Amphetamines

Note on spelling

In International Non-proprietary Names the digraph -ph- is usually replaced by -f-, although usage is not consistent, and -ph- is used at the beginnings of some drug names (for example, compare fenfluramine and phentermine) or when a name that beings with a ph- is modified by a prefix (for example, chlorphentermine). For the amphetamines we have used the following spellings: amfetamine, benzfetamine, dexamfetamine, metamfetamine (methylamphetamine), and methylenedioxymetamfetamine (ecstasy).

Dexamphetamine, metamfetamine, and methylenedioxymetamfetamine (MDMA, ecstasy) are covered in separate monographs.

General adverse effects and adverse reactions

Amfetamine is a sympathomimetic compound derived from phenylethylamine. However, the word amphetamines has become generic for the entire group of related substances, including benzfetamine, dexamfetamine, metamfetamine, and methylenedioxymetamfetamine (MDMA, ecstasy). Metamfetamine, a popular drug of abuse, is also known as “speed,” “meth,” “chalk,” “crank,” “ice,” “crystal,” or “glass.” Other amfetamine-like drugs include fenfluramine (used as an appetite suppressant) and methylphenidate (used in narcolepsy and attention deficit hyperactivity disorder (ADHD)). When it was first introduced, one of the most frequent uses of amfetamine was as an anorexigenic agent in the treatment of obesity. A number of anorectic agents, many of them related to amfetamine, have since been manufactured. Most are stimulants of the central nervous system; in descending order of approximate stimulatory potency, they are dexamfetamine, phentermine, chlorphentermine, mazindol, amfepramone (diethylpropion), and fenfluramine.

The amfetamine epidemic of the 1960s and early 1970s has now been superseded by cocaine abuse in the USA and many other Western countries. Realization of the risk of abuse and of dependence has led to the present attitude that there may be only a restricted place for amphetamines in medicine. Perhaps low-dose, short-term use in combating fatigue and altering depressed mood could be justified, but only for specific indications and under continuous medical supervision. However, in the USA there has been a resurgence of metamfetamine abuse on the West coast and in the Southwest and Midwest. This geographical distribution is thought to reflect the traffic from Mexico of ephedrine, a precursor for the synthesis of metamfetamine in the quick-bake method. Because primitive labs can be established in trailers, the spread to adjacent locals has been very rapid, resulting in escalation of migrating epidemics.

Adverse effects of “catecholaminergic stimulants,” such as amfetamine and cocaine, fall into several categories, based on dose, time after dose, chronicity of use, and pattern of use/abuse (for example 4–5 day bingeing episodes). Adverse effects include not only responses during the period of use but also intermediate and long-term residual effects after withdrawal. For example, in some abusers once an amfetamine psychosis has developed with chronic abuse, only one or two moderate doses are required to induce the full-blown psychosis in its original form, even long after withdrawal [ ]. This is also evidenced by the precipitous slide to severe re-addiction in former abusers who are re-introduced to stimulants.

Even with therapeutic use of stimulants, usually in moderate doses, careful monitoring for emergent psychosis, agitation, and abuse is important. Periodic checks for monodelusional syndromes are important with doses in the mid-to-high range [ ].

The use of amfetamine-type stimulants for depression, fatigue, and psychasthenia has fallen into disfavor since the early 1970s, because of the potential for abuse and the low rates of success, especially after tolerance is established. However, there have been reports and reviews of successes in carefully selected groups of patients [ ]. The underlying symptoms of patients who respond to stimulants are mild anhedonia, lack of mental and physical energy, easy fatiguability, and low self-esteem, but in the absence of the marked depressed mood disturbance, guilt, and hopelessness that are associated with major depression. Examples include patients with dysthymic disorders, medically ill patients (especially after a stroke), depressed patients, hospitalized cancer patients, and patients with significant cardiovascular disorders, all of whom can have anergia and easy fatiguability. HIV-related neuropsychiatric symptoms, including depression, respond to psychostimulants [ ]. Withdrawn apathetic geriatric patients without major dementia have positive responses [ ]. General adverse effects, such as tachycardia and agitation, are relatively mild and all reverse on withdrawal [ ]. The combination of stimulants with monoamine oxidase inhibitors in treatment-resistant depressed patients has been reported [ ]. However, this use should be restricted to patients in whom there is careful monitoring by specialists, because of the potential for hypertensive crisis.

The relative reinforcing effects or abuse potential of these drugs is thought to be related to their potency in releasing dopamine from nerve terminals, compared with serotonin release. Amfetamine, metamfetamine, and phenmetrazine are potent dopamine releasers with high euphoriant and stimulant properties, whereas the compounds with halide substitution in the phenol ring, for example chlorphentermine, are more potent releasers of serotonin and have greater sedative action in anorectic doses. Thus, in summary, those drugs with relatively strong serotonergic to dopaminergic releasing properties seem to provide anorectic effects without euphoria, except at high doses, and might be considered first in any patient who has potential for abuse [ , , ].

In a study of extended treatment (15 months) of ADHD, amfetamine was clearly superior to placebo in reducing inattention, hyperactivity, and other disruptive behavioral problems. The treatment failure rate was considerably lower and the time to treatment failure was longer in the treated group; adverse effects were few and relatively mild [ ].

There is an association between the illicit use of metamfetamine and traumatic accidents. A retrospective review of trauma patients in California showed that metamfetamine rates doubled between 1989 and 1994, while cocaine showed a minimal increase and alcohol a fall. Metamfetamine-positive patients were most likely to be Caucasian or Hispanic and were most commonly injured in motor vehicle collisions. The authors recommended intervention strategies, similar to those used for preventing alcohol consumption and driving, in order to minimize morbidity and mortality [ ].

Traumatic shock can be complicated by metamfetamine intoxication [ ]. Identifying the cause of shock is a key step in the management of patients with severe injuries. This is a challenge, because shock is occasionally caused by more than one mechanism; among the many causes, metabolic derangement attributable to drug abuse should be considered, and masked metabolic acidosis may be a clue to metamfetamine intoxication [ ]. With the increased emergence of metamfetamine abuse, clinicians should consider it in the differential diagnosis of any patient exhibiting violence, psychosis, seizures, or cardiovascular abnormalities.

Cardiovascular

Tachycardia, dysrhythmias, and a rise in blood pressure have been described after the administration of centrally acting sympathomimetic amines. Amfetamine acutely administered to men with a history of amfetamine abuse enhanced the pressor effects of tyramine and noradrenaline, while continuous amfetamine led to tolerance of the pressor response to tyramine. As with intravenous amphetamines, cardiomyopathy, cardiomegaly, and pulmonary edema have been reported with smoking of crystal metamfetamine [ ].

The cardiovascular response to an oral dose of d -amfetamine 0.5 mg/kg has been determined in 81 subjects with schizophrenia, 8 healthy controls who took amfetamine, and 7 subjects with schizophrenia who took a placebo [ ]. Blood pressure increased in both amphetamine groups, whereas placebo had no effect. However, pulse rate did not change in the schizophrenic group and only increased after 3 hours in the controls. Intramuscular haloperidol 5 mg produced a more rapid fall in systolic blood pressure in six subjects, compared with 12 subjects who did not receive haloperidol. The authors concluded that increased blood pressure due to amfetamine may have a dopaminergic component. They also suggested that haloperidol may be beneficial in the treatment of hypertensive crises caused by high doses of amfetamine or metamfetamine.

Two cases of myocardial infarction after the use of amfetamine have been reported [ , ].

• A 34-year-old man who smoked a pack of cigarettes a day took amfetamine for mild obesity. He developed an acute myocardial infarction 1 week later. Echocardiography showed inferior left ventricular hypokinesia and a left ventricular ejection fraction of 50%. Coronary cineangiography showed normal coronary arteries but confirmed the inferior left ventricular hypokinesia. Blood and urine toxicology were positive only for amfetamine.

• A 31-year-old man developed generalized discomfort after injecting four doses of amfetamine and metamfetamine over 48 hours, but no chest pain or tightness or shortness of breath. Electrocardiography showed inverted T-waves and left bundle branch block. Echocardiography showed reduced anterior wall motion.

The authors reviewed other reported cases of myocardial infarction associated with amphetamines. The patients were in their mid-thirties and most were men. The interval from the use of amphetamines to the onset of symptoms varied from a few minutes to years. No specific myocardial site was implicated. Coronary angiography in most cases showed non-occlusion. The cause of myocardial ischemia in these cases was uncertain, even though coronary artery spasm followed by thrombus formation was considered the most likely underlying mechanism. Some have suggested that electrocardiographic and biochemical cardiac marker testing should be considered in every patient, with or without symptoms suggesting acute coronary syndrome, after the use of amphetamines. Others have suggested that calcium channel blockers may play an important role in the treatment of myocardial infarction due to amfetamine use or abuse. In one patient, administration of beta-blockers caused anginal pain, suggesting that they should be avoided. All the patients except one had a good outcome.

Coronary artery rupture has been associated with amfetamine abuse [ ].

• A 31-year-old woman suddenly developed central chest pain, with a normal electrocardiogram. Changes in troponin and creatine kinase MB were consistent with acute myocardial infarction. Drug screening was positive for amphetamines and barbiturates. Coronary angiography showed an aneurysm with 99% occlusion of the proximal left circumflex coronary artery and extravasation of contrast material. A stent was inserted percutaneously and antegrade flow was achieved without residual stenosis.

An uncommon presentation of amfetamine-related acute myocardial infarction due to coronary artery spasm has been reported [ ].

• A 24-year-old man developed an acute myocardial infarction involving the anterior and inferior walls within 3 hours of taking intravenous amfetamine. A coronary angiogram showed plaques in the mid-portion of the left anterior descending artery, which developed spasm after the administration of intracoronary ergonovine. He was discharged after treatment with verapamil, isosorbide mononitrate, and aspirin. He subsequently developed early morning chest tightness 2 weeks, 1 month, 2 months, and 9 months after discharge. On each occasion he left against medical advice.

These findings suggest that coronary artery plaques played a role in endothelial dysfunction resulting from amfetamine use, and that induction of coronary artery spasm, a finding not reported before, was the likely mechanism of amfetamine-related acute myocardial infarction.

During short-term treatment with a modified-release formulation of mixed amfetamine salts in children with ADHD, changes in blood pressure, pulse, and QT _c interval were not statistically significantly different from the changes that were seen in children with ADHD taking placebo [ ]. Short-term cardiovascular effects were assessed during a 4-week, double-blind, randomized, placebo-controlled, forced-dose titration study with once-daily mixed amfetamine salts 10, 20, and 30 mg (n = 580). Long-term cardiovascular effects were assessed in 568 subjects during a 2-year, open extension study of mixed amfetamine salts 10–30 mg/day. The mean increases in blood pressure after 2 years of treatment (systolic 3.5 mmHg, diastolic 2.6 mmHg) and pulse (3.4/minute) were clinically insignificant. These findings differ from previously reported linear dose–response relations with blood pressure and pulse with immediate-release methylphenidate during short-term treatment [ ]. These differences may be attributable to differences in timing between dosing and cardiovascular measurements or to differences in formulations. Both amphetamine and methylphenidate have sympathomimetic effects that can lead to increases in systolic blood pressure and diastolic blood pressure at therapeutic doses, although the sizes of the effects on blood pressure may differ [ ].

Vertebral artery dissection has been described in a previously healthy man with a 3-year history of daily oral amfetamine abuse [ ].

• A healthy 40-year-old handed man presented with a 3-day history of an occipital headache and imbalance. He had a 3-year history of daily oral amfetamine abuse with escalating quantities, the last occasion being 12 hours before the onset of the symptoms. He had a history of “speed” abuse and a 20-pack-year history of tobacco use. He had mild right arm dysmetria without ataxia. His brain CT scan without contrast was normal. He then developed nausea, vomiting, visual loss, and progressive obtundation. He had hypertension (160/90 mmHg), bilateral complete visual loss, right lower facial weakness, mild dysarthria without tongue deviation, divergent gaze attenuated by arousal, bilateral truncal and appendicular dysmetria with inability to stand and walk, and generalized symmetrical hyper-reflexia with extensor plantar reflexes. His urine screen was positive for metamfetamine. A brain MRI scan showed infarction of both medial temporal lobes, the left posteromedial thalamus, and the right superior and left inferior cerebellum. Magnetic resonance angiography and fat saturation MRI showed reduced flow in the left vertebral artery and a ring of increased signal within its lumen, consistent with hematoma and dissection. He was treated with anticoagulants and made a partial recovery.

Since this patient had no known risk factors for vertebral artery dissection and had abused amfetamine daily for 3 years with escalating amounts, an association between metamfetamine and vertebral artery dissection could not be excluded. The local and systemic vascular impacts of amfetamine could have contributed to initial changes (along with smoking), resulting in dissection.

Of the other central stimulants, aminorex, doxapram, fenfluramine, and fenfluramine plus phentermine can cause chronic pulmonary hypertension, as can chlorphentermine, phentermine, phenmetrazine, and d -norpseudoephedrine [ ]. A genetic predisposition may be involved [ ]. Pulmonary hypertension may develop or be diagnosed a long time after the drug has been withdrawn.

A rare case of reverse left ventricular apical ballooning syndrome has been attributed to amphetamines [ ].

• A 25-year-old woman developed shortness of breath shortly after inhaling amfetamine. She had a sinus tachycardia (140/minute), a raised blood pressure (160/90 mm Hg), and pulmonary edema. An electrocardiogram showed ST segment depression. Her troponin concentration was raised at 7 ng/ml. An echocardiogram showed an ejection fraction of 20% with basal akinesia and moderate mitral and tricuspid regurgitation. She responded well to diuretic therapy. Ventriculography showed reverse apical ballooning with a hyperdynamic apex and akinetic basal walls. Angiography showed normal coronary arteries. She was discharged taking an ACE inhibitor and metoprolol and an electrocardiogram 2 weeks later showed complete recovery of left ventricular function.

Transient left ventricular apical ballooning syndrome was first described in Japan as “takotsubo cardiomyopathy” (see Adrenaline). Many variations of this syndrome have been reported, but the reverse type of this syndrome, with a hyperdynamic apex and complete akinesia of the base (as opposed to classical apical ballooning) is rare. The term “stress cardiomyopathy” is now commonly used to describe all varieties of this condition, defined as reversible left ventricular systolic dysfunction triggered by an acute stressful event without significant coronary artery disease. This syndrome can involve any segment of the left ventricular wall and has been classified into four types. The authors postulated that amfetamine-induced tachycardia and hypertension triggered reverse takotsubo cardiomyopathy in this patient.

Nervous system

In a case–control study using a telephone survey in California, prolonged exposure to amphetamines (amfetamine, metamfetamine, or dexamfetamine) was associated with an increased rate of Parkinson’s disease [ ]. “Prolonged exposure” was defined as twice per week for at least 3 months, or once a week for at least 1 year. In most cases, prior amphetamine exposure was unknown to the treating physician. The study did not distinguish between prescribed and non-prescribed use of amphetamines. A previous study had suggested amphetamine exposure as a possible risk factor for Parkinson’s disease [ ].

Metamfetamine toxicity in infants can mimic scorpion ( Centruroides sculpturatus ) envenomation [ , ]. However, the neurotoxic effect of envenomation can be distinguished from amfetamine-induced toxicity by the presence of cholinergic stimulation in scorpion envenomation, producing hypersalivation, bronchospasm, fasciculation of the tongue, purposeless motor agitation, involuntary and conjugate slow and roving eye movements, and often extraocular muscle dysfunction [ ]. Failure of the antivenin would bring scorpion neurotoxicity into great question [ ].

Concentrations of metamfetamine and its metabolite amfetamine were measured in autopsied brain regions of 14 human metamfetamine abusers [ ]. There was no evidence of variation in the regional distribution of amphetamines in the brain. Post-mortem redistribution of metamfetamine in the heart and lung has been reported before, although peripheral blood concentrations appear to remain constant [ , ].

Chorea

Chorea has been attributed to amphetamines.

• A 22-year-old man who had had ADHD since the age of 8 years took methylphenidate, and had an adequate response for 14 years [ ]. However, his symptoms worsened and he switched from methylphenidate to mixed amfetamine salts 20 mg bd. A month later he continued to have difficulty in focusing on tasks, and the dosage was eventually increased to 45 mg tds over several weeks, with symptomatic improvement. However, 5 days later, he awoke feeling nauseated and agitated and had choreiform movements of his face, trunk, and limbs. He had also taken escitalopram 10 mg/day for anxiety and depression for 2 months before any changes in his ADHD medications. He was treated with intravenous diphenhydramine, lorazepam, and diazepam without improvement in the chorea. Amfetamine was withdrawn and 3 days later his chorea abated. He restarted methylphenidate and the movement disorders did not recur.

• Choreoathetosis worsened in an 8-year-old boy with learning disabilities when he was treated with dexamfetamine, recurred on rechallenge with the same dose, and immediately resolved with diphenhydramine [ ].

The authors of the first report speculated that long-term therapy with methylphenidate could have desensitized the patient to the effects of amphetamines, since these drugs act in similar ways. It is also possible that amphetamine therapy interacted with the escitalopram. For this reason, they suggested caution when treating ADHD patients with amphetamines when they are also taking an SSRI.

Psychological, psychiatric

Amphetamines release monoamines from the brain and thereby stimulate noradrenergic, serotonergic, and particularly dopaminergic receptors. Under certain circumstances this leads to psychosis and compulsive behavior, as well as auditory hallucinations similar to those experienced in paranoid schizophrenia. In addition, amphetamines cause an acute toxic psychosis with visual hallucinations, usually after one or two extremely large doses [ ].

When an amfetamine is taken, even in a therapeutic dose, most people experience a sensation of enhanced energy or vitality, which, with repetitive administration, follows different patterns. Most often euphoria will develop, usually with a sense of heightened function or perception, and occasionally compulsive behavior as well as hallucinogenic delusions. Dysphoria occurs in some (especially older) individuals. The euphoric effect may enhance craving for amfetamine, and repeated reinforcement can lead to conditioned drug responses, which may facilitate dependence. Progression to severe dependence depends highly on individual vulnerability, the circumstances, the setting, the pattern of use, and especially escalation to high-dose patterns of use. Although most people probably use amphetamines for the original reason they were prescribed, and do not escalate the dosage, a significant proportion do, highlighting the abuse potential. The amphetamines are sometimes used recreationally for years in moderate doses. However, once inhalation and intravenous administration or higher doses are used, a “high-dose transition” into abuse usually occurs, and the capacity for low-dose occasional use is lost, presumably, forever (see the sections on Drug abuse and Drug dependence in this monograph).