a small molecule with a large impact

Author(s): Irsfeld M, Spadafore M, Pruess B

Abstract functional relatives of biogenic , we present information on other trace amines and biogenic amines as appropriate. General information about PEA is summarized in Chapter I, including the During a screen of bacterial nutrients as inhibitors of chemical properties of PEA (1.1), its natural O157:H7 biofilm, the Prub research occurrence and biological synthesis (1.2), and its team made an intriguing observation: among 95 chemical synthesis (1.3). Chapter II describes PEA’s carbon and 95 sources tested, β functions as a neurotransmitter in three examples of -phenylethylamine (PEA) performed best at reducing psychological disorders: hyper attention deficit bacterial cell counts and biofilm amounts, when hyperactivity disorder (2.1), depression (2.2), and supplemented to liquid beef broth medium (Lynnes et (2.3). A comparison of PEA’s action to al., 2013a). This review article summarizes what is that of other trace and biogenic amines is provided in known about PEA. this Chapter (Illustration 3). Finally, Chapter III After introducing the chemistry of the molecule, this describes the role of PEA in food processing, starting study focuses on PEA as a neurotransmitter and then with its occurrence in fermented food and meat as a moves on to its role in food processing, before result of microbial (3.1), and followed by detailing the reduction of bacterial cell counts and its occurrence in as a result of thermal biofilm amounts. Comparisons to biogenic amines are processing (3.2). The article concludes with the presented. Briefly, PEA is a trace whose recently described use of PEA as a modulator of gene molecular differs from biogenic expression to reduce biofilm amounts and bacterial amines, such as or . Especially cell counts (3.3). low or high concentrations of PEA may be associated with specific psychological disorders. For those Review disorders that are characterized by low PEA levels ( e.g. attention deficit hyperactivity disorder), PEA has been suggested as a ‘safe’ alternative to , such General Information as or , which are 1.1 Chemical Properties of PEA accompanied by many undesirable side effects. PEA is known under a variety of names including β In food, PEA and other biogenic amines can be -phenylethylamine, β-, and detected as a result of microbial metabolism. As a phenylethylamine. According to the International Union consequence, these chemicals can be used as of Pure and Applied Chemistry (IUPAC), the proper indicators of bacterial contamination. Intriguingly, PEA name of PEA is 2-phenylethylamine. Its molecular can be found in chocolate, where it is a result of the formula is denoted by C8H11N. thermal processing of the CACAO. As a conclusion of The general information on and the chemical this brief review, we will present our own evidence of properties of PEA are summarized in Illustration 1. PEA as an inhibitor of biofilm formation and cell Briefly, PEA has a molecular weight of 121.17964 division through a modulation of gene expression. g/mol, a high solubility in ddH2O (Cashin, 1972; Introduction Shannon et al., 1982), and a short half-life (Shannon et al., 1982). These chemical characteristics impact PEA’s biological functions. In particular, the lack of a ß-phenylethylamine (PEA) is a small molecule that methyl group distinguishes PEA from its structural exhibits an array of intriguing and seemingly unrelated relative, amphetamine. functions. The purpose of this review is to summarize 1.2 Natural Occurrence and Biological Synthesis general information about PEA as well as detailing a of PEA selection of the functions, namely its role as a The occurrence of PEA and its derivatives has neurotransmitter and in food processing. Since PEA is previously been reviewed (Bentley, 2006). PEA can a member of the trace amines which are structural and be found in many algae (Guven et al., 2010), fungi and

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(Kim et al., 2012) as well as a variety of decreases the amount of water intake, it aids weight different plant species (Smith, 1977). PEA is the loss efforts (Hoffman et al., 2006). Altogether, PEA product of (Illustration appears to have a number of positive effects on 2A). human health without the risks of its structural Two proposed mechanisms for relatives. decarboxylation are a dependent 1.3 Chemical Synthesis of PEA reaction and a non-pyridoxal phosphate dependent Two different pathways that lead to the chemical reaction. The reactions differ in the starting residue; synthesis of PEA have been established in the 1940s the first reaction utilizes a pyridoxal-5-phosphate and and 1950s. First, PEA is produced by reduction of a the latter uses a pyruvoyl residue. The free amino nitrile into an amine (Robinson & Snyder, 1955). acids needed for this decarboxylation may be provided Specifically, is mixed with the by bacterial proteolysis (Shalaby, 1996). In several Raney-Nickel catalyst in a calorimeter bomb. The bacterial species, the decarboxylation is catalyzed by formation of secondary amines in this reaction is the decarboxylase, which also reduced by the addition of . The reaction converts tyrosine to another , occurs at 13.9 Mpa and 130oC under . The (Marcobal et al., 2012; Pessione et al., 2009). cooled down liquid is removed from the catalyst by Intriguingly, PEA synthesized by fungi and bacteria filtration. This procedure has a yield of 83 to 87%. can also be found in food products (Onal et al., 2013), A second, simpler way of producing PEA is to reduce where it serves as an indicator of food quality and w-nitrostyrene with lithium aluminum hydride in ether freshness. Such foods include the Korean natto (Kim (NYSTROM & BROWN, 1948) (Illustration 2B). The et al., 2012) and commercial eggs (Figueiredo et al., experimental procedure that employs the use of 2013). Another food that contains PEA is chocolate, lithium aluminum in reduction reactions follows the where it is not produced by bacteria, but during the mechanism used in a Grignard synthesis. thermal processing of cocoa (Granvogl et al., 2006). w-nitrostyrene is added to the previously prepared PEA can also be found in members of the family lithium aluminum hydride in ether while stirring. This Leguminosae, which is the second-largest family of results in an alcoholate precipitate, which thickens the seed plants and is comprised of trees, shrubs, vines, solution, requiring more ether to be added. Finally, herbs (such as clover), and vegetables (such as beans using acid hydrolysis, the metal alcoholate is and peas). The various different species found within decomposed and the product can be isolated and this family have been used as food, green manure, extracted from the ether. and for medicinal purposes (Sanchez-Blanco et al., 2012). Smith and coworkers hypothesized that plant Recent literature focuses on the biological synthesis of synthesized PEA may serve as a defense mechanism PEA, rather than the chemical one. against insects and foraging animals (Smith, 1977). 1-phenylethylamine can be synthesized by Escherichia coli overexpressing ω-transaminase PEA has also been found in the of humans and (Cardenas-Fernandez et al., 2012). Likewise, the PEA other mammals (Paterson et al., 1990; Philips et al., biosynthetic enzyme from Enterococcus faecium can 1978). This is attributed to the high solubility of PEA in be expressed in E. coli, which leads to large amounts plasma and its ability to cross the blood- barrier of L-phenylalanine and tyrosine decarboxylase activity (Oldendorf, 1971). Like its α-methylated derivative, (Marcobal et al., 2006). Intriguingly, PEA can serve as amphetamine, PEA has effects which lead to a substrate for the synthesis of other drugs, such as the release of so called biogenic amines, including sulfonamides that are being used as anti-microbials dopamine and serotonin (Bailey et al., 1987; Rothman (Rehman et al., 2012). & Baumann, 2006). Unlike amphetamine, PEA is rarely found in high concentrations in the human body, II. PEA as a Neurotransmitter due to its oxidative deamination to PEA is a member of the so-called trace amines by the enzyme B (MAO) (Yang & (reviewed by Premont et al., 2001). The expression Neff, 1973). Phenylacetic acid has an effect that is “trace amine” is used to refer to a group of amines that similar to the activity of the natural endorphins, an occur at much lower intra- and extra-cellular effect that is known as a “runner’s high”. concentrations than the chemically and functionally Due to its impact on the levels of several ‘feel good related biogenic amines and ’ (see above), PEA has recently gained epinephrine, , serotonin, dopamine, popularity as a nutritional supplement that is sold by and . The molecular mechanism of the trace numerous health stores to improve mood. Since it also amines involves binding to a novel G -coupled

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, called TAAR (trace amine-associated r observation that was paralleled by reduced PEA levels eceptor) (Borowsky et al., 2001; Bunzow et al., 2001), in ADHD individuals (Baker et al., 1991; Kusaga, the most studied of which, TAAR1, can be activated by 2002). In a consecutive study (Kusaga et al., 2002), the amphetamine as well (Borowsky et al., 2001). those of the children suffering with ADHD were treated The downstream events that follow the initial with methylphenidate, also known as Ritalin. Patients interaction of PEA and TAAR1 are not nearly as well whose symptoms improved in response to treatment understood as the receptors and their various ligands with methylphenidate had a significantly higher PEA themselves (Zucchi et al., 2006); it is however level than patients who did not experience such an believed that binding of PEA to TAAR1 results in an improvement in their condition (Kusaga et al., 2002). alteration of the functions, While this is encouraging, amphetamine and which leads to inhibition of the re-uptake of dopamine, methylphenidate based drugs demonstrate many serotonin, and norepinephrine (Xie & Miller, 2008). undesirable side effects, including mild headaches, Eventually, this will cause an increased concentration nausea, , and constipation. Overdose, of these neurotransmitters at the . A similar whether accidental or intentional, of any of the increase in the synaptic concentrations of dopamine amphetamine or methylphenidate drugs has been can be accomplished by blocking the dopamine associated with cardiovascular effects, which were transporter directly. Methylphenidate is an example of attributed to increased levels of extracellular dopamine, a class of drugs that can perform this blockage (Gatley norepinephrine, and serotonin (Spiller et al., 2013). et al., 1999). While the connection between stimulant drugs as a The chemical properties of the biogenic amines, trace treatment for ADHD and cardiovascular disease at this amines, and structurally related drugs are summarized time still appears controversial (Olfson et al., 2012), in Illustration 3. Illustration 4 is a graphic naturopathic professionals have started to recommend representation of the regulatory pathway from the PEA as a treatment for ADHD because of the trace amine PEA to the increased concentration of the assumed lack of side- and long-term effects. biogenic amines and neurotransmitters dopamine and 2.2 Depression serotonin. The effects of the drugs amphetamine and Depression is a very common, sometimes serious methylphenidate are included. Chapter II summarizes disease that affects a wide range of people. It is the impact of PEA on three psychological disorders, currently the second leading cause of disability in 15 to attention deficit hyperactivity disorder, depression, and 44 year olds. It is predicted that by the year 2030, schizophrenia. depression will be the primary cause of disability 2.1 Attention deficit hyperactivity disorder (World Health Association, 2008). While depression A common disease that an estimated 4-9% of young may be most common in the age group of 15 to 44, it children suffer from is attention deficit hyperactive can affect people of all ages and backgrounds. Among disorder (ADHD) (reviewed by Cormier, 2008). ADHD the characteristics of depression that were is a chronic childhood disorder, which is characterized summarized in a review article (Voinov et al., 2013), by a number of behavioral symptoms, including a women are 50% more likely to be affected by small attention span, increased frustration, depression than men and depression can shorten a distractibility, and often depression and anxiety person’s life by 25-30 years (Voinov et al., 2013). (American Psychiatric Association, 2000). ADHD often Most medication that is currently available is about is paralleled by co-existing psychiatric disorders and 80% effective for those suffering from depression patients can have problems that are attributable to (Voinov, 2013). Selective serotonin re-uptake ADHD way into their adulthood (Brassett-Harknett & inhibitors (SSRI) are the most popular Butler, 2007). Diagnosis of ADHD has traditionally prescribed worldwide (Artigas, 2013). SSRI function been done by analysis of the symptoms (American by blocking the and thus Psychiatric Association, 2000). However, this has led inhibiting the re-uptake of serotonin (Gutman & Owens, to misdiagnosis and, consequently, overmedication. 2006; Peremans et al., 2006). This will result in an Having a , in conjunction with a symptomatic increase of the synaptic concentration of serotonin diagnosis, could reduce such misdiagnosis and/or (see Illustration 4). However, SSRI act very slowly at overmedication. PEA was recently described as the the beginning of the treatment, while exhibiting a first such biomarker for ADHD (Scassellati et al., range of side effects upon long term use. These 2012). Specifically, the urinary output of PEA was long-term side effects include resistance (Chen lower in a population of children suffering from ADHD, et al., 2012), bone density loss (Haney et al., 2007), as compared to the healthy control population, an and some poorly understood effects on the offspring

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of mothers with maternal depression (Olivier et al., (3.2). Finally, research by our own lab has shown that 2013). Although scientists question the next step in PEA can be added to food intentionally to modulate this research (Artigas, 2013), it is clear that novel gene expression which will lead to phenotypes that are approaches to depression treatment must be less harmful to humans. Two such phenotypes are a developed. The study by Xie and Miller (Xie & Miller, reduction in biofilm amounts and reduced bacterial cell 2008), which had shown that PEA altered the counts of E. coli O157:H7 (3.3). serotonin transporter by interacting with TAAR, may 3.1 PEA and other amines in food as a result of point towards a safer alternative to SSRI treatment of microbial contamination depression in the form of PEA. Some foods that contain can release 2.3 Schizophrenia high levels of amines, including the trace amines PEA, Schizophrenia is a rare mental disorder that could tyramine, and , the potentially be related to PEA. About 1% of the world’s histamine, and the and population is affected by schizophrenia, which is (Shalaby, 1996). Such amines are formed characterized by problematic thinking and perception by bacteria of the genera , , (Rossler et al., 2005). Typically, schizophrenia starts , and that contain around adolescence and will stay with the patients for amino acid decarboxylases, which remove an α the rest of their lives, though life expectancy can be -carboxyl group from the respective amino acid largely reduced due to suicide. An additional (Giraffa, 2003; Shalaby, 1996). complication is community attitude because many This increased concentration of amines is due to people perceive schizophrenic patients as potentially bacterial metabolic processes and is commonly dangerous (Stuart & Arboleda-Florez, 2001). associated with foods and food products made There are different ideas on how one develops through the process of fermentation (Bunkova et al., schizophrenia. One hypothesis proposes that 2013). A good example of this is the “cheese dopamine contributes to the development of reaction”, which refers to high levels of tyramine as a schizophrenia (Howes & Kapur, 2009). In agreement result of elevated levels of tyrosine in cheese that has with this hypothesis, patients suffering from had increased storage times at temperatures higher schizophrenia are hyper-sensitive to drugs (e.g. than recommended by the producer. As mentioned methylphenidate) that block the dopamine receptor earlier (Chapter 1.2), PEA can be a by-product of the (Lieberman et al., 1987). A new perspective is given tyrosine decarboxylase reaction because the same by the TAAR1 receptor (Illustration 4). TAAR1 enzyme that is capable of converting tyrosine to activation improves the symptoms that are associated tyramine can also metabolize phenylalanine to PEA with both schizophrenia and depression (in rodent and (Marcobal et al., 2012). In individuals taking primate models), without causing the range of monoamine oxidase inhibiting drugs, the ‘cheese negative effects that result from direct blockage of the reaction’ can result in a hypertensive crisis (Boulton et dopamine receptor (Revel et al., 2013). al., 1970; Da et al., 1988; Deftereos et al., 2012). Among other factors that may contribute to A second group of food or food product that contains schizophrenia are inflammatory cytokines (Zakharyan elevated levels of amines is meat and/or fish (Kulawik & Boyajyan, 2013) and phospholipase (Koh, 2013) . et al., 2013; Li et al., 2012; Liu et al., 2013), where Altogether, schizophrenia may be the most complex of amine production is part of the food spoilage reaction the psychological disorders discussed in this study and can be used as an indicator of food freshness and and it is quite apparent that many factors contribute to quality. Specifically, bacteria from the families its development. Enterobacteriaceae and Pseudomonadaceae can III. PEA and other Amines in Food produce cadaverine and putrescine in spoiled turkey meat. Fraqueza and coworkers suggested to use PEA is connected to food processing in several, tyramine, putrescine, and cadaverin to quantify meat seemingly unrelated ways. First, PEA and other freshness (Fraqueza et al., 2012). In vegetables, high amines can be found in food as a result of the levels of tyramine were only seen in brine, unless the metabolic activity of bacteria (3.1). As a consequence vegetables were contaminated prior to processing or of this, PEA can be used as a biomarker for the temperature and storage time were extreme contamination of food by the respective bacteria. A (Moret et al., 2005). second process which does not involve bacterial metabolism can lead to the production of PEA in Since elevated levels of amines are usually an chocolate through the thermal processing of cocoa indicator of food spoilage, it is possible to use

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detection of amines as an indicator of food freshness. In Chapter 3.1, we discussed contamination and food One such technique is thin-layer chromatography to spoilage by bacteria. One such initially contaminated separate and identify amounts of tyramine and PEA food can cross-contaminate additional food products (Garcia-Moruno et al., 2005). through the food processing chain because of the 3.2 PEA in chocolate as a result of thermal bacteria’s ability to attach to food contact surfaces and processing form biofilm (Giaouris et al., 2013). The connection between “food and mood” was Recent research advances that are aimed at the recognized long time ago (Ottley, 2000). In particular, prevention of biofilm include the manipulation of the chocolate craving has been the focus of intense bacteria’s signal transduction pathways, including research (Durkin et al., 2012; Hormes & Timko, 2011; quorum sensing (Bassler, 2010) and two-component Werthmann et al., 2013). Lately, the combination of signaling (Lynnes et al., 2013b). One such chocolate with coffee has been proposed as “a novel environmental signal that bacteria can respond to is elixir for a long and happy life” (Dal Moro, 2013). PEA, whose signal transduction pathway may include Besides a number of other beneficial substances (e.g. the flagellar and global regulator complex FlhD/FlhC antioxidants), chocolate also contains trace amounts (Stevenson et al., 2013). A reduction in flagella of PEA (Ziegleder et al., 1992), a result of the thermal synthesis would be expected to inhibit the first phase processing and fermentation of cocoa (Granvogl et al., of biofilm formation, reversible attachment. In our own 2006). Since we mentioned earlier that PEA is research lab (Lynnes et al., 2013a), PEA was the most promoted to aid , one may conclude that if inhibitory of the 95 carbon and 95 nitrogen sources a person eats enough chocolate they will lose weight! screened for their effect on E. coli O157:H7 growth, Careful readers, please note: in a study that attempted bacterial cell counts, and biofilm amounts. In liquid to determine the concentration of PEA in chocolate, beef broth medium, PEA reduced biofilm amounts. the detection limit for PEA was 3 mg/kg of chocolate Intriguingly, bacterial cell counts were reduced at the and the concentration of PEA in their chocolate same time and with a similar inhibitory concentration. samples was below this limit (Pastore et al., 2005). In In contrast, the effect of PEA on bacterial growth, as contrast, the recommendation for PEA as a nutritional measured by the optical density of the culture, was supplement is currently 500 mg/day (for an example, affected only at a much higher concentration of PEA. please, see http://www.bodybuilding warehouse.com). In a final experiment, bacterial cell counts of E. coli This means that the concentration of PEA in chocolate O157:H7 were determined from beef meat pieces that is not high enough to induce weight loss, so eating were treated with different dilutions of PEA and chocolate will still lead to weight gain. subsequently inoculated with the bacteria; this resulted in a 90% reduction of bacterial cell counts when the One interesting controversy around chocolate and beef was treated with a concentration of PEA at 150 PEA is the question of whether chocolate can cause mg/ml. We were unable to determine biofilm formation migraine and whether this may be due to PEA. Of on the beef meat pieces. Altogether, this study course, food in general can trigger migraine (Finocchi demonstrated how PEA could be used to alter gene & Sivori, 2012). Also, individual studies point towards expression in order to reduce biofilm formation and chocolate as one of those foods (Fukui et al., 2008), bacterial cell counts (Lynnes et al., 2013a). The but other studies are in contrast with these findings question arises whether it could be possible to (Marcus et al., 1997). The fact that other foods that integrate PEA into novel biomaterials that can then be contain PEA, tyramine, or histamine (e.g. cheese and used to coat food processing equipment to prevent wine) may also trigger migraine (Werthmann et al., biofilm formation on such equipment and cross 2013) raised the question whether dietary amines may contamination during the food processing chain. be responsible for this response. This question is justified, considering that PEA causes the release of Acknowledgement(s) nor-epinephrine into the synaptic space, which consequently constricts the aorta and the coronary arteries (Broadley et al., 2009). However, results The authors thank the NIH/NIAID for funding B.M.P. among various studies are inconclusive (Jansen et al., through grant 1R15AI089403. Dr. Shelley Horne 2003), and the connection between chocolate and (NDSU) and Jessica Ebert (NDSU) are thanked for migraines remains a mystery. critically reading the manuscript and helpful 3.3 PEA as a modulator of bacterial gene discussions. Laura Nessa (NDSU) is thanked for expression helpful discussions and valuable ideas.

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Illustrations Illustration 1

Table 1

Solvent independent properties Solvent dependent properties Reference

In ddH2O In In Plasma

Alternative phenylethylamine, NA NA NA http://pubchem.nc names β-phenylethylamine, bi.nlm.nih.gov 2-phenylethylamine, benzeneethanamine, phenethylamine, β-phenethylamine, 2-phenethylamine Molecular http://pubchem.nc C H N NA NA NA Formula 8 11 bi.nlm.nih.gov Molecular http://pubchem.nc 121.17964 g/mol NA NA NA weight bi.nlm.nih.gov Companies Forest Health, NA NA NA NA that sell Vitacost, Amazon, PEA Walmart Toxicity Mouse LD50 (oral) NA NA NA MSDS, TCI 400 mg/kg America High Low High MSDS, TCI Solubility NA solubility solubility solubility (Cashin, 1972), (Shannon et al., 1982) (Shannon et al., Half life NA NA NA ~5-10min 1982) WebmedCentral > Review articles Page 11 of 16 WMC004459 Downloaded from http://www.webmedcentral.com on 13-Dec-2013, 10:11:14 AM

Illustration 2

Figure

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Illustration 3

Properties and functions of biogenic amines, trace amines and structurally related drugs

I. Biogenic Amines Name Structure Synthesized Functions from: Dopamine L-Tyrosine CNS: regulates movement

Blood vessels:

Serotonin L- CNS: mood, sleep, memory, and learning

Gut: intestinal movement

Histamine CNS: sleep

Immune system: inflammatory response (allergy)

Epinephrine Tyrosine via CNS: response (fight or flight) () dopamine and nor-epinephrine Blood vessels: vasoconstriction

Nor-epinephrine Tyrosine via CNS: heart contractions (), (Nor-adrenaline) dopamine vascular tone ()

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II. Trace Amines Name Structure Synthesized Protein Targets from: ß-phenyl-ethylamin L-Phenylalanine TAAR1 e (PEA)

p-Tyramine L-Tyrosine TAAR1; dopamine receptor

Tryptamine L-Tryptophan 5-hydroxytryptamine receptor; NFκB1; Cytochrome P450

Octopamine Tyrosine via TAAR1 tyramine

III. Structurally related Drugs Name Structure Synthesized Function from: Amphetamine A stimulant of the that mimics the effects of dopamine, epinephrine, and norepinephrine.

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Methyl-phenidate Piperidine A stimulant of the central nervous derivative system that are used to treat attention deficit disorders and .

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Illustration 4

Fig 4

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