Continuing Education Activity

Amphetamines belong to a class of compounds called phenethylamines which induce catecholaminergic effects in the CNS and peripheral circulation. Recreational use of amphetamines has reached epidemic proportions in Asia, Australasia, and the United States. Most agree that psychosis following amphetamine use is characterized by persecutory delusions, visual hallucinations, and symptoms resembling acute psychosis most commonly observed in schizophrenia. This activity reviews amphetamine-related psychiatric disorders, including pathophysiology, presentation, and diagnosis, and highlights the interprofessional team's role in the management of these patients.

Objectives:

• Identify the pathophysiology of amphetamine-related psychiatric disorders.
• Outline the typical presentation of a patient with amphetamine-related psychiatric disorders.
• Outline the available treatment and management options for amphetamine-related psychiatric disorders.
• Discuss the interprofessional team strategies for improving care and outcomes in patients with amphetamine-related psychiatric disorders.

Introduction

Amphetamines, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), belong to a class of compounds called phenethylamines which induce catecholaminergic effects in the CNS and peripheral circulation. Amphetamine was first manufactured in 1893 to treat asthma and upper respiratory congestion, but indications and usage in the medical field have increased over the last century. Today, amphetamines are clinically used to treat short-term obesity, narcolepsy, and attention deficit disorder with hyperactivity. Recreational use of amphetamines has reached epidemic proportions in Asia, Australasia, and the United States. The majority of illegal amphetamines in North America are produced in rural areas of Mexico and the United States in clandestine labs. Amphetamines can be easily manufactured using common household materials, including acetone, red phosphorus, sodium hydroxide, sulfuric acid, ammonia, toluene, along with over-the-counter medicines, ephedrine, and pseudoephedrine.[1][2]

The routes of amphetamine administration may be inhalation, intravenous, intramuscular, or transmucosal (oral/nasal). Peak plasma levels can range from 5 to 10 minutes via intravenous administration and up to 2 to 3 hours if taken transmucosal. Symptoms typically last hours to days, based on dosage and strength, and dissipate once the drug is eliminated from the body. Given the acute symptoms associated with amphetamine intoxication, it is difficult for the clinician to distinguish amphetamine-associated psychosis from the acute psychosis of a primary mental disorder. Most agree that psychosis following amphetamine use is characterized by persecutory delusions, visual hallucinations, and symptoms resembling acute psychosis most commonly observed in schizophrenia.

There is also a clear pattern of high dosage and daily usage correlating with higher risks of substance-induced psychosis. Amphetamines impair the cognitive thought process and subsequently precede acute psychosis. This suggests that continued impairment due to amphetamine use is a precursor to psychosis.

Etiology

Amphetamine-related psychiatric disorders are frequently associated with acute and chronic use of amphetamines, and these disorders have been extensively studied for methamphetamine in particular.

Epidemiology

After cannabis, amphetamines are the most widely abused illicit drug worldwide. According to the 2019 United Nations World Drug Report, it is estimated that in 2017, roughly 0.6 percent of the global population aged 15–64, or 29 million people, had used amphetamines in the past year. Of these, an estimated 17 million people are dependent on amphetamines. Based on the most recent 2018 United States National Survey on Drug Use and Health, approximately 1.9 million people aged 12 or older used amphetamines in the past year, with overall use remaining steady since 2015. Overdose deaths attributed to amphetamines increased by 33% from 2015 to 2016, with 10,333 overdose deaths in 2017.[3] Demographic characteristics associated with increased risk of amphetamine use disorder include living in rural areas, Caucasian, Hispanic and Asian ethnicities, lower socioeconomic status, male gender, preexisting mood disorder, adverse childhood events, and prior substance use disorders.[4][5][6]

In addition to this, patients who have an amphetamine use disorder and are entering substance abuse treatment centers have a higher likelihood of being referred by the criminal justice system than patients with all other substance use disorders combined (59% versus 38%). Users of amphetamines are also twice as likely to need long-term treatment than users of other drugs (17% versus 8%). Some studies have suggested about 30% of patients with amphetamine-induced psychosis end up with a primary psychosis over time.

Pathophysiology

Amphetamines inhibit monoamine (dopamine, norepinephrine, epinephrine, serotonin) reuptake, leading to increased monoamine concentrations in the neuronal synapse. Amphetamines can also lead to increased monoamines in the cytosol by interactions with vesicular monoamine transporter 2. Dopamine and norepinephrine release in the nucleus accumbens results in a feeling of euphoria and a reward feedback loop, which may result in addiction. In vivo studies found changes in the prefrontal cortex of rats exposed to repeated amphetamine use. This leads to a change in cognitive-behavioral function, which is thought to be a precursor to primary psychosis.[7]

Studies also suggest increased dopaminergic pathways lead to glutamate excesses in the cerebral cortex, altering the function of cortical GABAergic neurons. This damage leads to dysregulation of glutamate in the cerebral cortex, a precursor to psychosis. Prior psychiatric studies have found that GABAergic cortical dysfunction seems to relate to schizophrenia.

Toxicokinetics

Amphetamines belong to a class of CNS stimulants called phenethylamines. Amphetamines contain a methyl group to the alpha position on its carbon chain resulting in lipophilicity, increasing its volume of distribution, and CNS stimulation. Amphetamines block monoamine reuptake transport systems resulting in high synaptic concentrations. Amphetamines are also indirect neurotransmitters leading to increased cytosolic levels of monoamines. It is theorized the excess dopamine in the cytosol leads to drug craving and seeking and psychiatric symptoms. These two processes lead to both alpha and beta-adrenergic receptor stimulation, causing sympathomimetic symptoms (hypertension, tachycardia, hyperthermia, vasoconstriction, and diaphoresis). Amphetamines are metabolized via the cytochrome CYP2D6 pathway and renally and hepatically excreted.

History and Physical

Amphetamine-related psychiatric disorders can occur with acute or chronic use. Acute amphetamine use with resultant psychosis can present like a sympathomimetic toxidrome. Vital signs and a detailed history are difficult to obtain secondary to agitation, paranoia, and the extent of psychosis. The diagnosis should be considered in any patient with tachycardia, hypertension, and psychosis. If possible, the history should focus on the route of administration, dosage (amount and the number of usages), and time frame. Clinicians should also ask about co-ingestions to help distinguish mixed presentations and symptoms, as most users frequently use sedatives (alcohol, opioids, benzodiazepines, cannabis). At all times, the protection of the patient and the medical staff need to be considered if agitation or psychosis is present.

Physical exam findings usually reveal a malnourished, disheveled individual with variable mood or behavior changes. Tachycardia, hypertension, hyperthermia, and diaphoresis are some of the hallmark sympathomimetic symptoms seen with amphetamine use. Skin excoriations are very common due to delusions of parasitosis, and “skin picking” often results in prurigo nodularis, or “speed bumps.” The intraoral exam reveals decayed dental enamel and inflamed gingiva, commonly called “meth mouth.” This is due to poor oral hygiene, decreased salivation, and teeth grinding. Patients can also display choreiform movements, continuous pacing, or other repetitive actions. Acute and chronic use is associated with paranoid delusions, hallucinations, mood swings, homicidal or suicidal thoughts, and psychosis.

Evaluation

Urine or serum toxicology screening may be helpful for patients unwilling or unable to provide a cogent history regarding their substance use. Full electrolyte panel, serum lactate, BUN/creatinine, creatine phosphokinase, coagulation factors, thyroid function tests, and hepatic enzymes should all be checked. An electrocardiogram is helpful in tachycardic patients for rhythm identification and associated ischemia. X-ray imaging helps rule out associated trauma, pneumothorax, pneumomediastinum, or pneumonia. CT imaging may be considered for potential strokes, vascular dissections, and intra-abdominal or intra-thoracic pathology.

Treatment / Management

An extensive systematic review from 2015 provides evidence-based clinical guidelines for the treatment of amphetamines-related psychiatric disorders.[8] Generally, acutely agitated psychotic patients are treated with intravenous benzodiazepines (lorazepam, diazepam, or midazolam) as first-line agents. However, if a second-line agent is needed, antipsychotic medicines like risperidone, haloperidol, ziprasidone, and olanzapine have been successful in managing amphetamine-associated psychosis. Lipophilic beta-blockers, such as metoprolol and labetalol, have also been used successfully to resolve agitation and hyperadrenergic vital signs.

Clinicians should never delay the treatment of suspected amphetamine-related psychiatric disorders while awaiting urine or serum toxicology. Remission of psychotic symptoms usually resolves in one week with abstinence. This suggests most amphetamines-related psychiatric disorders resolve without the need for long-term pharmacologic therapy, instead of relying on abstinence and cognitive behavioral therapy combined with 12-step programs (Alcoholics Anonymous, Narcotics Anonymous) to strengthen patients’ support system.[9][10][11]

Differential Diagnosis

The diagnosis of amphetamine-related psychiatric disorders requires a high index of suspicion for patients presenting with a sympathomimetic toxidrome. These include tachycardia, hypertension, mydriasis, hyperthermia, and agitation. Many overdoses and toxidromes have similar presentations to those associated with amphetamines, but there are several key points to remember. With anticholinergic toxicity, patients have anhidrosis, not diaphoresis. Also, the duration of action is an important consideration. Other psychostimulants like cocaine have shorter half-lives than amphetamines (one hour versus roughly 10 hours). Other intoxications, such as monoamine oxidase inhibitors, neuroleptic malignant syndrome (NMS), and serotonin syndrome, are much harder to distinguish but typically do not produce as much agitation and/or psychosis as seen with amphetamines. Hyperthermia versus heatstroke can often be distinguished from history, but patients may have varying degrees of confusion and either anhidrosis or diaphoresis. Thyrotoxicosis and pheochromocytomas can be present with hyperadrenergic symptoms and further delineated with thyroid-stimulating hormone (TSH), free T3, T4, and plasma metanephrine or 24-hour urine catecholamines, respectively. Co-ingestion is common, possibly delaying diagnosis because of mixed toxidromes.

Prognosis

Compared to schizophrenic psychosis, amphetamine-induced acute psychosis induced appears to demonstrate a more rapid recovery. It also seems to resolve with substance abstinence; however, this recovery may be incomplete.[12][13] Research out of Japan has provided evidence that amphetamine-induced psychosis may actually have a much longer recovery period, even up to several years.[14]

Complications

• Depression
• Psychosis
• Generalized anxiety
• Insomnia
• Loss of memory
• Neurological deficits
• Additional substance abuse
• Social dysfunction

Pearls and Other Issues

• Never wait for toxicology results before instituting treatment in amphetamine-related psychiatric disorders or CNS toxicity.
• Suspect amphetamine-related psychiatric disorders in all patients presenting with agitation/psychosis, tachycardia, and/or hypertension.
• Consider co-ingestions in all suspected cases of amphetamine-related psychiatric disorders as it can cloud the clinical picture.
• Most symptoms of amphetamine-related psychiatric disorders resolve without pharmacotherapy in as little as one week with abstinence, and antipsychotics are not needed.
• A larger percentage of methamphetamine-associated psychotic patients go on to develop a primary psychosis in the future.
• After cannabis, amphetamines are the most commonly used drug worldwide.

Enhancing Healthcare Team Outcomes

Patients with amphetamines-related psychiatric disorders are commonly encountered in the emergency department. This spectrum of diagnoses has high morbidity and should be rapidly diagnosed and treated, and as such, management of this condition requires the efforts of an interprofessional healthcare team that includes clinicians, nurses, pharmacists, and psychological professionals. When these various disciplines operate in a coordinated fashion with open communication, patient outcomes will improve. [Level 5]

Emergency department clinicians and nurses must be aware of this diagnosis and its treatment and make appropriate referrals for treatment. Because these patients may suffer from various acute psychiatric disorders, including suicidal or homicidal thoughts, close monitoring is vital. There is a high risk of interpersonal violence and self-harm in this subgroup, and healthcare staff should maintain caution while in close proximity. The outcomes of these patients depend on the severity of psychiatric impairment and other comorbidities. For patients who abstain from the further use of amphetamines, the prognosis is good. However, many of these patients also have additional psychiatric disorders and often fail to comply with treatment. Many get lost to follow up and may eventually end up with legal problems leading to incarceration.[15][16] [Level 5]