Background
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) describes the following 11 amphetamine-related psychiatric disorders: [1]
Amphetamine-induced anxiety disorder
Amphetamine-induced bipolar disorder
Amphetamine-induced depressive disorder
Amphetamine-induced psychotic disorder
Amphetamine-induced sexual dysfunction
Amphetamine-induced sleep disorder
Amphetamine intoxication
Amphetamine intoxication delirium
Amphetamine withdrawal
Amphetamine-induced obsessive-compulsive and related disorder
Unspecified stimulant-related disorder
Either prescription or illegally manufactured amphetamines can induce these disorders. Prescription amphetamines are used frequently in children and adolescents to treat attention deficit hyperactivity disorder (ADHD), and they are the most commonly prescribed medications in children. The dose of Adderall(XR) (dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, amphetamine sulfate) needed to produce toxicity and psychiatric symptoms in a child is as low as 2 mg. A typical dose is 2.5–40 mg/d. In adults, narcolepsy, ADHD of the adult type, and some depression can be treated with amphetamines. Although they are controlled substances, abuse is possible, especially in persons with alcoholism or substance abuse.
The substance 3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational stimulant commonly referred to as ecstasy, which was manufactured legally in the 1980s. [2] MDMA has the desired effects of euphoria, high energy, and social disinhibition lasting 3–6 hours. The drug is often consumed in dance clubs, where users dance vigorously for long periods. The drug sometimes causes toxicity and dehydration, as well as severe hyperthermia. Several other amphetamine derivatives are para-methoxyamphetamine (PMA), 2,5-dimethoxy-4-bromo-amphetamine (DOB), methamphetamine (crystal methamphetamine, crystal meth, or "Tina"), and 3,4-methylenedioxyamphetamine (MDA). Crystal meth is the pure form of methamphetamine and, because of its low melting point, it can be injected.
In a web-based survey of 1,006 individuals who admitted mephedrone use, which is the largest survey to date, results showed that users consider mephedrone's effects to compare best with those of MDMA; the appeal of mephedrone for these individuals is in its availability, low price, and reliable purity. [3]
Khat (Catha edulis Forsk) is the only known organically derived amphetamine. It is produced from the leaves of the Qat tree located throughout East Africa and the Arabian Peninsula. The leaves of the tree are chewed, extracting the active ingredient, cathinone, and producing the desired effects of euphoria and, unlike other amphetamines, anesthesia.
In the midwestern United States, methcathinone, the synthetic form of cathinone, has been produced illegally since 1989, after a student at the University of Michigan stole research documents and began to illegally manufacture the drug. Methcathinone is relatively easy to produce and contains the same chemicals found in over-the-counter (OTC) asthma and cold medicines, paint solvents and thinners, and drain openers (eg, Drano). Its addiction potential is similar to that of crack cocaine.
Amphetamine-related psychiatric disorders are conditions resulting from intoxication or long-term use of amphetamines or amphetamine derivatives. Such disorders can also be experienced during the withdrawal period from amphetamines. The disorders are often self-limiting after cessation, though, in some patients, psychiatric symptoms may last several weeks after discontinuation. Some individuals experience paranoia during withdrawal as well as during sustained use. Amphetamine use may elicit or be associated with the recurrence of other psychiatric disorders. People addicted to amphetamines sometimes decrease their use after experiencing paranoia and auditory and visual hallucinations. Furthermore, amphetamines can be psychologically but not physically addictive.
The symptoms of amphetamine-induced psychiatric disorders can be differentiated from those of related primary psychiatric disorders by time. If symptoms do not resolve within 2 weeks after the amphetamines are discontinued, a primary psychiatric disorder should be suspected. Depending on the severity of symptoms, symptomatic treatment can be delayed to clarify the etiology.
Amphetamine-induced psychosis (delusions and hallucinations) can be differentiated from psychotic disorders when symptoms resolve after amphetamines are discontinued. Symptoms of amphetamine use may be indistinguishable from those associated with the cocaine use. Amphetamines, unlike cocaine, do not cause local anesthesia and have a longer psychoactive duration.
Amphetamine-induced delirium follows a reversible course similar to other causes of delirium, and it is identified by its relationship to amphetamine intoxication. After the delirium subsides, little to no impairment is observed. Delirium is not a condition observed during amphetamine withdrawal.
Mood disorders similar to hypomania and mania can be elicited during intoxication with amphetamines. Depression can occur during withdrawal, and repeated use of amphetamines can produce antidepressant-resistant amphetamine-induced depression. Of interest, low-dose amphetamines can be used as an adjunct in the treatment of depression, especially in patients with medical compromise, lethargy, hypersomnia, low energy, or decreased attention.
Sleep disturbances appear in a fashion similar to mood disorders. During intoxication, sleep can be decreased markedly. In withdrawal, sleep often increases. A disrupted circadian rhythm can result from late or high doses of prescription amphetamines or from chronic or intermittent abuse of amphetamines. Individuals who use prescription amphetamines can easily correct their sleep disturbance by lowering the dose or taking their medication earlier in the day than they have been. Insomnia is the most common adverse effect of prescription amphetamines.
Unspecified stimulant-related disorder is a diagnosis assigned to those who have several psychiatric symptoms associated with amphetamine use but who do not meet the criteria for a specific amphetamine-related psychiatric disorder.
Case study
A 36-year-old male who works as a real estate agent arrives at your office appearing disheveled and slightly agitated. He is guarded, but describes coworkers manipulating his clock to read 9:11 and episodes of police driving by with their sirens on at 4:20. He refuses to open his mail because he recognizes messages targeted at him in the letters. He spends his free time staying up at night, fixing his computer for an "impending apocalypse." On the weekends, he sleeps in until 2 pm and reports low mood and unintentional weight loss of 25 lbs in the last 3 months. When asked about a burn mark on his hand, he admits to "smoking some T." On further questioning he discloses a 5-month period of crystal methamphetamine use.
Pathophysiology
The pathophysiology of amphetamine-related psychiatric disorders is multifactorial, as amphetamines influence many neural systems. Methamphetamine may induce psychosis through inhibition of the dopamine transporter, resulting in increased dopamine within the synaptic cleft. [4] Similarly, chronic amphetamine use may cause psychiatric symptoms due to inhibition of the dopamine transporter in the striatum and nucleus accumbens. The longer the duration of use, the greater the magnitude of dopamine reduction.
Amphetamine-induced psychosis results after increased use of amphetamines, as observed in binge use or after protracted use. Prescription amphetamines induce the release of dopamine in a dose-dependent manner; low doses of amphetamines deplete large storage vesicles, and high doses deplete small storage vesicles. This increase in dopaminergic activity likely induces psychotic symptoms, as the use of D2-blocking agents (eg, haloperidol) ameliorates symptoms. Amphetamine-induced psychosis has been used as a model to support the dopamine hypothesis of schizophrenia, in which overactivity of dopamine in the limbic system and striatum is associated with psychosis. However, negative symptoms commonly observed in schizophrenia are relatively rare in amphetamine psychosis.
MDMA causes the acute release of serotonin and dopamine and inhibits the reuptake of serotonin. MDMA has neurotoxic properties in animals and, potentially, in humans. Reports suggest that MDMA use is associated with cognitive, neurologic, and behavioral abnormalities, as well as hyperthermia, but these reports are confounded by the association with other factors (eg, heat, exertion, poor diet, other drug use).
Delirium caused by amphetamines may be related to the anticholinergic activity, as observed in different classes of drugs, such as tricyclic antidepressants, benzodiazepines, sedatives, and dopamine-activating drugs. Rapid eye movement during the first phase of sleep is decreased during intoxication, and a rebound elevation of rapid eye movement occurs during withdrawal. This effect eventually alters the circadian rhythm and results in sleep disturbances.
Epidemiology
Frequency
United States
Among people aged 12 years or older in 2020, 0.9% used methamphetamine in the past year. Adolescents aged 12–17 years had the lowest rates of methamphetamine use at 0.1%, while adults aged 26 years and older had the highest rates of use at 1.1%. Of adults aged 12 years or older, 0.3% met criteria for prescription stimulant disorder over the past year. [5]
Psychosis, delirium, mood symptoms, anxiety, insomnia, and sexual dysfunction are considered rare adverse effects of therapeutic doses of prescription amphetamines. These symptomas are more likely to occur with methamphetamine use given the unpredictable composition of substances purchased off the street.
Data about the frequency of amphetamine-related psychiatric disorders are unreliable because of comorbid primary psychiatric illnesses.
International
Methamphetamine was first synthezised in Japan in 1919. During World War II, it was used by both Allied and Axis powers to keep pilots awake during long flights. In the 1940s–1950s, post-war Japan experienced its first meth epidemic as a result of methamphetamine introduction during the war. [6]
Catha edulis, also known as khat, an evergreen plant gathered in many countries in the east African and Arabian Peninsula like Yemen, Ethiopia, Kenya, and Somalia contains the compound cathinone, similar in structure to S-amphetamine. Cathinone metabolizes to norpseudoephedrine and norepherdine in mature leaves, producing many of the stimulant effects of methamphetamine. While Khat increases altertness, it also contributes to oral decay, gastric ulcers, hypertension, and stroke. Prolonged use can lead to dependence, psychotic symptoms, and loss of productivity, which is why the WHO first classified it as a "hazardous and harmful substance" in its Primary Care Geneva report in 2011. [7]
Mortality/Morbidity
The Drug Abuse Warning Network (DAWN) Annual Medical Examiner Data for 2021 showed that 11.2% of all drug-related hospital emergency department visits were associated with methamphetamine use, listed 3rd after alcohol and opioid-related presentations. The South and Western regions of the United States accounted for greater than 70% of all methamphetamine-related ED visits. [8]
In high doses, illicit and prescription amphetamines can produce cardiovascular collapse, myocardial infarction, stroke, seizures, renal failure, ischemic colitis, and hepatotoxicity. Heart attacks, seizures, subarachnoid, intracranial hemorrhage, and strokes may also result in death. The rate of suicide and accidents can increase during periods of toxicity and withdrawal.
In high doses, prescription amphetamines and amphetamine derivatives increase sexual arousal and disinhibition, increasing the risk of exposure to sexually transmitted diseases.
Memory impairment can result after long-term use of high doses of amphetamines because of damage to serotonin-releasing neurons. In the emergency department patients with amphetamine-related disorders are one third more likely than patients with cocaine-related disorders to be transferred to an inpatient psychiatric ward. This difference may partly be because amphetamine withdrawal lasts longer then cocaine withdrawal, and amphetamines are more likely to cause psychotic symptoms than cocaine.
Amphetamine withdrawal is characterized by low mood, increased suicidal ideation, fatigue, increased need for sleep, slowed reaction time, irritability, and vivid and unpleasant dreams. Acute symptoms typically last 1–2 days. Protracted withdrawal may occur and is termed Post-Acute Withdrawl Symptoms (PAWS). It is characterized by impaired short-term memory, inability to concentrate, lack of self control, cravings, and insomnia. [9]
Race-, sex-, and age-related demographics
Methamphetamine-related ED visits in 2021 were most prevalent among White males aged 26–44 years old. White patients accounted for 62.45% of all methamphetamine-associated ED visits, with a greater proportion of men (69%) than women (31%) coming in for methamphetamine-associated sequelae. Together, the South and West regions of the United States accounted for more than 70% of all methamphetamine-related ED visits. [9]
Prognosis
The patient's prognosis depends on the severity of psychiatric impairment and on the medical complications.
Overall, the prognosis is good if the patient abstains from drug use after the initial psychiatric impairment occurs.
The prognosis worsens if personality disorders are co-morbid.
Patient Education
Instruct the patient to abstain from alcohol and illicit drugs, especially because dual diagnosis is a real issue. While abstinence from illicit substances is preferred, harm reduction strategies may be employed to reduce use.
Patients should be in a support group.
Family members should educated about the patient's substance use and triggers so they may provide support.
Refer the patient for psychosocial counseling.
Hospitalize the patient if he or she is suicidal or homicidal.
Refer the patient for substance use counseling.
Helpful Web sites include the following:
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National Institute on Drug Abuse, Methamphetamine Abuse and Addiction
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NIDA InfoFacts: Stimulant ADHD Medications - Methylphenidate and Amphetamines
