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Amphetamine Toxicity
Introduction
Amphetamine abuse is widespread and associated with a significant impact on cardiovascular and neurological systems in overdose. In many parts of the world, amphetamines have been an abused class of drugs since the 1930s. Methamphetamine (METH) and its derivative, 3,4-methylenedioxymethamphetamine (MDMA), are extensively abused drugs, and the acute effects of these drugs include increased alertness, hyperthermia, decreased appetite, and euphoria. However, long-term abuse can result in neurotoxicity and psychosis. Amphetamines increase the neurotransmission of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) by entering neurons via the 5-HT and DA transporters and displacing storage vesicles. MDMA has a greater affinity for 5-HT transporters, causing an increased release of 5-HT. The clinical effects of amphetamine overdose are significant and usually observed in emergency departments.[1][2][3]
Etiology
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Etiology
Amphetamine use, both acute and chronic, may lead to amphetamine toxicity. Amphetamine use has increased steadily over time.[4] The reasons for the increased use of amphetamines are numerous, including a sustained desire for favorable drug effects like euphoria, mood elevation, and appetite suppression, the availability of amphetamine compounds as both legal and illegal substances, an increase in the production of amphetamines for sale in the illegal drug trade, and the affordability of illicit amphetamines as compared to other illicit drugs.[4] Recently, stress and anxiety related to the COVID-19 pandemic may have also contributed to increased amphetamine use.[5] Amphetamine dependence is not a prerequisite for toxicity, but those who become dependent on amphetamines may be at higher risk of experiencing it. Dependence is likely due to increased tolerance to amphetamine effects and the requirement of escalating doses to achieve the desired effect.
Epidemiology
In 2021, it was estimated that 36 million people used amphetamines across the globe. The majority of amphetamine users (55%) are men. For people undergoing treatment for drug use disorders, amphetamines are the primary drug of abuse 18% of the time in the Americas and 42% of the time in Asia.[United Nations Office of Drugs and Crime World Drug Report, 2023] The 2023 "Monitoring the Future Survey" estimated that 2.1% of adolescents in the US used illicit amphetamines.[Monitoring the Future National Survey Results on Drug Use, 1975-2023] Additionally, an estimated 1.8 million Americans 12 years and older have a methamphetamine use disorder.[SAMHSA NSDUH, 2022]
Pathophysiology
Amphetamines are structural analogs of the neurotransmitter phenethylamine (see Image. Phenethylamine Chemical Structure and Image. Amphetamine Chemical Structure), which regulates monoamine neurotransmission through the modulation of the trace amine-associated receptor 1 (TAAR1) and inhibition of the vesicular monoamine transporter 2 (VMAT2). TAAR1 is expressed in multiple locations within the central nervous system (CNS), including the dorsal and ventral caudate nucleus, putamen, substantia nigra, nucleus accumbens, ventral tegmental area, locus ceruleus, amygdala, and raphe nucleus.[6] Many of these areas play important roles in the development of addiction. Thus, the use of amphetamines begets the desire to continue using amphetamines.
The effects of TAAR1 agonism may extend beyond the central nervous system. Downstream effects from receptor activation may lead to increased reactive oxygen species, mitochondrial dysfunction, and alterations in intracellular calcium. These metabolic abnormalities have been implicated in the accelerated development of cardiovascular disease.[7][8][9] Amphetamines also cause necrotizing vasculitis of small- and medium-sized blood vessels, which can yield a myriad of end-organ complications (strokes and neurodegenerative diseases, coronary artery disease, ischemic bowel disease). The underlying etiology is not well understood and may result from the amphetamines or potential adulterants or contaminants.[10][11][12][13][14]
Toxicokinetics
Amphetamine has an oral bioavailability of about 75%. Peak plasma concentrations are found approximately 3 hours after ingestion. Peak cardiovascular effects occur approximately 1 hour after ingestion, while behavioral changes are seen around 2 hours after ingestion.[15] No ceiling effect has been noted.[16] However, these effects are relatively short-lived, owing to a rapid decline in monoamine release after peak concentrations are reached. Amphetamine is hepatically metabolized by multiple enzymes, including (cytochrome) CYP2D6, dopamine β-hydroxylase, and flavin-containing monooxygenase-3.[17] Only 30% to 40% of amphetamine is eliminated as an unchanged drug in the urine. An acidic urine pH traps amphetamine in the renal tubules and decreases its elimination half-life.[18]
Methamphetamine can be ingested orally, insufflated nasally, smoked, or injected intravenously. Bioavailability is reliable (~70% or greater) with these ingestion routes. Peak serum concentrations of methamphetamine occur approximately 3 to 6 hours after oral ingestion. Nasal insufflation leads to a peak serum concentration in 5 to 10 minutes, and smoking leads to peak serum concentrations within 5 minutes. Methamphetamine is more lipophilic than amphetamine and is less prone to metabolism by monoamine oxidase. Methamphetamine is hepatically metabolized and renally eliminated, similarly to amphetamine.
History and Physical
Amphetamines are used for fatigue, appetite suppression, and narcolepsy treatment. Patients experiencing amphetamine toxicity thus often present with anorexia, dehydration, weight loss, and insomnia. Patients may be highly agitated, even to the point of risking the safety of healthcare staff and themselves. Patients should be asked what drug(s) they used, the route of administration they utilized, and the duration of their drug use. Blood pressure, heart rate, and other vital signs should be taken immediately upon presentation. The physical examination should include assessments for hyperthermia, evidence of end-organ damage (eg, neurological deficits, respiratory compromise, or new cardiac murmurs), and skin ulcerations or abscesses.
Evaluation
When patients appear intoxicated and have symptoms consistent with amphetamine toxicity, testing for metabolites of amphetamine can be useful to confirm a diagnosis of the condition. However, ingestion of some amphetamines, including 3,4-methylenedioxymethamphetamine, will not reliably result in a positive test for the presence of amphetamines.[19][20] Conversely, some non-amphetamine medications may cause false-positive results for the presence of amphetamines. These drugs include pseudoephedrine,[21] mebeverine,[22] metoprolol,[23] tetracaine,[24] dimethylamylamine,[25] aripiprazole,[26] and ranitidine.[27] Thus, clinicians should not rely on drug metabolite testing alone to make a diagnosis of amphetamine toxicity. Obtaining an accurate medication history for the patient may allow a diagnosis to be made independently of drug metabolite testing. Therefore, obtaining medication histories should always be a focus during the evaluation of patients who are intoxicated.
Additionally, laboratory and radiologic evaluation for patients with suspected amphetamine toxicity should focus on confirming that the toxic effects of amphetamines are present and ruling out other causes for them. Dehydration and hyponatremia may be confirmed with a basic metabolic panel. An electrocardiogram, chest x-ray, and troponin test are necessary to assess the presence of coronary ischemia, including myocardial infarction and aortic dissection. Computed tomography of the head is also useful to assess hemorrhagic stroke as a potential cause of neurologic deficits. Finally, obtaining serum creatine kinase and lactic acid levels may help identify muscle damage and tissue ischemia related to tonic-clonic seizures, myoclonus, or hyperthermia.
Treatment / Management
Treating amphetamine toxicity is supportive. There are no specific antidotes for amphetamine or amphetamine-like compounds. Therefore, treatment should focus on symptom and complication management. Patients with agitation should be treated with parenteral benzodiazepines. Diazepam is an ideal choice if intravenous access is available; otherwise, intramuscular lorazepam or midazolam is appropriate.
Patients who present with delirium may benefit from adjunctive treatment with a dopamine antagonist, like haloperidol. However, while the dopamine blockade can help treat the psychiatric and psychomotor disorders associated with amphetamine toxicity, these agents may cause harm. They can decrease the seizure threshold,[28] cause extrapyramidal side effects, increase heat production by altering thermoregulatory function,[29][30][31] and prolong the QTc interval. Thus, judicious and cautious use of these agents in the setting of amphetamine toxicity is required. (B2)
Hypertension related to amphetamine toxicity may abate with agitation treatment. However, some patients may require antihypertensive treatment to combat hypertensive urgency or emergency. Peripheral vasodilators like nitroglycerin and nicardipine may be effective in lowering blood pressure. Beta-blockers should not be used as sole antihypertensive therapies as their use may lead to unopposed α-adrenergic tone and a worsened hypertensive state. Similarly to hypertension, hyperthermia may abate with the treatment of agitation. However, external cooling with ice baths, misting, or cooled IV fluids may also be required to achieve euthermia. External cooling therapies should be rapidly administered when patients present with temperatures exceeding 107 °F.
Seizures should initially be treated with parenteral benzodiazepines. Barbiturates and propofol may be added for further seizure control. Phenytoin, fosphenytoin, and valproic acid should be avoided due to their ineffectiveness in aborting toxicologic seizures. There are no approved treatments for amphetamine use disorder. Naltrexone has been evaluated for this indication based on its ability to decrease the effects of the dopamine reward system. Some studies have shown promising results for naltrexone.[32][33] In contrast, others have shown a lack of appreciable effects on cravings or amphetamine use.[34][35][36] However, many of these studies were conducted on animals. There is an overall paucity of high-quality data from human subjects to base conclusions on naltrexone's efficacy. As a result, consultation with an addiction specialist, cognitive behavioral therapy, and group therapy remain the primary means to treat amphetamine use disorder.(A1)
Differential Diagnosis
To diagnose amphetamine toxicity, other toxicities need to be explored, including toxicities to cocaine, methylxanthine, phencyclidine, and other sympathomimetics. Neurocognitive disorders and stroke should also be ruled out. Schizophrenia, mania, alcohol withdrawal, and meningitis should also be considered.
Complications
Clinicians should screen patients experiencing amphetamine toxicity for complications related to the sympathetic surge that accompanies it. These complications include hemorrhagic strokes,[37][38][39] seizures,[40] hyperthermia,[41][42] serotonin syndrome, acute coronary syndrome,[43][44], cardiomyopathy,[45][46] cardiac valvulopathies,[47][48] aortic dissection,[49][50] rhabdomyolysis,[51] dehydration, acute kidney injury, arrhythmias, and hyponatremia.[52] Additionally, amphetamine toxicity may result in widespread vasospasm. These widespread vasospastic effects can cause ischemia anywhere in the body, including the bowel.[53][54][55][56] Lastly, amphetamine intoxication may be associated with psychosis, paranoid delusions, and hallucinations that resemble schizophrenia.[57][58][59]
Patients who chronically use amphetamines have an increased risk of developing pulmonary hypertension,[60][61][62] heart failure, and embolic strokes. Additionally, patients who chronically use amphetamines often have poor nutritional status, [63][64] oral hygiene, and widespread skin lesions.[65][66] Frequently, skin lesions result from delusions parasitosis, or Ekbom syndrome, where patients pick at their skin to remove imaginary insects.[67] Chronic use of amphetamines can also cause choreoathetoid movements, which can persist from weeks to years after cessation of amphetamine use.[68][69]
Deterrence and Patient Education
When treating a patient with an amphetamine use disorder, it is important to first medically stabilize them and then discuss the complications associated with use and ascertain their readiness for help and treatment. If they desire treatment and sobriety, they should be connected to an outpatient clinic that can provide further management.
Enhancing Healthcare Team Outcomes
Physicians, advanced practitioners, nurses, pharmacists, and other healthcare professionals play critical roles in managing amphetamine toxicity. They must accurately identify symptoms, assess severity, and differentiate toxicity from other conditions, utilizing comprehensive evaluations and medication histories. Effective communication and collaboration among team members facilitate coordinated care, ensuring patient safety and optimized outcomes. Clinicians must also apply evidence-based strategies in symptom management and complication prevention, utilizing supportive care approaches. Continuous evaluation and improvement of interventions enhance patient-centered care, promoting a holistic approach to addressing amphetamine abuse and associated toxicities.
Media
(Click Image to Enlarge)
Amphetamine Chemical Structure. The illustration describes the structure of the stimulant amphetamine.
Public Domain via Wikimedia Commons
(Click Image to Enlarge)
Structure of amphetamine. creative commons license
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