Misplaced Pages

#259740

109-439: Harper is a bank robber posing as a traveling salesman. He arrives in the town of Bradenville, soon to be joined by sadistic benzedrine addict Dill and bookish Chapman. Boyd Fairchild is the manager of the local copper mine who is troubled by his philandering wife. He considers an affair with nurse Linda Sherman, although he truly loves his wife. His associate Shelley Martin has a happy home life although his son believes that he

218-486: A bunch of grapes . This acid, when naturally produced in grapes, is only the right-handed version of the molecule, better known as tartaric acid . In many Germanic languages racemic acid is called “grape acid” e.g. German traubensäure and Swedish druvsyra . Carl von Linné gave red elderberry the scientific name Sambucus racemosa as the Swedish name, druvfläder , means 'grape elder', so called because its berries grow in

327-438: A chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. The first known racemic mixture was racemic acid , which Louis Pasteur found to be a mixture of the two enantiomeric isomers of tartaric acid . He manually separated the crystals of a mixture, starting from an aqueous solution of the sodium ammonium salt of racemate tartaric acid. Pasteur benefited from

436-624: A dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs . The effects of amphetamine on gene regulation are both dose- and route-dependent. Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor. This suggests that medical use of amphetamine does not significantly affect gene regulation. As of December 2019, there

545-469: A vasovagal response , Raynaud's phenomenon (reduced blood flow to the hands and feet), and tachycardia (increased heart rate). Sexual side effects in males may include erectile dysfunction , frequent erections, or prolonged erections . Gastrointestinal side effects may include abdominal pain , constipation , diarrhea , and nausea . Other potential physical side effects include appetite loss , blurred vision , dry mouth , excessive grinding of

654-585: A 2008 article, the Village Voice called the film "the reigning king of Southwestern noir." The New York Press said: " Violent Saturday seems rooted in tradition, but as an exciting pulp story with a profound center, it manages to break all the rules." George Robinson of Cine-Journal wrote, "With the possible exception of The Narrow Margin , this is Richard Fleischer's best film ... Great, nasty fun." Michael Sragow of The New Yorker said, "Packed with twists and surprises. Marvin proves most unsettling as

763-510: A chemical reaction that makes a chiral product will always yield a racemate. That can make the synthesis of a racemate cheaper and easier than making the pure enantiomer, because it does not require special conditions. This fact also leads to the question of how biological homochirality evolved on what is presumed to be a racemic primordial earth. The reagents of, and the reactions that produce, racemic mixtures are said to be "not stereospecific " or "not stereoselective ", for their indecision in

872-584: A day, which is roughly 100 times the maximum daily therapeutic dose. Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma . In 2013, overdose on amphetamine, methamphetamine, and other compounds implicated in an " amphetamine use disorder " resulted in an estimated 3,788 deaths worldwide ( 3,425–4,145  deaths, 95% confidence ). In rodents and primates, sufficiently high doses of amphetamine cause dopaminergic neurotoxicity , or damage to dopamine neurons, which

981-461: A fuel substrate. Dextroamphetamine also activates TAAR1 in peripheral organs along the gastrointestinal tract that are involved in the regulation of food intake and body weight. Together, these actions confer an anorexigenic effect that promotes satiety in response to feeding and may decrease binge eating as a secondary effect. Medical reviews of randomized controlled trials have demonstrated that lisdexamfetamine, at doses between 50-70 mg,

1090-404: A grape-like cluster. A racemic mixture is denoted by the prefix (±)- or dl- (for sugars the prefix dl - may be used), indicating an equal (1:1) mixture of dextro and levo isomers. Also the prefix rac- (or racem- ) or the symbols RS and SR (all in italic letters) are used. If the ratio is not 1:1 (or is not known), the prefix (+)/(−) , d/l - or d/l- (with a slash)

1199-627: A greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin. Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the REM sleep cycle and function as "REM-off" cells, with amphetamine's effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses. The American Academy of Sleep Medicine (AASM) 2021 clinical practice guideline conditionally recommends dextroamphetamine for

SECTION 10

#1732869106260

1308-450: A hard guy who's always snorting from an inhaler (it's psychosomatic: he once had a wife with a perpetual cold). Mature, with his stricken manliness, reminds you of why James Agee thought he would be perfect as Diomed in Troilus and Cressida ." Benzedrine Amphetamine (contracted from a lpha - m ethyl ph en et hyl amine ) is a central nervous system (CNS) stimulant that

1417-411: A higher cost in cases where the use requires specifically one isomer (e.g., for a stereospecific reagent); compare omeprazole and esomeprazole . Moving from a racemic drug to a chiral specific drug may be done for a better safety profile or an improved therapeutic index. This process is called chiral switching and the resulting enantiopure drug is called a chiral switch . As examples, esomeprazole

1526-481: A more favorable pharmacokinetic profile and easy crushability (especially tablets). Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels. Chronic overuse of dextroamphetamine can lead to severe drug dependence , resulting in withdrawal symptoms when drug use stops. According to the International Programme on Chemical Safety (IPCS) and

1635-461: A nine-month randomized controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5  IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity. Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces

1744-450: A particular stereoisomerism . A frequent scenario is that of a planar species (such as an sp carbon atom or a carbocation intermediate) acting as an electrophile. The nucleophile will have a 50% probability of 'hitting' either of the two sides of the planar grouping, thus producing a racemic mixture: Some drug molecules are chiral, and the enantiomers have different effects on biological entities. They can be sold as one enantiomer or as

1853-414: A preference for spending time in places where they have previously used amphetamine. Addiction is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses; in fact, lifetime stimulant therapy for ADHD that begins during childhood reduces the risk of developing substance use disorders as an adult. Pathological overactivation of

1962-724: A pronounced gene-related phenotype ) in the D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient for many of the neural adaptations and regulates multiple behavioral effects (e.g., reward sensitization and escalating drug self-administration ) involved in addiction. Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression. It has been implicated in addictions to alcohol , cannabinoids , cocaine , methylphenidate , nicotine , opioids , phencyclidine , propofol , and substituted amphetamines , among others. ΔJunD ,

2071-406: A racemate; three of which H. W. B. Roozeboom had distinguished by 1899: The separation of a racemate into its components, the individual enantiomers, is called a chiral resolution . Various methods exist for this separation, including crystallization, chromatography , and the use of various reagents. Without a chiral influence (for example a chiral catalyst , solvent or starting material),

2180-478: A racemic mixture. Examples include thalidomide , ibuprofen , cetirizine and salbutamol . A well known drug that has different effects depending on its ratio of enantiomers is amphetamine . Adderall is an unequal mixture of both amphetamine enantiomers. A single Adderall dose combines the neutral sulfate salts of dextroamphetamine and amphetamine, with the dextro isomer of amphetamine saccharate and D/L-amphetamine aspartate monohydrate. The original Benzedrine

2289-410: A reserve capacity that is normally off-limits. At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature . Amphetamine, specifically the more dopaminergic dextrorotatory enantiomer ( dextroamphetamine ),

SECTION 20

#1732869106260

2398-515: A reward and motivation), positive reinforcement and positively-valenced emotions, particularly ones involving pleasure . Large recreational doses of dextroamphetamine may produce symptoms of dextroamphetamine overdose . Recreational users sometimes open dexedrine capsules and crush the contents in order to insufflate (snort) it or subsequently dissolve it in water and inject it. Immediate-release formulations have higher potential for abuse via insufflation (snorting) or intravenous injection due to

2507-457: A specific chemical, the racemic free base , which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer , and recreationally as an aphrodisiac and euphoriant . It

2616-605: A stimulant psychosis that may involve a variety of symptoms, such as delusions and paranoia. A Cochrane review on treatment for amphetamine, dextroamphetamine, and methamphetamine psychosis states that about 5–15% of users fail to recover completely. According to the same review, there is at least one trial that shows antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis rarely arises from therapeutic use. Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine,

2725-509: A task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. 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. Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs. However, high amphetamine doses that are above

2834-564: A time-limited withdrawal syndrome that occurs within 24 hours of their last dose." This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in roughly 88% of cases, and persist for 3–4  weeks with a marked "crash" phase occurring during the first week. Amphetamine withdrawal symptoms can include anxiety, drug craving , depressed mood , fatigue , increased appetite , increased movement or decreased movement , lack of motivation, sleeplessness or sleepiness, and lucid dreams . The review indicated that

2943-510: A transcription factor, and G9a , a histone methyltransferase enzyme, both oppose the function of ΔFosB and inhibit increases in its expression. Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB). Similarly, accumbal G9a hyperexpression results in markedly increased histone 3 lysine residue 9 dimethylation ( H3K9me2 ) and blocks

3052-432: Is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use. 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

3161-416: Is a chiral switch of (±)-omeprazole and levocetirizine is a chiral switch of (±)-cetirizine. While often only one enantiomer of the drug may be active, there are cases in which the other enantiomer is harmful, like salbutamol and thalidomide . The (R) enantiomer of thalidomide is effective against morning sickness, while the (S) enantiomer is teratogenic, causing birth defects. Since the drug racemizes,

3270-478: Is a coward because he did not serve in World War II. Harry Reeves, the manager of the local bank, is a peeping tom, and librarian Elsie Braden resorts to larceny to escape her debts. As the bank robbers execute their plan to rob the bank, Fairchild's wife is slain and Reeves is wounded in a gunfight. Martin is held hostage on a farm with an Amish family. With the help of the family's pacifist father, he defeats

3379-454: Is a serious risk with heavy recreational amphetamine use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., hallucinations , delusions and paranoia ) 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

Violent Saturday - Misplaced Pages Continue

3488-424: Is also used recreationally as a euphoriant and aphrodisiac, and like other amphetamines ; is used as a club drug for its energetic and euphoric high. Dextroamphetamine (d-amphetamine) is considered to have a high potential for misuse in a recreational manner since individuals typically report feeling euphoric , more alert, and more energetic after taking the drug. A notable part of the 1960s mod subculture in

3597-472: Is characterized by dopamine terminal degeneration and reduced transporter and receptor function. There is no evidence that amphetamine is directly neurotoxic in humans. However, large doses of amphetamine may indirectly cause dopaminergic neurotoxicity as a result of hyperpyrexia , the excessive formation of reactive oxygen species , and increased autoxidation of dopamine. Animal models of neurotoxicity from high-dose amphetamine exposure indicate that

3706-402: Is characterized by recurrent and persistent episodes of compulsive binge eating. These episodes are often accompanied by marked distress and a feeling of loss of control over eating. The pathophysiology of BED is not fully understood, but it is believed to involve dysfunctional dopaminergic reward circuitry along the cortico-striatal-thalamic-cortical loop . As of July 2024, lisdexamfetamine

3815-412: Is dangerous. Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants . Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively. Zinc supplementation may reduce

3924-507: Is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes across 9 categories of outcomes related to academics, antisocial behavior , driving, non-medicinal drug use, obesity, occupation, self-esteem , service use (i.e., academic, occupational, health, financial, and legal services), and social function. One review highlighted

4033-421: Is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system); however, amphetamine may increase motility when the smooth muscle of the tract is relaxed. Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids . FDA-commissioned studies from 2011 indicate that in children, young adults, and adults there

4142-458: Is known to produce abnormal dopamine system development or nerve damage, but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth. Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of

4251-601: Is known to strongly induce cocaine- and amphetamine-regulated transcript (CART) gene expression , a neuropeptide involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival in vitro . The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique G i /G o -coupled GPCR . Amphetamine also inhibits monoamine oxidases at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines. In humans,

4360-779: Is no association between serious adverse cardiovascular events ( sudden death , heart attack , and stroke ) and the medical use of amphetamine or other ADHD stimulants. However, amphetamine pharmaceuticals are contraindicated in individuals with cardiovascular disease . At normal therapeutic doses, the most common psychological side effects of amphetamine include increased alertness , apprehension, concentration , initiative, self-confidence and sociability, mood swings ( elated mood followed by mildly depressed mood ), insomnia or wakefulness , and decreased sense of fatigue. Less common side effects include anxiety , change in libido , grandiosity , irritability , repetitive or obsessive behaviors, and restlessness; these effects depend on

4469-491: Is no effective pharmacotherapy for amphetamine addiction. Reviews from 2015 and 2016 indicated that TAAR1 -selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; however, as of February 2016, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs . Amphetamine addiction is largely mediated through increased activation of dopamine receptors and co-localized NMDA receptors in

Violent Saturday - Misplaced Pages Continue

4578-455: Is not an effective monotherapy for amphetamine addiction. A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction; it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. There was low- to moderate-strength evidence of no benefit for most of

4687-466: Is safe and effective for the treatment of moderate-to-severe BED in adults. These reviews suggest that lisdexamfetamine is persistently effective at treating BED and is associated with significant reductions in the number of binge eating days and binge eating episodes per week. Furthermore, a meta-analytic systematic review highlighted an open-label, 12-month extension safety and tolerability study that reported lisdexamfetamine remained effective at reducing

4796-586: Is sufficiently overexpressed, it begins to increase the severity of addictive behavior (i.e., compulsive drug-seeking) with further increases in its expression. While there are currently no effective drugs for treating amphetamine addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction. Exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction. Chronic use of amphetamine at excessive doses causes alterations in gene expression in

4905-478: Is the only USFDA - and TGA -approved pharmacotherapy for BED. Evidence suggests that lisdexamfetamine's treatment efficacy in BED is underpinned at least in part by a psychopathological overlap between BED and ADHD, with the latter conceptualized as a cognitive control disorder that also benefits from treatment with lisdexamfetamine. Lisdexamfetamine's therapeutic effects for BED primarily involve direct action in

5014-405: Is thought to phosphorylate SERT via TAAR1 . Like dopamine, amphetamine has low, micromolar affinity at the human 5-HT1A receptor . Acute amphetamine administration in humans increases endogenous opioid release in several brain structures in the reward system . Extracellular levels of glutamate , the primary excitatory neurotransmitter in the brain, have been shown to increase in

5123-431: Is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy , and obesity ; it is also used to treat binge eating disorder in the form of its inactive prodrug lisdexamfetamine . Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu , and then as a drug in the late 1920s. It exists as two enantiomers : levoamphetamine and dextroamphetamine . Amphetamine properly refers to

5232-492: Is used instead. The usage of d and l is discouraged by IUPAC . A racemate is optically inactive ( achiral ), meaning that such materials do not rotate the polarization of plane- polarized light. Although the two enantiomers rotate plane-polarized light in opposite directions, the rotations cancel each other out because they are present in equal amounts of negative (-) counterclockwise ( levorotatory ) and positive (+) clockwise ( dextrorotatory ) enantiomers. In contrast to

5341-430: Is usually not noticeable, but when respiration is already compromised, it may be evident. Amphetamine also induces contraction in the urinary bladder sphincter , the muscle which controls urination, which can result in difficulty urinating. This effect can be useful in treating bed wetting and loss of bladder control . The effects of amphetamine on the gastrointestinal tract are unpredictable. If intestinal activity

5450-479: The central nervous system after conversion to its pharmacologically active metabolite, dextroamphetamine. Centrally, dextroamphetamine increases neurotransmitter activity of dopamine and norepinephrine in prefrontal cortical regions that regulate cognitive control of behavior. Similar to its therapeutic effect in ADHD, dextroamphetamine enhances cognitive control and may reduce impulsivity in patients with BED by enhancing

5559-428: The firing rate of dopamine neurons, preventing a hyper-dopaminergic state. Amphetamine is also a substrate for the presynaptic vesicular monoamine transporter , VMAT2 . Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from synaptic vesicles into the cytosol via dopamine efflux through VMAT2. Subsequently,

SECTION 50

#1732869106260

5668-531: The hypothalamic–pituitary–adrenal axis . In December 2017, the first study assessing the interaction between amphetamine and human carbonic anhydrase enzymes was published; of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the human brain , with low nanomolar through low micromolar activating effects. Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects; but, based upon

5777-523: The indirect activation of both dopamine D 1 receptor and α 2 -adrenergic receptor in the prefrontal cortex . A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation , in turn leading to improved recall of information . 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 (motivation to perform

5886-528: The lateral hypothalamus , leading to significantly reduced cerebrospinal orexin levels; this reduction is a diagnostic biomarker for type 1 narcolepsy. Lateral hypothalamic orexin neurons innervate every component of the ascending reticular activating system (ARAS), which includes noradrenergic , dopaminergic , histaminergic , and serotonergic nuclei that promote wakefulness . Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing monoamine neurotransmitter activity in

5995-508: The mesocorticolimbic projection , which arise through transcriptional and epigenetic mechanisms. The most important transcription factors that produce these alterations are Delta FBJ murine osteosarcoma viral oncogene homolog B ( ΔFosB ), cAMP response element binding protein ( CREB ), and nuclear factor-kappa B ( NF-κB ). ΔFosB is the most significant biomolecular mechanism in addiction because ΔFosB overexpression (i.e., an abnormally high level of gene expression which produces

6104-476: The mesolimbic pathway , a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens , plays a central role in amphetamine addiction. Individuals who frequently self-administer high doses of amphetamine have a high risk of developing an amphetamine addiction, since chronic use at high doses gradually increases the level of accumbal ΔFosB , a "molecular switch" and "master control protein" for addiction. Once nucleus accumbens ΔFosB

6213-413: The minimum effective dose of amphetamine when it is used for the treatment of ADHD. In general, there is no significant interaction when consuming amphetamine with food, but the pH of gastrointestinal content and urine affects the absorption and excretion of amphetamine, respectively. Acidic substances reduce the absorption of amphetamine and increase urinary excretion, and alkaline substances do

6322-504: The neurobiological effects of physical exercise suggests that daily aerobic exercise, especially endurance exercise (e.g., marathon running ), prevents the development of drug addiction and is an effective adjunct therapy (i.e., a supplemental treatment) for amphetamine addiction. Exercise leads to better treatment outcomes when used as an adjunct treatment, particularly for psychostimulant addictions. In particular, aerobic exercise decreases psychostimulant self-administration, reduces

6431-457: The phenethylamine class . 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 . As a member of the phenethylamine class, amphetamine is also chemically related to the naturally occurring trace amine neuromodulators, specifically phenethylamine and N -methylphenethylamine , both of which are produced within

6540-504: The prefrontal cortex . Stimulants 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. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans. The Cochrane reviews on

6649-603: The presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly. As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter. Upon entering the presynaptic neuron, amphetamine activates TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation . Phosphorylation by either protein kinase can result in DAT internalization ( non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces

SECTION 60

#1732869106260

6758-405: The reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D 2 (DRD2) density in the striatum . This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density. One review noted that exercise may also prevent the development of a drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of

6867-432: The reversal of dopamine transport through DAT (i.e., dopamine efflux ). Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent pathway, in turn producing dopamine efflux. Through direct activation of G protein-coupled inwardly-rectifying potassium channels , TAAR1 reduces

6976-422: The reward system . Drug tolerance develops rapidly in amphetamine abuse (i.e., recreational amphetamine use), so periods of extended abuse require increasingly larger doses of the drug in order to achieve the same effect. According to a Cochrane review on withdrawal in individuals who compulsively use amphetamine and methamphetamine, "when chronic heavy users abruptly discontinue amphetamine use, many report

7085-529: The ARAS. This includes noradrenergic neurons in the locus coeruleus , dopaminergic neurons in the ventral tegmental area , histaminergic neurons in the tuberomammillary nucleus , and serotonergic neurons in the dorsal raphe nucleus . Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines. In contrast, levoamphetamine may have

7194-1140: The U.S. Food and Drug Administration (FDA), amphetamine is contraindicated in people with a history of drug abuse , cardiovascular disease , severe agitation , or severe anxiety. It is also contraindicated in individuals with advanced arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism (excessive production of thyroid hormone), or moderate to severe hypertension . These agencies indicate that people who have experienced allergic reactions to other stimulants or who are taking monoamine oxidase inhibitors (MAOIs) should not take amphetamine, although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented. These agencies also state that anyone with anorexia nervosa , bipolar disorder , depression, hypertension, liver or kidney problems, mania , psychosis , Raynaud's phenomenon , seizures , thyroid problems, tics , or Tourette syndrome should monitor their symptoms while taking amphetamine. Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in

7303-485: The UK was recreational amphetamine use, which was used to fuel all-night dances at clubs like Manchester's Twisted Wheel . Newspaper reports described dancers emerging from clubs at 5 a.m. with dilated pupils. Mods used the drug for stimulation and alertness , which they viewed as different from the intoxication caused by alcohol and other drugs. Dr. Andrew Wilson argues that for a significant minority, "amphetamines symbolised

7412-527: The amount of amphetamine used is the primary factor in determining the likelihood and severity of adverse effects. Amphetamine products such as Adderall , Dexedrine, and their generic equivalents are currently approved by the U.S. FDA for long-term therapeutic use. Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes. Cardiovascular side effects can include hypertension or hypotension from

7521-477: The brain, such as the right caudate nucleus of the basal ganglia . 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 2 years have demonstrated treatment effectiveness and safety. Two reviews have indicated that long-term continuous stimulant therapy for ADHD

7630-506: The brain. The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine because of its effects on monoamine transporters . The reinforcing and motivational salience -promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the mesolimbic pathway . The euphoric and locomotor-stimulating effects of amphetamine are dependent upon

7739-421: The clinical use of carbonic anhydrase inhibitors , carbonic anhydrase activation in other tissues may be associated with adverse effects, such as ocular activation exacerbating glaucoma . Racemic mixture In chemistry , a racemic mixture or racemate ( / r eɪ ˈ s iː m eɪ t , r ə -, ˈ r æ s ɪ m eɪ t / ) is one that has equal amounts of left- and right-handed enantiomers of

7848-438: The cognitive processes responsible for overriding prepotent feeding responses that precede binge eating episodes. In addition, dextroamphetamine's actions outside of the central nervous system may also contribute to its treatment effects in BED. Peripherally, dextroamphetamine triggers lipolysis through noradrenergic signaling in adipose fat cells, leading to the release of triglycerides into blood plasma to be utilized as

7957-408: The crooks. In the aftermath, Martin becomes a hero to his son and Linda comforts Fairchild as he grieves for his wife. The film was based on the eponymous novel by William L. Heath , although the story's location was changed from Alabama to Arizona for the screenplay. In August 1954, studio chief Darryl F. Zanuck recommended that 20th Century-Fox acquire the screen rights prior to publication, and

8066-792: The cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at DAT . Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of epinephrine . Based upon neuronal TAAR1 mRNA expression, amphetamine is thought to affect norepinephrine analogously to dopamine. In other words, amphetamine induces TAAR1-mediated efflux and non-competitive reuptake inhibition at phosphorylated NET , competitive NET reuptake inhibition, and norepinephrine release from VMAT2 . Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine. Amphetamine affects serotonin via VMAT2 and, like norepinephrine,

8175-420: The drug cannot be considered safe for use by women of child-bearing age, and its use is tightly controlled when used for treating other illness. Methamphetamine is available by prescription under the brand name Desoxyn . The active component of Desoxyn is dextromethamphetamine hydrochloride . This is the right-handed isomer of methamphetamine. The left-handed isomer of methamphetamine, levomethamphetamine ,

8284-456: The expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction. Consequently, ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sexual addictions , which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use. These sexual addictions are associated with

8393-413: The fact that ammonium tartrate salt gives enantiomeric crystals with distinct crystal forms (at 77 °F). Reasoning from the macroscopic scale down to the molecular, he reckoned that the molecules had to have non-superimposable mirror images. A sample with only a single enantiomer is an enantiomerically pure or enantiopure compound. From racemic acid found in grapes; from Latin racemus , meaning

8502-589: The fetus or newborns (i.e., it is not a human teratogen ), but amphetamine abuse does pose risks to the fetus. Amphetamine has also been shown to pass into breast milk, so the IPCS and the FDA advise mothers to avoid breastfeeding when using it. Due to the potential for reversible growth impairments, the FDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical. The adverse side effects of amphetamine are many and varied, and

8611-426: The highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate). Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy , 12-step programs , non-contingent reward-based therapies, psychodynamic therapy , and other combination therapies involving these. Additionally, research on

8720-607: The human body. Phenethylamine is the parent compound of amphetamine, while N -methylphenethylamine is a positional isomer of amphetamine that differs only in the placement of the methyl group . Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy (a sleep disorder), obesity , and, in the form of lisdexamfetamine , binge eating disorder . It is sometimes prescribed off-label for its past medical indications , particularly for depression and chronic pain . Long-term amphetamine exposure at sufficiently high doses in some animal species

8829-434: The human brain. Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine. Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects. In certain brain regions, amphetamine increases the concentration of dopamine in the synaptic cleft . Amphetamine can enter

8938-677: The inactive prodrug lisdexamfetamine . Amphetamine increases monoamine and excitatory neurotransmission in the brain, with its most pronounced effects targeting the norepinephrine and dopamine neurotransmitter systems . At therapeutic doses, amphetamine causes emotional and cognitive effects such as euphoria , change in desire for sex , increased wakefulness , and improved cognitive control . It induces physical effects such as improved reaction time, fatigue resistance, decreased appetite , elevated heart rate, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown . Addiction

9047-461: The induction of ΔFosB-mediated neural and behavioral plasticity by chronic drug use, which occurs via H3K9me2 -mediated repression of transcription factors for ΔFosB and H3K9me2-mediated repression of various ΔFosB transcriptional targets (e.g., CDK5 ). ΔFosB also plays an important role in regulating behavioral responses to natural rewards , such as palatable food, sex, and exercise. Since both natural rewards and addictive drugs induce

9156-431: The interacting substance, or both. Inhibitors of enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3 ) will prolong its elimination half-life , meaning that its effects will last longer. Amphetamine also interacts with MAOIs , particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine); therefore, concurrent use of both

9265-668: The magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum . Amphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a G s -coupled and G q -coupled G protein-coupled receptor (GPCR) discovered in 2001, which is important for regulation of brain monoamines. Activation of TAAR1 increases cAMP Tooltip cyclic adenosine monophosphate production via adenylyl cyclase activation and inhibits monoamine transporter function. Monoamine autoreceptors (e.g., D 2 short , presynaptic α 2 , and presynaptic 5-HT 1A ) have

9374-427: The neuronal monoamine transporters , amphetamine also inhibits both vesicular monoamine transporters , VMAT1 and VMAT2 , as well as SLC1A1 , SLC22A3 , and SLC22A5 . SLC1A1 is excitatory amino acid transporter 3 (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes , and SLC22A5 is a high-affinity carnitine transporter. Amphetamine

9483-443: The nucleus accumbens; magnesium ions inhibit NMDA receptors by blocking the receptor calcium channel . One review suggested that, based upon animal testing, pathological (addiction-inducing) psychostimulant use significantly reduces the level of intracellular magnesium throughout the brain. Supplemental magnesium treatment has been shown to reduce amphetamine self-administration (i.e., doses given to oneself) in humans, but it

9592-795: The number of binge eating days for the duration of the study. In addition, both a review and a meta-analytic systematic review found lisdexamfetamine to be superior to placebo in several secondary outcome measures, including persistent binge eating cessation, reduction of obsessive-compulsive related binge eating symptoms, reduction of body-weight, and reduction of triglycerides. Lisdexamfetamine, like all pharmaceutical amphetamines, has direct appetite suppressant effects that may be therapeutically useful in both BED and its comorbidities. Based on reviews of neuroimaging studies involving BED-diagnosed participants, therapeautic neuroplasticity in dopaminergic and noradrenergic pathways from long-term use of lisdexamfetamine may be implicated in lasting improvements in

9701-507: The occurrence of hyperpyrexia (i.e., core body temperature  ≥ 40 °C) is necessary for the development of amphetamine-induced neurotoxicity. Prolonged elevations of brain temperature above 40 °C likely promote the development of amphetamine-induced neurotoxicity in laboratory animals by facilitating the production of reactive oxygen species, disrupting cellular protein function, and transiently increasing blood–brain barrier permeability. An amphetamine overdose can result in

9810-762: The only post-synaptic receptor at which amphetamine is known to bind is the 5-HT1A receptor , where it acts as an agonist with low micromolar affinity. The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or neurotransmission of dopamine , serotonin , norepinephrine , epinephrine , histamine , CART peptides , endogenous opioids , adrenocorticotropic hormone , corticosteroids , and glutamate , which it affects through interactions with CART , 5-HT1A , EAAT3 , TAAR1 , VMAT1 , VMAT2 , and possibly other biological targets . Amphetamine also activates seven human carbonic anhydrase enzymes, several of which are expressed in

9919-419: The onset of fatigue ), while improving reaction time . Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system. Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a "safety switch", allowing the core temperature limit to increase in order to access

10028-447: The opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors. Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1 co-localization in the associated monoamine neurons. In addition to

10137-435: The opposite. Due to the effect pH has on absorption, amphetamine also interacts with gastric acid reducers such as proton pump inhibitors and H 2 antihistamines , which increase gastrointestinal pH (i.e., make it less acidic). Amphetamine exerts its behavioral effects by altering the use of monoamines as neuronal signals in the brain, primarily in catecholamine neurons in the reward and executive function pathways of

10246-663: The other medications used in RCTs, which included antidepressants (bupropion, mirtazapine , sertraline ), antipsychotics ( aripiprazole ), anticonvulsants ( topiramate , baclofen , gabapentin ), naltrexone , varenicline , citicoline , ondansetron , prometa , riluzole , atomoxetine , dextroamphetamine, and modafinil . A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had

10355-670: The quality of evidence for these findings is low and is consequently reflected in the AASM's conditional recommendation for dextroamphetamine as a treatment option for narcolepsy. In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory , long-term episodic memory , inhibitory control , and some aspects of attention , in normal healthy adults; these cognition-enhancing effects of amphetamine are known to be partially mediated through

10464-443: The regulation of eating behaviors that are observed even after the drug is discontinued. Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness, cataplexy , and sleep paralysis . Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms. Type 1 narcolepsy results from the loss of approximately 70,000 orexin -releasing neurons in

10573-413: The risk of developing a substance use disorder as an adult. Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems ; these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to

10682-568: The severity of withdrawal symptoms is positively correlated with the age of the individual and the extent of their dependence. Mild withdrawal symptoms from the discontinuation of amphetamine treatment at therapeutic doses can be avoided by tapering the dose. An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care. The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine. Tolerant individuals have been known to take as much as 5 grams of amphetamine in

10791-425: The smart, on-the-ball, cool image" and that they sought "stimulation not intoxication [...] greater awareness, not escape" and " confidence and articulacy" rather than the " drunken rowdiness of previous generations." Dextroamphetamine's dopaminergic (rewarding) properties affect the mesocorticolimbic circuit ; a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for

10900-502: The striatum following exposure to amphetamine. This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of EAAT3 , a glutamate reuptake transporter, in dopamine neurons. Amphetamine also induces the selective release of histamine from mast cells and efflux from histaminergic neurons through VMAT2 . Acute amphetamine administration can also increase adrenocorticotropic hormone and corticosteroid levels in blood plasma by stimulating

11009-563: The studio paid a reported $ 30,000. Victor Mature had been feuding with Fox but agreed to play the lead. Filming began on December 6, 1954. Location filming occurred in Bisbee, Arizona . Richard Fleischer later wrote in his memoirs that "besides being the first CinemaScope picture ever made for under $ 1 million, it was a damn good movie. Darryl Zanuck, the studio's big boss, was very taken with it, and we – [producer] Buddy [Adler] and I – became sort of heroes. The direct result of this minor triumph

11118-413: The teeth , nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold , tics (a type of movement disorder), and weight loss . Dangerous physical side effects are rare at typical pharmaceutical doses. Amphetamine stimulates the medullary respiratory centers , producing faster and deeper breaths. In a normal person at therapeutic doses, this effect

11227-603: The therapeutic range can interfere with working memory and other aspects of cognitive control. Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects , such as increased endurance and alertness; however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies. In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength , acceleration, athletic performance in anaerobic conditions , and endurance (i.e., it delays

11336-656: The treatment of both type 1 and type 2 narcolepsy. Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g., modafinil ) and is considered a third-line treatment option. Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy. Amphetamine appears to be most effective at improving symptoms associated with hypersomnolence , with three reviews finding clinically significant reductions in daytime sleepiness in patients with narcolepsy. Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms. However,

11445-591: The treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects . A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.   Binge eating disorder (BED)

11554-647: The two pure enantiomers, which have identical physical properties except for the direction of rotation of plane-polarized light, a racemate sometimes has different properties from either of the pure enantiomers. Different melting points are most common, but different solubilities and boiling points are also possible. Pharmaceuticals may be available as a racemate or as the pure enantiomer, which might have different potencies. Because biological systems have many chiral asymmetries, pure enantiomers frequently have very different biological effects; examples include glucose and methamphetamine . There are four ways to crystallize

11663-501: The user's personality and current mental state. Amphetamine psychosis (e.g., delusions and paranoia ) can occur in heavy users. Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy. According to the FDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility. Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses, meaning that individuals acquire

11772-431: Was a racemic mixture, and isolated dextroamphetamine was later introduced to the market as Dexedrine. The prescription analgesic tramadol is also a racemate. In some cases (e.g., ibuprofen and thalidomide ), the enantiomers interconvert or racemize in vivo . This means that preparing a pure enantiomer for medication is largely pointless. However, sometimes samples containing pure enantiomers may be made and sold at

11881-416: Was that I was given a five year directing contract and Buddy became Darryl's most favored producer." New York Times film critic Bosley Crowther disapproved of the violence in the film, calling it an "unedifying spectacle," while praising the performance of Lee Marvin as a hood "so icily evil he is funny." Borgnine's performance was panned by Crowther as "a joke." Later reviewers have been favorable. In

#259740