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Amphetamine itself has been abused since the 1930s but the first derivative to gain acceptance on the street was 3,4-methylenedioxyamphetamine (MDA), known at the time as the ‘love drug‘ because it purportedly dispelled feelings of hate or anger and encouraged emotional closeness between users. MDA abuse began in the USA in the mid-1960s but the drug was declared illegal in 1970. However, a large number of other amphetamine derivatives were introduced during this period and the banning of MDA merely opened the door to related drugs such as MDMA (3,4-methylenedioxymethamphetamine or ecstasy). DOM is an example of an especially hallucinogenic derivative, while methamphetamine is highly stimulatory. MDMA itself seems to have particularly prominent effects on central 5-hydroxytryptamine (5HT) neurones. This may explain why MDMA intoxication seems to involve an overly emotional element. The drug also has a low hallucinogenic potential with less stimulatory effect than amphetamine.

Other related drugs with less potent sympathomimetic effects and less abuse potential, such as phentermine, are still used as appetite suppressants in the treatment of obesity. Another derivative methylphenidate, is used to treat attention deficit hyperactivity disorder in children.

Amphetamine

History

Amphetamine was first synthesised in 1887 and has since been used to treat a range of medical conditions; some of these are listed in table below. Amphetamine use proliferated in the 1930s when it was found to have similar, although more potent, effects to the widely used drug ephedrine. Ephedrine was extracted from plants and so supplies were limited and expensive.

Vast quantities of amphetamine were synthesised and issued to troops and workers during World War II for use as a stimulant during periods of strenuous activity. Amphetamine was also widely used to treat comparatively trivial conditions such as rhinitis. Together, these two factors played a large part in facilitating the early rise of amphetamine abuse; the population could obtain amphetamine easily and experiment freely with its psychoactive effects. The drug is known on the street as ‘speed‘, ‘whiz‘ or ‘uppers‘.

Therapeutic Uses Of Amphetamine

Historical Uses

• Depression
• Anxiety, lethargy and other ‘personality’ disorders
• Analeptic in barbiturate poisoning
• Appetite suppressant
• Parkinsonism
• Nasal decongestant
• Stimulant for troops and factory workers in wartime
• Nocturnal enuresis

Modern Uses of Dexamphetamine

• Narcolepsy and other hypersomnic states
• Attention deficit hyperactivity disorder in children
• ‘Space sickness’, usually in association with hyoscine or an antihistamine

Effects Shought

The social abuser seeks the mental and physical stimulation which amphetamine may produce. The individual typically becomes alert, full of self-confidence, happy and talkative; he or she may also feel energetic, strong, impulsive and have increased stamina. This usually lasts up to four hours and as the effects begin to wear off may be succeeded by a period of restlessness, anxiety, fatigue, disinterest or tiredness.

Larger initial doses can provoke an exhilarating euphoria and feelings of great mental power but may also be associated with more intense negative feelings afterwards, such as depression and lethargy (a ‘crash‘). Regular users develop tolerance such that progressively greater doses are needed with time.

Some abusers seek the stimulating properties of amphetamine for other purposes. Students may use the drug to decrease tiredness, enabling revision for long periods of time. Those in monotonous occupations may abuse amphetamine in the workplace and sportsmen claim that amphetamine enables them to train for longer periods of time.

Administration

Amphetamine may be taken orally, via nasal inhalation or by injection. It is occasionally smoked. Amphetamine is a basic drug and the duration of its effects can be increased by the administration of sodium bicarbonate (baking soda) or any other substance which alkalinises the urine. Alkaline urine favours the formation of the non-ionised form of amphetamine which is much more readily reabsorbed into the bloodstream from urine. Bicarbonate therefore effectively delays the excretion of amphetamine. Similarly, abusers may use vitamin C, cranberry juice or ammonium chloride to terminate the effects of amphetamine more abruptly when required. It is usually supplied as a white or off-white powder in small card or paper ‘wraps‘.

Pharmacokinetics and Pharmacology

Amphetamine is a sympathomimetic agent which principally causes the release of amines from central and peripheral neurones. The main neurotransmitters involved are noradrenaline, dopamine and 5-HT. The detailed pharmacology of many of the amphetamine-related drugs remains to be investigated but most have fewer peripheral actions than amphetamine itself.

The half-lives of both laevo- and dextro-rotatory amphetamine are approximately 12 to 13 hours. The metabolic fate of amphetamine is partly determined by urinary pH, but deamination, N-hydroxylation, aromatic p-hydroxylation and conjugation all occur to varying extents. When urinary pH is unregulated, about 15 per cent of each dose is excreted as unchanged drug.

Adverse effects

The onset of amphetamine effects is often heralded by a range of adrenergic ‘fight-or-flight actions, such as sweating and tachycardia; initial side effects can also include nausea, headache and abdominal cramps. These effects may be short-lived or more persistent. A detailed list of adverse reactions is given above. Note that many of the acute, serious adverse effects are inter-related; this is discussed more fully below under ecstasy. Amphetamine will usually only cause rhabdomyolysis and sequelae as a consequence of heavy intravenous use and/or overdose. Unlike ecstasy, the reaction is less commonly linked to overexercise in a hot environment; this may be because amphetamine has a reduced interaction with 5-HT in the brain.

Most psychoactive drugs will occasionally produce unpleasant psychotomimetic effects; these are probably determined by the expectations of the user, their frame of mind at the time and the surroundings. Amphetamine is no exception; extreme anxiety, frightening hallucinations or panic reactions may occur and many of these responses seem to involve paranoid delusions. True psychosis may develop after single or repeated use and can be a long-term problem. It has been suggested that the population most at risk may be those with a predisposition to mental illness.

Although amphetamine does not produce physical dependence there is often a short-lived craving for the drug after cessation of chronic use. This usually responds to simple anti-anxiety management; a withdrawal scheme involving tapered amphetamine dosage is rarely required. Abstinence from amphetamine has been encouraged by the use of a short course of desipramine. However, this treatment has been associated with a ‘jitters’ reaction which may encourage a return to stimulant abuse because it resembles the euphoria experienced with stimulant drugs. Consequently, fluoxetine has been proposed as a better tolerated alternative and reported to be effective in preventing relapse in two very small studies. An antidepressant may also be needed in the longer term to counteract the depression which is a common finding in those who have abused amphetamine chronically.

Methamphetamine

History

Methamphetamine has been abused episodically in the past but relatively recently a different form of the drug has appeared in the USA and concern has been expressed that its use may spread rapidly. Just as ‘crack‘ represents a highly purified form of cocaine, ‘ice‘ is a very pure form of methamphetamine which first came to light in Hawaii in the mid-1980s. It is thought that the synthesis procedure allows crystallisation of the drug into tiny colourless spindle shapes which resemble ice crystals, hence the street name. However, the exact preparative process remains unknown. Other street names include ‘crystal‘, ‘crank‘ and ‘meth‘. The main centres for production appear to be in Southeast Asia and the drug has been popular in Japan. As yet only small-scale abuse has been identified in the UK.

Administration

‘Ice‘ is vaporised, often in a glass tube, and the vapour inhaled to produce a long-lasting ‘high’ of some 10 to 12 hours. Furthermore, the same sample of drug can be reheated several times and still produce the desired effect because it has a high melting point and is stable to thermal decomposition. The drug is not usually smoked with tobacco because the availability of methamphetamine is thereby greatly reduced.

Pharmacokinetics

The half-life following inhalation of methamphetamine vapour has been estimated at an average of 11.7 hours, although a half-life of 10.2 hours was obtained following oral administration. This value is heavily determined by the pH of urine. Aromatic hydroxylation, N-dealkylation and deamination occur in the liver followed by renal elimination. About one-third of a dose is excreted unchanged in urine.

Adverse Effects

Relatively little is known about the problems that may be associated with abuse of ‘ice’. Some reports suggest that it is highly addictive and that abusers may become violent under the influence of the drug. Methamphetamine has more pronounced stimulatory effects on the central nervous system (CNS) than amphetamine and less potent peripheral actions. However, judgement is impaired and abusers may become restless and agitated; high doses can produce psychotic reactions characterised by hallucinations, paranoia and mania. Post-abuse ‘crashes’ can also be particularly intense. The drug is known to destroy dopaminergic and serotonergic neurones in the CNS. Other acute and chronic adverse reactions are similar to those experienced after use of amphetamine.

Ecstasy

History

MDMA has a variety of street names including ‘Adam‘, ‘XTC‘, ‘M‘, and ‘AKA‘. However, it is usually known as ‘ecstasy‘ or ‘E’. Some tablets are known by particular names according to the motif embossed upon them (e.g. ‘doves‘), or their colour (e.g. ‘strawberries‘). It was first  synthesised by E. Merck Pharmaceuticals in 1914 and investigated as an appetite suppressant. However, it was not until MDA was declared an illegal drug in the 1070 that MDMA became widely available. In the 1970s, MDMA was used legally by US psychotherapists to aid counselling, particularly in the field of disturbed interpersonal relationships, such as marriage guidance. MDMA was claimed to promote emotional harmony to reduce enmity. Some therapists still use the drug for this purpose. By 1985, street abuse had reached such heights in the USA that ecstasy was declared an illegal substance. In the UK, the legislature was one step ahead of the illicit manufacturers; all amphetamine-related compounds (including MDMA) were classified as illegal substances under an amendment to the Misuse of Drugs Act as early as 1977.

Effects Sought

In the UK, ecstasy has been available in reasonable quantities since the late 1980s. The drug is both synthesised within the UK and imported. Users seek a state of tranquil euphoria in which there is high degree of emotional empathy between associates, greater insight into personal problems and an expanded mental perspective. Abusers feel ‘at peace with the world‘ and aggressive and violent feelings are suppressed. Those under the influence of the drug feel benevolent, less defensive and more interested in interacting with others. The hallucinogenic potential is relatively low, but perceptions may be enhanced. There is often a subjectively altered sense of time. Ecstasy also has amphetamine-like stimulant properties, seeming to give abusers boundless energy although these effects are less potent than those of amphetamine itself.

Although initially associated with the growth of ‘acid house‘ music scene, in Britain today the use of ecstasy is more intimately associated with the ‘rave‘ culture in which young people, largely between the ages of 16 and 25, gather in night clubs or more secluded ‘private‘ parties and dance through the night to rave music. The term ‘rave‘ is somewhat defunct as a descriptive term at street level but might be used generically to describe a wide range of repetitive musical styles, often with minimal lyrics, which encourage long periods of dancing. Ecstasy can provide the stamina to dance for lengthy periods but thus us also the basic cause of some of the more serious side-effects.

Administration

Ecstasy is taken orally, usually in the form of white or off-white tablets which are often embossed and/or scored. These are illustrated in the figures below. Capsules are occasionally seen. A typical dose for a first time user should be 75 to 100 mg but because the development of tolerance the dose needs to be gradually increased to achieve the same effect if taken regularly. However, there is no evidence of physical dependence. A regular user might take up to 200 mg as a single dose followed by a smaller booster dose several hours later in order to maintain intoxication.

Some abusers use ecstasy in association with other drugs. Nitrites, LSD and amphetamine are commonly used concurrently. Users may also employ a variety of preparations to make the aftermath of an ecstasy experience more tolerable. This is called ‘coming down‘. Preparations used include Vicks VapoRub or Sines, the caffeine-rich herbal product guarana, and fluoxetine. Some users, aware of the potential 5-HT-depleting properties of ecstasy (see below), may take ‘smart drug‘ drinks containing 5-HT precursors in an attempt to prevent any CNS damage. Smart drugs will be discussed on another article.

It is clear that many ecstasy tablets do not contain pure ecstasy. A variety of patterns have emerged:

• A small proportion of tablets contain no psychoactive drugs at all.
• Most tablets contain ecstasy together with a variety of adulterants including caffeine, paracetamol, amphetamine, methamphetamine, MDEA, ephedrine, selegiline and ketamine.
• Some tablets contain ecstasy alone.
• Other tablets contain a psychoactive substitute for ecstasy, e.g. ketamine, MDEA, MDA or any one of the bewildering array of amphetamine derivatives which exist.

This lack of purity makes it difficult to identify the substance abused and to treat any adverse effects.

Pharmacokinetics

The average half-life of ecstasy is 7.6 hours. Approximately two-thirds of a dose is eliminated unchanged in the urine. About 7 per cent of a dose is excreted as MDA which is also psychoactive.

Adverse Effects

Whenever a novel substance abuse appears, the immediate concern of non-users is the toxicity potential. In the case of ecstasy this has been of particular concern because until recently it has been ‘marketed‘ as a ‘clean‘ drug (i.e. no side-effects). Broadly speaking it appears to have a similar side-effect profile to amphetamine in most respects but few data are available. Many abusers take the drug intermittently, use other drugs concomitantly or in-between times and have only vague ideas of the doses taken. To further complicate the picture, many samples are not pure but contain a range of excipients from harmless bulking agents to other street drugs. Consequently, the abuser is most unlikely to know exactly what he or she has taken.

As with amphetamine, the desired effects are heralded by a ‘fight-or-flight‘ type of reaction and some individuals feel sick or have a headache. Bruxism (grinding of the teeth) or trismus (uncomfortable rigidity of the jaw muscles) are more common with ecstasy than with amphetamine.

Many of the more severe adverse effects of ecstasy are believed to be linked in aetiology. The stimulant properties of the drug can lead individuals to overexercise in the dance floor. This may lead simply to dhydration or later exhaustion but, depending on the level of activity, can progress to rhabdomyolysis (skeletal muscle break-down) and/or hyperpyrexia. Hyperprexia may trigger convulsions or collapse and further fuels the process of rhabdomyolysis. This in turn may result in acute renal failure, either via muscle breakdown products accumulation in the kidney tubules or via disseminated intravascular coagulation. Rhabdomyolysis is not always easy to diagnose because although it often produces muscle pain, swelling and tenderness, many patients are asymptomatic.

Hyperpyrexia seems to play an important role in the development of many aspects of severe ecstasy toxicity. It is known that the drug affects the production of 5-HT in the brain of animals, so disruption of 5-HT transmission in the human hypothalamus may incapacitate central thermoregulatory control in some way. This pattern of adverse effects can occur with other amphetamine-related drugs but in the UK has been described most consistently with ecstasy, probably because of the close association between ecstasy and dance music (i.e. high levels of physical activity). The chain of events is not necessarily linked to the dose although higher doses probably increase the risk. First-time users are just as vulnerable as those who abuse the drug regularly.

In the USA, where ecstasy does not tend to be abused in this milieu, hyperpyrexia associated adverse effects are more rarely reported. In the UK, many fatalities have been reported. The hyperpyrexia has been treated with dantrolone.

The risks of hyperpyrexia-related death or serious injury can be reduced by encouraging users to following some straightforward advice, including:

• Avoid dancing for prolonged periods of time. Take regular rests and relax in a cool place for a while. Many nightclub owners and hosts of rave events provide ‘chill out’ areas for this purpose.
• Drink plenty of fluid to reduce dehydration but avoid overhydration. Taking electrolyte replacement solutions is to be preferred.
• Wear light, loose clothes.

An increasingly reported problem is that of hyponatraemia. This occurs when the subject becomes very thirsty and drinks excessive quantities of salt-poor fluids. This polydipsia could be due simply to becoming hot whilst taking exercise (dancing) and following the standard advice to drink plenty of fluid when taking ecstasy. This can lead to severe water intoxication and hyponatraemia. However, it has also been suggested that ecstasy can cause the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but this has been disputed. Whatever the precise mechanism of hyponatraemia the effects of it can be severe. Agitation, variable consciousness, dystonias, cerebral oedema, convulsions and coma are notable sequelae. Deaths have occured.

Animal studies have shown the ecstasy is neurotoxic. In various mammals, destruction of central 5-HT neurones and decreased synthesis of 5-HT has been demonstrated. Primates appear to be even more sensitive to this effect than rats, since the effects may be permanent. However, it is not clear whether these changes will occur in man,whether they are reversible or not, or even if they are important. Physically, animals with ecstasy-induced neurological changes were indistinguishable from controls.

When damaged nerve tissue regrows after exposure to ecstasy in animals, it does so slowly. It is also incomplete. The axons generated do not make the same connections to adjacent nerves as their predecessors. The implications of this drug-induced ‘re-wiring’ are unclear. At high doses, ecstasy also damages dopaminergic neurones.

If ecstasy causes long-lasting damage to central 5-HT pathways in humans, drug abuse might result in a range of chronic disorders. For example, serotonergic neurones are prevalent in areas of the brain. connected with emotions and many antidepressant drugs enhance their effects. In addition, CNS turnover of this neurotransmitter is reduced in those suffering from depression. Ecstasy, like amphetamine, can also trigger temporary or persistent psychosis. The long-term legacy of ecstasy abuse might be a tendency towards endogenous depression or other mood disorder. Lethargy and depression after the effects of ecstasy have worn off are quite common reactions. This might be a psychological response in certain individuals who feel so content and cheerful during an ecstasy trip that ‘real life’ seems very unsatisfactory by comparison. On the other hand, it might equally be due to an ecstasy-induced depletion of central 5-HT. At the time of writing it is not known whether ecstasy can cause serotonergic neurone damages in humans, although the concentration of serotonin metabolites in cerebrospinal fluid are decreased for weeks after exposure to ecstasy and this could be due to increased destruction of serotonergic nerve tissue. Nerve distruction has been observed in all other mammalian species studied.

Immunosuppressant properties have been attributed to ecstasy, because abusers seem more likely to contract colds and other minor infections. These effects may be more related to the abuser’s lifestyle than to the drug itself. Dancing in a hot, crowded environment is very conducive to the spread of minor infections diseases and to the development of ‘chills’ after leaving gathering.

Potential Side-effects of Amphetamine and Ecstasy-related Drugs

Minor Adverse Effects

Relatively common and generally short-lived reactions, which occur shortly after taking a dose:

• Mydriasis, photophobia
• Headache
• Anorexia, nausea, dry mouth, abdominal cramps, diarrhoea
• Sweating, tachypnoea, tachycardia, palpitations, tremor (’fight-or-flight’ reaction)
• Bruxism (grinding of the teeth)
• Trismus (uncomfortable rigidity of the jaw muscles)
• Gait disturbance, ataxia

Serious acute adverse effects

These reactions are not common:

• Unpleasant hallucinations, severe anxiety, agitation, panic attacks, paranoia
• Hypertension, especially with amphetamine
• Cardiac arrhythmias
• Cardiomyopathy
• Intracerebral Haemorrhage
• Severe central chest pain (probably due to intercostal muscle spasm)
• Severe abdominal cramps
• Accidental death or injury while intoxicated state, e.g. road traffic accidents, aspiration of vomit
• Urinary retention; one case reported after a very large dose of ecstasy

In Certain Circumstances

Many of these effects have a related aetiology. In ecstasy users, overexercise in a hot environment seems to be an important aetiological factor; in amphetamine users, high doses are more likely to be the cause.

• Over-exertion, dehydration, collapse
• Hyperpyrexia
• Convulsions (with or without hyperpyrexia or history of epilepsy)
• Rhabdomyolysis
• Disseminated intravascular coagulation, cerebrovascular accidents
• Acute renal failure, metabolic acidosis
• Polydipsia, hyponatraemia and stupor

Delayed Reactions to Exposure

These side-effects occur after exposure to amphetamines

• Chronic exhaustion, fatigue, muscular aches (may persist for several days after a single dose)
• Jaundice, hepatotoxicity
• Weight loss (associated with repeated use and due to increased amount of exercise while intoxicated and the anorexic effects of amphetamines)
• ‘Flashbacks’ (repeatedly experiencing a (usually) unpleasant ‘trip’ some time after the original event.
• Insomnia (may be persistent)
• Depression (associated with withdrawal; usually brief after short-term use but may be chronic following discontinuation of a long-term habit)
• Psychosis (may be an acute short-lived reaction or a more persistent problem).

Amphetamine Related Medicines

Diethylpropion, phentermine, methylphenidate and pemoline are all controlled by the Misuse of Drugs Act. Since black market availability of these drugs is limited, street abuse is a comparatively minor problem. The drugs have only mild amphetamine-like properties and so large doses are needed for the purpose of abuse.

Methylphenidate is probably the most widely abused of the prescription amphetamine derivatives. The drug has only amphetamine effects when taken orally due to poor bioavailability. However, these drawbacks are overcome when it is abused by the intravenous route. This practice has been reported particularly from the USA. The injection is prepared by crushing tablets and dissolving the drug in water.

Wolf et al. described in ‘eosinophilic syndrome‘ in 16 intravenous methylphenidate abusers. This was typically characterised by eosinophilia, fever, musculoskeletal complaints (e.g. arthralgia) and pulmonary symptoms (e.g. pleuritic chest pain, dyspnoea, wheezing). The exact presentation varied quite widely between patients. The reaction may have been at least partly due to tablet excipients.

Retinopathy was described in a series of 12 patients in the USA. Emboli of insoluble tablet excipients were probably responsible (see Adverse Consequences of Drug Injection). Sufficient emboli can wedge in the blood vessels of the lungs to cause pulmonary hypertension and a death has been reported. In a group of 22 intravenous methylphenidate abusers, the average daily dose was 200 mg (range: 40-700 mg). Abusers, who all had a history of drug abuse, often obtained the drug initially after their children were prescribed the drug for hyperactivity. Later, supplies were maintained by duping a variety of physicians into prescribing it or by altering legitimate prescriptions in their favour.

Several over-the-counter sympathomimetic drugs have amphetamine-like properties and are sometimes abused. Examples include pseudoephredine and phenylpropanolamine.

Are You Addicted To Amphetamines and Ecstasy?

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