The adverse side effects of<unk>  are many and varied, and the amount of<unk>  used is the primary factor in determining the likelihood and severity of adverse effects.<unk>  products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use. Recreational use of<unk>  generally involves much larger doses, which have a greater risk of serious adverse drug effects than dosages used for therapeutic purposes. Physical Cardiovascular side effects can include hypertension or hypotension from 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 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.<unk>  stimulates the medullary respiratory centers, producing faster and deeper breaths. In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.<unk>  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<unk>  on the gastrointestinal tract are unpredictable. If intestinal activity is high,<unk>  may reduce gastrointestinal motility (the rate at which content moves through the digestive system); however,<unk>  may increase motility when the smooth muscle of the tract is relaxed.<unk>  also has a slight analgesic effect and can enhance the pain relieving effects of opioids. USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of<unk>  or other ADHD stimulants. However,<unk>  pharmaceuticals are contraindicated in individuals with cardiovascular disease. Psychological At normal therapeutic doses, the most common psychological side effects of<unk>  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 the user's personality and current mental state.<unk>  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 USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.<unk>  has also been shown to produce a conditioned place preference in humans taking therapeutic doses, meaning that individuals acquire a preference for spending time in places where they have previously used<unk> . Reinforcement disorders Addiction Addiction is a serious risk with heavy recreational<unk>  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 the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in<unk>  addiction. Individuals who frequently self-administer high doses of<unk>  have a high risk of developing an<unk>  addiction, since chronic use at high doses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction. Once nucleus accumbens ΔFosB 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<unk>  addiction, regularly engaging in sustained aerobic exercise appears to reduce the risk of developing such an addiction. Sustained aerobic exercise on a regular basis also appears to be an effective treatment for<unk>  addiction; exercise therapy improves clinical treatment outcomes and may be used as an adjunct therapy with behavioral therapies for addiction. Biomolecular mechanisms Chronic use of<unk>  at excessive doses causes alterations in gene expression in 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 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<unk> s, among others. ΔJunD, 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 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 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<unk>  addiction and<unk> -induced sexual addictions, which are compulsive sexual behaviors that result from excessive sexual activity and<unk>  use. These sexual addictions are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs. The effects of<unk>  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<unk>  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<unk>  does not significantly affect gene regulation. Pharmacological treatments there is no effective pharmacotherapy for<unk>  addiction. Reviews from 2015 and 2016 indicated that TAAR1-selective agonists have significant therapeutic potential as a treatment for psychostimulant addictions; however, the only compounds which are known to function as TAAR1-selective agonists are experimental drugs.<unk>  addiction is largely mediated through increased activation of dopamine receptors and NMDA receptors in 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<unk>  self-administration (i.e., doses given to oneself) in humans, but it is not an effective monotherapy for<unk>  addiction. A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for<unk>  and methamphetamine addiction; it found only low-strength evidence that methylphenidate might reduce<unk>  or methamphetamine self-administration. There was low- to moderate-strength evidence of no benefit for most of 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. Behavioral treatments A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for<unk> , methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had 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 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<unk>  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 the reinstatement (i.e., relapse) of drug-seeking, and induces increased dopamine receptor D2 (DRD2) density in the striatum. This is the opposite of pathological stimulant use, which induces decreased striatal DRD2 density. One review noted that exercise
Amphetamine
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