Methamphetamine (METH) belongs to a class of compounds called phenethylamines which exhibits catecholaminergic, dopaminergic, and serotonergic effects. It was first manufactured in 1893 for the treatment of asthma and upper respiratory congestion, but indications and usage in the medical field have increased over the last 124 years. Today, methamphetamines are clinically used for the treatment of short-term obesity, narcolepsy, and attention deficit disorder with hyperactivity. Recreational use of methamphetamines has reached epidemic proportions in the South Pacific (Asia, Japan, China, Philippines), as well as the United States. The majority of illegal methamphetamines are produced in the United States in rural areas in what is known as clandestine labs. Using common household materials, including, acetone, red phosphorus, sodium hydroxide, sulfuric acid, ammonia, toluene, along with over the counter cold medicines, ephedrine and pseudoephedrine, methamphetamines can be easily manufactured. The routes of methamphetamine 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 transmucosally. 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 are seen with intoxication, it is difficult for the clinician to distinguish methamphetamine-associated psychosis from the acute psychosis of a primary mental disorder. Most agree that psychosis following the use of methamphetamines is characterized by persecutory delusions, visual hallucinations, and symptoms resembling acute psychosis, most likely schizophrenia. There is also a clear pattern of high dosage and daily usage correlating with higher risks of substance-induced psychosis. Methamphetamines impair the cognitive thought process and subsequently precede acute psychosis. This suggests that continued impairment due to methamphetamine use is a precursor to psychosis.
Amphetamine-related psychiatric disorders are a rare condition associated with amphetamines.
Worldwide between 14 and 55 million people between the ages of 15 to 64 are estimated to use amphetamines as reported by the United Nations Office on Drugs and Crime 2015. Of these, an estimated 17 million people are dependent on amphetamines. In the United States in 2008 approximately 13 million (5%) of people 12 and older had reported using amphetamines in their lifetime. While this number was down from 6.5% in 2002 (NSDVH 2009), these numbers are still extremely high and relevant to the medical community. Demographic characteristics associated with risk of the methamphetamine use disorder include living in rural areas, Hispanic and Asian ethnicities, lower socioeconomic status, gay or bisexual orientation, male gender, preexisting mood disorder, adverse childhood events, and prior substance use disorders. In addition to this, patients who have a methamphetamine use disorder and are entering substance abuse treatment centers have a higher likelihood to be referred by the criminal justice system then do patients with all other substance use disorders combined (59% versus 38%). This former group is also twice as likely to need long-term treatment than patients abusing other drugs (17% versus 8%; SAMHSA 2009). Some studies have suggested about 30% of patients with methamphetamine-induced psychosis end up with a primary psychosis over time. After cannabis, methamphetamines are the most widely abused illicit drug worldwide.
Amphetamines inhibit dopamine reuptake leading to an increase of dopamine concentrations in neuronal synapsis. Amphetamines also can lead to increased amounts of dopamine in the cytosol by interactions with vesicular monoamine transporter 2. By acting on the nucleus accumbens by inducing dopamine and norepinephrine release, a feeling of euphoria is elicited. However, this dopamine-induced reward feedback loop is the cause of addiction. Studies in rats found changes in the prefrontal cortex of those exposed to repeated amphetamine usage. This leads to a change in cognitive behavioral function which is thought to be a precursor to primary psychosis. Studies in Asia suggest increased dopaminergic pathways lead to glutamate excesses in the cerebral cortex, altering the function of GABAergic neurons in the cerebral cortex. This damage leads to dis-regulation of glutamate in the cerebral cortex, a precursor to psychosis. Prior psychiatric studies have found that GABAergic cortical dysfunction seems to relate to schizophrenia.
Amphetamines belong to a class of central nervous system (CNS) stimulants called the phenethylamines. Amphetamines contain a methyl group to the alpha position on its carbon chain while methamphetamines have a second methyl group. This allows methamphetamine to be very lipophilic, increasing its volume of distribution and CNS stimulation. Methamphetamine is an indirect neurotransmitter causing increased levels of dopamine, epinephrine, and norepinephrine in the cytosol. Another effect of methamphetamine is blocking the neurotransmitter reuptake transport system. These two processes lead to both alpha and beta-adrenergic receptor stimulation causing sympathomimetic symptoms (hypertension, tachycardia, hyperthermia, vasoconstriction, and diaphoresis). The excess dopamine in the cytosol leads to drug craving/seeking phenomenon and psychiatric symptoms. Amphetamines are both renally and hepatically excreted, including the cytochrome CYP2D6 pathway.
Acute methamphetamine usage and resultant psychosis can present like a sympathomimetic toxidrome. Vital signs and a detailed history are difficult to obtain secondary to agitation, intoxication, and possible withdrawal. 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 number of usages), and over what time frame. Also, ask about co-ingestions, as most users will use sedatives (alcohol, opioids, benzodiazepines, cannabis) to help distinguish mixed presentations and symptoms. At all times, protection of the patient and the medical staff need to be considered if agitation or psychosis 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 are seen with methamphetamine use. Excoriations are very common due to psychosis and “skin picking.” 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 and are hyperstimulated with continuous pacing or other repetitive actions. Both acute and chronic usage has been associated with paranoid delusions, hallucinations, mood swings, homicidal or suicidal thoughts, and psychosis.
Never delay treatment of suspected methamphetamine psychosis while awaiting urine or serum toxicology. False negatives (excretions and metabolism abnormalities) and false positives (cross-reactivity) are not unusual and can cloud the clinical picture and healthcare providers’ judgment. Full electrolyte panel, serum lactate, BUN/creatinine, creatinine phosphokinase, coagulation factors, and hepatic enzymes should all be checked. An electrocardiogram is helpful in the tachycardic patient for rhythm identification and associated ischemia. X-ray imaging is helpful in ruling out associated trauma, pneumothorax due to inhalation, and aspiration or infiltrates. CT imaging rules out more complex issues like strokes, vascular dissections, and intra-abdominal or intra-thoracic infections.
Evidenced-based clinical guidelines for the treatment of methamphetamine associated psychosis are not readily available. This is largely due to a lack of large randomized clinical trials of pharmacologic agents used for the treatment of this disorder. 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, and olanzapine have been successful in managing methamphetamine associated psychosis. Little is known on the efficacy and safety in children/adolescents, and extreme caution is advised in this population because they are prone to more adverse effects of antipsychotics than adults. It is important to mention that remission of psychotic symptoms usually resolves in one week with abstinence from methamphetamines. This suggests most methamphetamine associated psychosis resolve without pharmacologic therapy. Long-term therapy usually relies on abstinence and cognitive behavioral therapy in combination with 12 step programs (Alcoholics Anonymous, Narcotics Anonymous) to strengthen the patients’ support system.
The key to diagnosing methamphetamine psychosis is identifying the symptoms associated with its sympathomimetic presentation. These include tachycardia, hypertension, mydriasis, hyperthermia, and agitation. A wide variety of overdoses and toxidromes have similar presentations, but there are several key points to remember. With anticholinergic toxicity, patients have anhidrosis, not diaphoresis. Also, duration of action is an important key. Other psychostimulants like cocaine (30 minutes) and PCP (less than 8 hours) do not have as long of a peak action potential as methamphetamine (more than 20 hours). Other intoxications from serotonin or monoamine oxidase inhibitors are much harder to distinguish, but typically do not produce as much agitation/psychosis and also have frequent tremors of the extremities. Heat stroke can be distinguished hopefully from history but may have varying degrees of confusion, and either anhidrosis or diaphoresis. Thyrotoxicosis and pheochromocytomas can be ruled out with TSH, free T3, T4, and plasma metanephrine or 24-hour urine catecholamines, respectively. Co-ingestion is common, also delaying diagnosis because of mixed toxidromes. Typical drugs of abuse, as well as, over the counter medicines can be measured with urine or serum marker levels.
Never wait for toxicology results before instituting treatment in methamphetamine-associated psychosis or methamphetamine toxicity, as urine toxicology is susceptible to false positives and negatives.
Antipyretics have no role in methamphetamine-associated hyperthermia, as this is caused by muscle activity and not changes in the hypothalamus.
Suspect methamphetamine-associated psychosis in all patients who present with agitation/psychosis, with hypertension, tachycardia, hyperthermia, and anhidrosis.
Look for co-ingestions in all suspected cases of methamphetamine associated psychosis as other drugs of abuse are common and can cloud the clinical picture.
Most symptoms of methamphetamine associated psychosis 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, methamphetamine is the most commonly abused drug worldwide.