Wednesday, 22nd March 2017

Amphetamines

Amphetamine Toxicity

General Introduction

Much of the scientific literature as to the acute toxic effects of amphetamines has focused on amphetamine psychosis – a condition similar to schizophrenia.  This condition tends to be associated with use of the drug at high dosages and/or for prolonged periods.  The maximum therapeutic dose is 60mg dexamphetamine (equivalent to 120mg ‘pure’ illicit amphetamine which is an equal mix of two stereoisomers – d-amphet being psychoactive whereas l-amphet is not), but even therapeutic doses can give rise to psychotic symptoms.
The most common side-effects of amphetamine, according to the British National Formulary, are “insomnia, restlessness, irritability and excitability, nervousness, night terrors, euphoria, tremor, dizziness, headache; convulsions, dependence and tolerance, sometimes psychosis; anorexia, gastro-intestinal symptoms, growth restriction in children, dry mouth, sweating, tachycardia (and anginal pain), palpitation, increased blood pressure; visual disturbances; cardiomyopathy reported with chronic use; central stimulants have provoked choreoathetoid movements, tics and Tourette syndrome in predisposed individuals... very-rarely angle-closure glaucoma;”  In overdose situations the BNF advises “These cause wakefulness, excessive activity, paranoia, hallucinations, and hypertension followed by exhaustion, convulsions, hyperthermia, and coma. The early stages can be controlled by diazepam or lorazepam; advice should be sought from the National Poisons Information Service (see Further Information and Advice) on the management of hypertension. Later, tepid sponging, anticonvulsants, and artificial respiration may be needed.”

Schiorring described the typical pattern of psychotic behaviours following amphetamine intoxication “The following behavioral aberrations in humans were found: (1) motor stereotypies with bizarre movements; repetitive, aimless activities; ("pottering"= "knick-knacking"= "punding") with various objects, including own body; repetition of single words, phrases or musical expressions; stereotyped drawing and writing (phenomena which are examples of mental stereotypy); (2) social stereotypies: prolonged sexual intercourse without ejaculation; collective monologues; (3) social withdrawal: "autism", social isolation with no or inappropriate responses to social stimuli; (4) paranoia; (5) hallucinations and illusions: auditory, visual, tactile (microhallucinations).”

Overdose/Poisoning

The scientific literature contains many references to case-histories involving amphetamine poisoning, with fatal and/or sublethal symptoms including pyrexia, asthmatic attacks, seizures, cerebral vasculitis (inflammation of small blood vessels in the brain), pulmonary oedema acute renal failure and convulsions, myocardial infarction (heart attack), cardiorespiratory arrest, infectious endocarditis, movement disorders toxic epidermal necrolysis

Case Studies:  Derlet et al reviewed 127 cases of acute amphetamine toxicity admitted to hospital as emergencie cases, noting “The most common presenting symptoms seen were agitation, hallucinations, suicidal behavior, and chest pain.”  Soong et al noted two cases of infant toxicity, finding clinical signs to include “restlessness, hyperactivity, hypertension, tachycardia and tachypnea”  Chern & Tsai reported a case of perverse catatonia in a 30 year old woman “who developed immobility, rigidity, mutism and staring after the intake of four grams of amphetamine powder. She initially had generalized twitching, but finally came to a state of total immobility. One hour after admission, apnea and cyanosis occurred suddenly and she died about half an hour later.”

Williamson et al surveyed 158 users of stimulant drugs, finding side-effects to include “anxiety problems, depression, mood swings, feelings of paranoia, and panic attacks. Sleep and appetite disturbances were the most commonly reported problems. About half of all subjects reported depression and paranoid feelings associated with their stimulant use.” and noting “Amphetamine use was associated with significantly more adverse effects and with more severe adverse effects than Ecstasy or cocaine.”  Gray et al reviewed 156 amphetamine-related admissions, finding “Of those 156 patients, over half were habitual drug users (89 [57.1%] used amphetamines at least weekly), and the majority were men (111 [71.2%]). The mean age was 28 years (range, 16-55 years). Presentations were of high acuity: 104 patients [66.7%] were rated 1, 2 or 3 on the Australasian Triage Scale; 50 (32.1%) arrived by ambulance; and 25 (16.0%) arrived with police. The mean time spent in the ED was 6 h (range, 0.5-24 h). Fifty patients (32.1%) required sedation, and the likelihood of requiring sedation increased almost threefold if the heart rate was over 100 beats/min on presentation. Sixty-two patients (39.7%) were admitted and 58 (37.2%) required psychiatric evaluation. Repeat attendance was common, with 71 patients (45.5%) having previous amphetamine-related presentations to the RPH ED. Patients are often agitated and aggressive, require extensive resources, and frequently re-attend.”

Lan et al reported features of acute methamphetamine intoxication in 18 patients, comparing clinical signs of those who survived with patients who died, concluding “the adverse prognostic features in patients with acute methamphetamine intoxication include coma, shock, convulsion, oliguria, and high core temperature. Acidosis, volume depletion, and ischemic renal damage were potential risk factors for development of acute renal failure in these patients.”  Bae et al found “white matter hyperintensities in methamphetamine abusers, which may be related to methamphetamine -induced cerebral perfusion deficits. In addition, female methamphetamine abusers had less severe white matter hyperintensities than male methamphetamine abusers, possibly due to estrogen's protective effect against ischemic or neurotoxic effects of methamphetamine.”

Nakatani & Hara described two case studies reporting disturbance of consciousness following methamphetamine use “Following consecutive methamphetamine administration, the patients developed acute intoxication, during which time they showed a unique type of disturbance of consciousness: delirium and twilight state. In both cases, mental status changed, passing through three distinct stages: restlessness and insomnia, hallucinatory paranoid state, and disturbance of consciousness.”  Robertsen et al described 5 patients admitted with amphetamine overdose, and noted “Two of the patients died: one with disseminated intravascular coagulation and circulatory collapse, one with severe rhabdomyolysis and ischemic colitis. Among the other three cases, one developed acute psychosis, hyperthermia and rhabdomyolysis, one developed acute respiratory distress syndrome and one pericarditis.”  Kashani and Ruha reported on the case of a 20 year old female who suffered “multiple seizures, altered mental status, tachycardia and hypertension shortly after admitting to having drugs (methamphetamine) enclosed in plastic bags in her vagina” There is emerging evidence that use of cannabis can offer some protection against amphetamine-induced neurotoxicity

Reviews:  Hedetoft & Christensen found symptoms of stimulant poisoning to include “tachycardia, hypertension and seizures, later hypotension and coma. Hyperpyrexia, rhabdomyolysis and affections of the kidneys, lung and liver function are also often seen. Hyperpyrexia is an important marker of poor prognosis, and must be handled aggressively.”  Gettig et al described symptoms of methamphetamine abuse as “agitation; aggressive behavior; rapid mood swings; hypertension; tachycardia; and eventually lesion-marked skin, clinical depression, and paranoid psychosis”

 

Reviewing drug-related deaths in the UK, Webb et al noted “stimulants particularly featured in traumatic accidents, with amphetamine use most associated with cardio-vascular fatality”  Degenhardt et al, reviewing drug-related deaths in Australia, found “suicide was the most prevalent underlying factor, particularly for amphetamine... related deaths”  A 30 year trawl of cases in Belgium by de Letter et al found “Acute to subacute cardiopulmonary failure was the most frequent mechanism of death, followed by (poly)trauma, mechanical asphyxia, and hyperthermia, respectively.”

A level teaspoon is likely to contain between 3 and 5 grams of amphetamine powder.  Assuming the purity to be 8% this would be equivalent to between 240 and 400mg pure drug, or 2-3 times the maximum therapeutic dose.  Such a quantity would represent a very high dose for a first-time user, who might expect to use 30-50mg as a recreational dose.

Brain Haemorrhages

Amphetamine causes increases in heart rate and blood pressure, and can cause significant increases in cerebral blood flow with overall increases of around 30% and can be doubled in local regions of the brain, particularly the left frontal cortex  This activity can lead to haemorrhages and other forms of stroke.  Karch et al, reviewing 413 methamphetamine-related deaths noted “ten cases of subarachnoid and intracranial hemorrhage in the methamphetamine-related group” and concluded: “Methamphetamine use is strongly associated with coronary artery disease and with subarachnoid hemorrhage.”

First-time users of amphetamine are not immune from risk, Brorholt-Petersen et al described “a fatal case of massive intracerebral hemorrhage in a 20-year-old woman after first-time amphetamine abuse”, and neither are users of low-doses – El-Omar et al described “a young female who suffered a massive intracerebral bleed following the ingestion of a small quantity of amphetamine (speed)”.

Diet-pills: Forman et al noted “several cases have been reported of patients in whom intracerebral hemorrhage developed, with and without concomitant angiographic evidence of vasculitis, after taking phenylpropanolamine.”  Propanolamine was also associated with “several neurological manifestations including psychosis, stroke, severe headache, seizures, and intracerebral hematoma.” by Glick et al, who reported “a case of intracerebral hematoma and subarachnoid hemorrhage in a young woman with angiographic and biopsy-proven vasculitis of the central nervous system (CNS) induced by PPA in her diet pills”  Edwards et al reported “the case of a young woman who suffered a cerebral infarction after taking a single oral dose of phenylpropanolamine” while Stoessl et al reported “two cases of serious intracerebral haemorrhage occurring in young women following their first use of oral medications containing catecholaminergic agents (phenylpropanolamine in combination with ephedrine or pseudoephedrine).”

Case Studies:  Jha et al reported a case of “non-hypertensive intracerebral hemorrhages ... subsequent to ... amphetamine abuse”  In a study of subarachnoid hemorrhage Kothavale et al reported “history of prior cocaine or amphetamine use... were predictive of LV regional wall motion abnormalities”  Klys et al reported “the death of a young female drug addict due to intracerebral hemorrhage. Liquid chromatography with mass spectrometry (determined presence) of amphetamine within an intracerebral hematoma that had persisted for 13 days. In view of the fact that the deceased was young, did not suffer from any detectable diseases, and the narcotic substance was only detected within the hematomas, the case should be classified among rare complications of amphetamine abuse.”  Haematomas were also attributed to amphetamine use by Agaba et al

Schuff et al reported “Cerebral hemorrhages are rare complications that occur after the consumption of amphetamine; the mortality rate is estimated at 50 %. It is assumed that cerebral hemorrhages are caused by amphetamine-induced hypertensive crises coinciding with pre-existing vascular alterations (congenital vascular malformations, vasculitis). In the present case report, a 40-year-old man, who is said to have regularly consumed hashish, heroin and speed, died of a massive cerebral hemorrhage located in the region of the basal ganglia shortly after the intravenous administration of amphetamine and heroin. In the course of the post-mortem investigation, neither vascular malformations nor vasculitis could be detected in the brain.”

Ho et al reported a case of subarachnoid haemorrhage attributed to ecstasy (MDMA), Chen et al noted amphetamine to be “a potent sympathomimetic that may lead to vascular events, including stroke and myocardial infarction. Most reports of stroke after amphetamine abuse are of intracerebral hemorrhage. In this report, the authors describe a ruptured aneurysm of the right internal carotid artery in a young man with amphetamine abuse.”  Auer et al warned “A history of severe headache immediately after using amphetamine, Ecstasy, or cocaine should alert doctors to the possibility of intracerebral haemorrhage.”  Moriya et al described the death of a 44 year old male following “massive hemorrhage in the cerebral ventricles” concluding “intraventricular hemorrhage might have occurred shortly after intravenous self-administration of methamphetamine. Cerebral arterial spasm and hypertension resulting from the administration of methamphetamine might have resulted in intraventricular hemorrhage”  Kaku et al noted “Cocaine, especially recently, was the drug used most frequently in drug-related strokes.”

Janik et al described “young male who suffered intracerebral hemorrhage (ICH) following nasal use of amphetamine. He recovered completely within several weeks of hospitalization. Angiography and MRI did not reveal vascular malformation and therefore we suspect that the ICH in our patient may be attributed to the effect of amphetamine alone.”  Perez et al described four cases of methamphetamine-related stroke from one hospital, Chaudhuri et al reported an amphetamine-induced “massive intracerebral hemorrhage” and concluded “Amphetamine or other illicit drug abuse should be considered in young patients with cerebrovascular events”, Goplen et al described “five fatal cases of intracerebral haemorrhage following use of amphetamine. The symptoms occurred few hours after amphetamine intake, and all patients had considerably increased blood pressure upon admission. Autopsy was performed on four of the patients and did not reveal any predisposing factors for haemorrhage, such as trauma, vascular malformations or vasculitis” concluding “Cerebral CT should always be performed when severe headache and/or altered consciousness occur in relation to abuse of amphetamine-like compounds.” 

Liao et al described a 28 year old man with a history of amphetamine abuse who suffered “acute inferior wall myocardial infarction and cerebral hemorrhage.”  Selmi et al reported “two cases of intracerebral haematoma due to amphetamine abuse whether an underlying arteriovenous malformation was found” concluding “Amphetamine abuse may be complicated by intracerebral, subdural or subarachnoid haemorrhage.”  An “Intraventricular hemorrhage following amphetamine abuse” was reported by Imanse et al, while Lessing et al reported an “Intracranial haemorrhage caused by amphetamine abuse” and Kringsholm described a “fatal intracerebral hemorrhage associated with consumption of amphetamine”  Conci et al described “intracerebral hemorrhage and spasm-induced changes in the cerebral vessels.” Biller et al noted a case of subarachnoid hemorrhage caused by amphetamine arteritis, whereas Sine et al described “callosal syndrome following cerebral hemorrhage and amphetamine abuse in a 26-year-old right-handed man” Salanova et al reported “a case of amphetamine-related intracranial haemorrhage and vasculitis” and Harrington et al noted “Four patients suffered intracerebral hemorrhages following the oral or nasal use of amphetamine or related compounds. Two of these patients had abnormal-appearing cerebral blood vessels on angiography. Review of previously reported cases showed that intracerebral hemorrhage may occur in patients using the drug for the first time and for nonrecreational purposes.”

Matick et al noted “Cerebral vasculitis associated with oral amphetamine overdose.”, Wooten et al reported “Intracerebral hemorrhage occurred in a 20-year-old man following self-administration of ephedrine. Changes seen on cerebral angiography were typical of vasculitis” Lukes reported “Intracerebral hemorrhage from an arteriovenous malformation after amphetamine injection.” and Shukla “Intracranial hemorrhage associated with amphetamine use.”  Early papers described similar case histories

It is possible to misattribute a drug-related cause to a haemorrhage where insufficient investigation has occurred, Magdalan et al reported “A 27-year-old man was found unconscious in a street. A head CT revealed numerous small intracerebral hemorrhages, and patient's urine contained high concentration of amphetamine. A presumptive diagnosis of amphetamine poisoning complicated by intracranial hemorrhage was proposed. The repeat head CT revealed traumatic injury of the skull in a form of depression. Based on this result, the patient was diagnosed with a posttraumatic intracranial hemorrhage.”

Reviews:  In a review of cerebral haemorrhage cases, Dale et al concluded “Intracerebral bleeding in the younger age group was related to arteriovenous malformations, abuse of heroin or amphetamine.”  Buxron & McConachie concluded “Amphetamines taken by any route can cause cerebral vasculitis and intracranial haemorrhage. 8 cases were seen in a neurosurgical unit over 3.5 years. The published work indicates that those who experience these complications, mainly young adults, have poor outcomes.”  Uldri et al concluded “Cerebrovascular complications are also noticed in abusers of cocaine or other stimulants of the central nervous system: amphetamine, phenylpropanolamine, xanthines.”

In a 1977 review, Olsen noted “A review of the English-language literature produced 3 other cases of fatal amphetamine-induced intracranial hemorrhage and seven nonfatal cases. Some were the result of overdose, others of hypersensitivity. Angiographic evidence suggests that such hemorrhages result from the development of fibrinoid necrosis and the formation of microaneurysms in the small intracerebral vessels.”  In 1975 Kalant & Kalant reported “43 reports of deaths associated with amphetamines in a 35-year period. These included seven cerebrovascular accidents, six sudden cardiac deaths, three cases of hyperpyrexia, eight poisonings of uncertain mechanism and seven cases of medical complications of intravenous injection; the remainder were of uncertain cause.”

Diez-Tejedor et al concluded “Amphetamine and cocaine have a potent sympathicomimetic action, so they have important effects on the Central Nervous and Cardiovascular Systems. Their neurological complications are principally: psychic alterations, seizures and stroke (hemorrhagic and ischemic). The latter are the most important in the clinical practice. Their capacity to produce transit arterial hypertension and cerebral vascular constriction could be the physiopathological substrate of such alterations” Buchanan et al noted “amphetamine overdose characterised by tachycardia, hypertension, hyperthermia, diaphoresis, mydriasis, agitation, muscle rigidity, and hyper-reflexia. Death usually results from arrhythmias, hyperthermia or intracerebral haemorrhage”