ChemistryAmphetamines and methamphetamine are synthetic substances that do not exist in nature. They are weakly basic substances and can exist as either in a free base form or react with various acids to form salts such as amphetamine hydrochloride. The salt forms of the amphetamines are highly water-soluble whereas the free base forms are less so (Budavari, 1996).
AmphetaminesAmphetamines are structurally similar to dopamine and noradrenaline. They are a chiral molecule; that is, they can exist in two different chemical forms (enantiomers) that are identical in two dimensions, but in three dimensions they are mirror images of each other. The enantiomers of amphetamines are usually referred to as dexamphetamine (also denoted as S(+)-amphetamine) and levoamphetamine (also denoted as R(-)-amphetamine). Dexamphetamine is more centrally active and therefore more of a 'typical' amphetamine than levoamphetamine (Ferris & Tang, 1979).
MethamphetamineMethamphetamine only differs from amphetamines in the addition of a methyl group on the chain. As with amphetamines, it exists in two chemical forms (+) methamphetamine and (-) methamphetamine (Budavari, 1996).
PharmacokineticsAmphetamines may be administered orally, intranasally or intravenously. The peak response occurs one to three hours after oral administration (Angrist, Corwin, Bartlik & Cooper, 1987) or approximately 15 minutes after injection (Jonsson, Anggard & Gunne, 1971). A single dose may maintain an effect for up to 7–12 hours (Cook, Jeffcoat, Hill, Pugh et al., 1993). However, when urine is alkaline (pH greater than 6.7), the half-life may increase to 18–34 hours (Anggard, Jonsson, Hogmark & Gunne, 1973;Wan, Matin & Azarnoff, 1978).
Amphetamines are metabolised by the liver by a range of enzymes, including cytochrome P450 2D6 (Li, Wang, Pankiewicz & Stein, 2001;Wu, Otton, Inaba, Kalow & Sellers, 1997). Metabolites include 4-hydroxyamphetamine, 4 hydroxynorephedrine, hippuric acid, benzoic acid and benzyl methyl ketone (Kraemer & Maurer, 2002; Musshoff, 2000). Methamphetamine is metabolised to amphetamine. Some amphetamines are also excreted unchanged in the urine.Top of page
PharmacodynamicsAmphetamines increase the activity of monoaminergic systems. The primary mechanism is by increasing release of dopamine from nerve terminals (Kegeles, Zea-Ponce, Abi-Dargham, Rodenhiser et al., 1999; Silvia, Jaber, King, Ellinwood & Caron, 1997). Amphetamines are thought to enter the nerve terminal via the transporter, disrupt storage vesicles of dopamine and reverse the direction of the dopamine transporter through which large amounts of dopamine are released (Leviel, 2001). The ability of amphetamines to release dopamine is dose-related (Kuczenski, Segal, Cho & Melega, 1995).
In addition to this, amphetamines are able to inhibit dopamine metabolism and its reuptake. Amphetamines are able to increase the release of noradrenaline and serotonin (Berridge & Stalnaker, 2002; Kuczenski et al., 1995; Rothman, Baumann, Dersch, Romero et al., 2001).
Methamphetamine acts by similar mechanisms, although some research suggests that amphetamines and methamphetamine may possess different neurochemical profiles in different brain areas (Shoblock, Sullivan, Maisonneuve & Glick, 2003).
Sex differencesThere may be sex differences in acute responses to amphetamines and other psychostimulants. In animal studies, oestrogen enhances the acute behavioural and neurochemical responses to psychomotor stimulants in female compared to male animals (Becker, 1999).
Effects on the user
Sought-after effectsThe psychological effects produced by amphetamines are dependent on dose, the characteristics of the individual and the context in which they take the drug. Amphetamines produce euphoria, mood elevation and a sense of wellbeing (Becker, 1999; de Wit, Enggasser & Richards, 2002; Johanson & Uhlenhuth, 1980). This is combined with an increase in energy and wakefulness, a reduction in fatigue and increased concentration and alertness (Chapotot, Pigeau, Canini, Bourdon & Buguet, 2003; Pigeau, Naitoh, Buguet, McCann et al., 1995).
Other behavioural effectsAn increase in motor and speech activities may present as increased talkativeness (Higgins & Stitzer, 1989). Amphetamines can improve physical performance (Chandler & Blair, 1980). Performance of simple mental tasks may also improve (Brauer & De Wit, 1997; Soetens, Casaer, D'Hooge & Hueting, 1995; Wiegmann, Stanny, McKay, Neri & McCardie, 1996), although higher doses or chronic use are associated with deficits in cognitive and motor performance (Ornstein, Iddon, Baldacchino, Sahakian et al., 2000; Rogers, Everitt, Baldacchino, Blackshaw et al., 1999; Simon, Domier, Carnell, Brethen et al., 2000).
At higher doses, the euphoria becomes more intense, but adverse effects also increase. They include restlessness, tremor, changes in libido, anxiety, dizziness, tension, irritability, insomnia, confusion and aggression (Degenhardt & Topp, 2003). Teeth grinding may occur and may produce distinctive wearing of teeth (Richards & Brofeldt, 2000).
Psychosis, delirium, auditory, visual and tactile illusions, paranoid hallucinations, panic stages and loss of behavioural control (Angrist, Sathananthan, Wilk & Gershon, 1974; Degenhardt & Topp, 2003; Iwanami, Sugiyama, Kuroki,Toda et al., 1994; Janowsky & Risch, 1979; Miczek & Tidey, 1989) may occur. Delusions of being monitored with hidden electrical devices are common, as is the preoccupation with 'bugs' that are felt and seen on the skin, leading to picking and excoriation of the skin. Restless, choreoathetoid and tic-like movements are often present. Experienced amphetamine users may describe the combination of paranoia and compulsive movements as 'tweaking' (Forster, Buckley & Phelps, 1999). Alterations in consciousness may also occur (Nakatani & Hara, 1998).Top of page
Physiological effectsAmphetamines are sympathomimetic agents associated with a range of cardiovascular effects. Increases in both systolic and diastolic blood pressure are typically observed after amphetamine administration (Angrist, Sanfilipo & Wolkin, 2001; Brauer, Ambre & De Wit, 1996; Brauer & De Wit, 1997; Rush, Essman, Simpson & Baker, 2001). Effects on heart rate are varied. Amphetamines may have little effect on heart rate at low doses (Angrist et al., 2001; Rush et al., 2001), although higher doses may lead to increased heart rate (Brauer et al., 1996; Brauer & De Wit, 1997). Physiological effects of amphetamines may vary with the social context of use (de Wit, Clark & Brauer, 1997).
Adverse effects reported by methamphetamine users include sweating, palpitations, chest pain, shortness of breath, headache, tremors and hot-cold flushes (Degenhardt & Topp, 2003). In addition to their cardiovascular effects, amphetamines and methamphetamine are able to increase body temperature and stimulate the respiratory centre, increasing rate and depth of respiration (Mediavilla, Feria, Fernandez, Cagigas et al., 1979). They reduce appetite and may also increase metabolic rates (Jones, Caul & Hill, 1992).
Methamphetamine produces similar effects to amphetamines, but at smaller doses, it produces prominent CNS stimulation with fewer significant peripheral effects. At higher doses methamphetamine similarly increases blood pressure and cardiac output.
ToxicityUse of amphetamines can lead to a range of toxic presentations. The toxic dose of amphetamines varies widely and whilst higher doses are more likely to produce toxic effects, toxicity is sometimes idiosyncratically observed after ingestion of low doses. Some studies have suggested that polymorphisms in the cytochrome P450 enzyme system (mainly CYP2D6) are responsible for individual variations in drug toxicity, although these findings have been largely refuted (Kraemer & Maurer, 2002).
Toxic central effects include psychosis (Iwanami et al., 1994), hyperthermia (Callaway & Clark, 1994) and seizures (Alldredge, Lowenstein & Simon, 1989; Hanson, Jensen, Johnson & White, 1999). Rhabdomyolysis may also occur (Richards, Johnson, Stark & Derlet, 1999).
Cardiovascular toxicity includes ventricular arrhythmias (Sloan & Mattioni, 1992), acute myocardial infarction (Bashour, 1994; Costa, Pizzi, Bresciani,Tumscitz et al., 2001; Hung, Kuo & Cherng, 2003) and cardiomyopathies (Hong, Matsuyama & Nur, 1991). Cerebrovascular crises may occur including stroke, aneurysm and cerebral haemorrhage (Biller, Toffol, Kassell, Adams et al., 1987; Buxton & McConachie, 2000; Chen, Liang, Lu & Lui, 2003; Moriya & Hashimoto, 2002; Perez, Arsura & Strategos, 1999; Sloan & Mattioni, 1992;Yen, Wang, Ju, Chen et al., 1994).
Use of methamphetamine may also produce neurological changes that may persist after cessation of drug use, often referred to as neurotoxicity. Research in both primates and humans suggests that chronic methamphetamine use leads to dopamine depletion, accompanied by reductions in other markers of dopamine function, such as dopamine transporters and enzymes (Davidson, Gow, Lee & Ellinwood, 2001). Changes may persist after periods of abstinence and may also occur in markers of serotonergic function (Davidson et al., 2001).
Although the precise mechanisms associated with these changes are not entirely clear, it is thought that they may be associated with excessive dopamine concentrations within the synapse (Davidson et al., 2001). However, excessive dopamine may not be essential for neurotoxic effects (Yuan, Callahan, McCann & Ricaurte, 2001). Other contributing factors may include hyperthermia, formation of reactive oxygen species or increased glutamate activity (Davidson et al., 2001; Miller & O'Callaghan, 2003). It has been suggested that these changes may be associated with motor and cognitive impairments (Volkow, Chang,Wang, Fowler, Leonido-Yee et al., 2001).Top of page