Amphetamines

Amphetamines

Snorting amphetamines

Amphetamine^{[note 1]} (contracted from alpha‑methylphenethylamine) is a potent central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered in 1887 and exists as two enantiomers:^{[note 2]} levoamphetamine anddextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers, levoamphetamine and dextroamphetamine, in their pure amine forms. However, 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 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.^{[sources 1]}

The first pharmaceutical amphetamine was Benzedrine, a brand which was used to treat a variety of conditions. Currently, pharmaceutical amphetamine is prescribed as racemic amphetamine, Adderall,^{[note 3]} dextroamphetamine, or the inactive prodrug lisdexamfetamine. Amphetamine, through activation of a trace amine receptor, increases monoamine and excitatory neurotransmitter activity in the brain, with its most pronounced effects targeting the catecholamine neurotransmitters norepinephrineand dopamine.^{[sources 2]}

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 decreased reaction time, fatigue resistance, and increased muscle strength. Larger doses of amphetamine may impair cognitive function and induce rapid muscle breakdown. Drug addiction is a serious risk with large recreational doses but is unlikely to arise from typical long-term medical use at therapeutic doses. Very high doses can result in psychosis (e.g., 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.^{[sources 3]}

Amphetamine belongs to the phenethylamine class. It is also the parent compound of its own structural class, the substituted amphetamines,^{[note 4]} which includes prominent substances such as bupropion, cathinone, MDMA (ecstasy), 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 the human body. Phenethylamine is the parent compound of amphetamine, while N-methylphenethylamine is a constitutional isomer that differs only in the placement of the methyl group.^{[sources 4]}

Medical

Amphetamine is used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy (a sleep disorder), and obesity, and is sometimes prescribed off-label for its pastmedical indications, such as depression.^[2][16][35] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormaldopamine system development or nerve damage,^[49][50] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.^[51][52][53] 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 the brain, such as the right caudate nucleus of the basal ganglia.^[51][52][53]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD.^[54][55][56] Controlled trials spanning two years have demonstrated treatment effectiveness and safety.^[54][56] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.^[54]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems;^[57] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the locus coeruleus and prefrontal cortex.^[57]Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.^[26][57][58]Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.^[59] 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.^[60][61] The Cochrane Collaboration's reviews^{[note 5]} on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.^[63][64] A Cochrane Collaboration 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.^[65]

Enhancing performance

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, unambiguous improvements in cognition, including working memory, episodic memory, inhibitory control and some aspects of attention, in normal healthy adults;^[66][67]the cognition-enhancing effects of amphetamine are known to occur through its indirect activation of both dopamine receptor D₁ and adrenoceptor α₂ in the prefrontal cortex.^[26][66] A systematic review from 2014 noted that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.^[68] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.^[26][69] Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.^[26][70][71] 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.^[26][71][72] Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.^[73][74][75] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.^[26][71]

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;^[27][40] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.^[76][77] 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 the onset of fatigue), while improving reaction time.^[27][78][79] Amphetamine improves endurance and reaction time primarily through reuptake inhibition andeffluxion of dopamine in the central nervous system.^[78][79][80] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertionby overriding a "safety switch" that allows the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.^[79][81][82] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;^[27][78] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.^[28][39][78]

Contraindications

See also: Amphetamine § Interactions

According to the International Programme on Chemical Safety (IPCS) and United States Food and Drug Administration (USFDA),^{[note 6]} amphetamine is contraindicated in people with a history of drug abuse,^{[note 7]}heart disease, severe agitation, or severe anxiety.^[84][85] It is also contraindicated in people currently experiencing arteriosclerosis (hardening of the arteries), glaucoma (increased eye pressure), hyperthyroidism(excessive production of thyroid hormone), or moderate to severe hypertension.^[84][85][86] People who have experienced allergic reactions to other stimulants in the past or who are taking monoamine oxidase inhibitors (MAOIs) are advised not to take amphetamine,^[84][85] although safe concurrent use of amphetamine and monoamine oxidase inhibitors has been documented.^[87][88] 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.^[84][85] Evidence from human studies indicates that therapeutic amphetamine use does not cause developmental abnormalities in the fetus or newborns (i.e., it is not a humanteratogen), but amphetamine abuse does pose risks to the fetus.^[85] Amphetamine has also been shown to pass into breast milk, so the IPCS and USFDA advise mothers to avoid breastfeeding when using it.^[84][85]Due to the potential for reversible growth impairments,^{[note 8]} the USFDA advises monitoring the height and weight of children and adolescents prescribed an amphetamine pharmaceutical.^[84]

Side effects

The side effects of amphetamine are varied, and the amount of amphetamine used is the primary factor in determining the likelihood and severity of side effects.^[28][39][40] Amphetamine products such as Adderall, Dexedrine, and their generic equivalents are currently approved by the USFDA for long-term therapeutic use.^[36][39] Recreational use of amphetamine generally involves much larger doses, which have a greater risk of serious side effects than dosages used for therapeutic reasons.^[40]

Physical

At normal therapeutic doses, the physical side effects of amphetamine vary widely by age and from person to person.^[39] Cardiovascular side effects can include hypertension or hypotension from a vasovagal response, Raynaud's phenomenon (reduced blood flow to extremities), and tachycardia (increased heart rate).^[39][40][89] Sexual side effects in males may include erectile dysfunction, frequent erections, or prolonged erections.^[39] Abdominal side effects may include abdominal pain, appetite loss, nausea, and weight loss.^[39][90] Other potential side effects include blurred vision, dry mouth, excessive grinding of the teeth, nosebleed, profuse sweating, rhinitis medicamentosa (drug-induced nasal congestion), reduced seizure threshold, and tics (a type of movement disorder).^{[sources 5]} Dangerous physical side effects are rare at typical pharmaceutical doses.^[40]

Amphetamine stimulates the medullary respiratory centers, producing faster and deeper breaths.^[40] In a normal person at therapeutic doses, this effect is usually not noticeable, but when respiration is already compromised, it may be evident.^[40] Amphetamine also induces contraction in the urinary bladder sphincter, the muscle which controls urination, which can result in difficulty urinating.^[40] This effect can be useful in treating bed wetting and loss of bladder control.^[40] The effects of amphetamine on the gastrointestinal tract are unpredictable.^[40] If intestinal activity is high, amphetamine may reduce gastrointestinal motility (the rate at which content moves through the digestive system);^[40] however, amphetamine may increase motility when the smooth muscle of the tract is relaxed.^[40] Amphetamine also has a slight analgesic effect and can enhance the pain relieving effects of opioids.^[40]

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 amphetamine or other ADHD stimulants.^{[sources 6]}

Psychological

Common psychological effects of therapeutic doses can include increased alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elated mood followed by mildly depressed mood), increased initiative, insomnia or wakefulness, self-confidence, and sociability.^[39][40] Less common side effects include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness;^{[sources 7]} these effects depend on the user's personality and current mental state.^[40] Amphetamine psychosis (e.g., delusions and paranoia) can occur in heavy users.^[28][39][41] Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy.^[28][39][42] According to the USFDA, "there is no systematic evidence" that stimulants produce aggressive behavior or hostility.^[39]

Amphetamine has also been shown to produce a conditioned place preference in humans taking therapeutic doses,^[63][97] meaning that individuals acquire a preference for spending time in places where they have previously used amphetamine.^[97][98]

Overdose

An amphetamine overdose can lead to many different symptoms, but is rarely fatal with appropriate care.^[85][99] The severity of overdose symptoms increases with dosage and decreases with drug tolerance to amphetamine.^[40][85] Tolerant individuals have been known to take as much as 5 grams of amphetamine in a day, which is roughly 100 times the maximum daily therapeutic dose.^[85] Symptoms of a moderate and extremely large overdose are listed below; fatal amphetamine poisoning usually also involves convulsions and coma.^[28][40] 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).^{[note 9][100]}

Pathological overactivation of the mesolimbic pathway, a dopamine pathway that connects the ventral tegmental area to the nucleus accumbens, plays a central role in amphetamine addiction.^[101][102] Individuals who frequently overdose on amphetamine during recreational use have a high risk of developing an amphetamine addiction, since repeated overdoses gradually increase the level of accumbal ΔFosB, a "molecular switch" and "master control protein" for addiction.^{[103][104][105]} 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.^[103][106] 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.^[107][108] Sustained aerobic exercise on a regular basis also appears to be an effective treatment for amphetamine addiction;^{[106][107][109]} exercise therapy improves clinical treatment outcomes and may be used as a combination therapy with cognitive behavioral therapy, which is currently the best clinical treatment available.^{[107][109][110]}

There is a risk of addiction, but the evidence is that this is only particularly likely with heavy use. If someone does become addicted then tolerance grows quickly requiring ever increasing doses. Surprisingly amphetamine overdoses rarely prove fatal and there is little evidence to show that it can result in heart attack, strokes or other cardiovascular events.It may seem strange but one of the few legitimate medical uses of the stimulant amphetamine is in the treatment of attention deficit hyperactivity disorder (ADHD). For most people though, the effects of taking amphetamines are feeling energised and confident.

What excessive doses can do is effectively change the wiring of the brain making addiction stronger or more likely.

Perhaps the best known and most sinister of amphetamines side effects is “speed psychosis”. One study found that nearly 20% of heavy users had clinical levels of psychosis. Of these up to 15% never fully recover. The symptoms of amphetamine psychosis are very similar to schizophrenia with hallucinations, delusions of persecution and extreme agitation being common.
And this is why amphetamines make it onto this list.