Amphetamine-Related Psychiatric Disorders

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Amphetamine-Related Psychiatric Disorders

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) describes the following 10 amphetamine-related psychiatric disorders:1

Amphetamine-induced anxiety disorder
Amphetamine-induced mood disorder
Amphetamine-induced psychotic disorder with delusions
Amphetamine-induced psychotic disorder with hallucinations
Amphetamine-induced sexual dysfunction
Amphetamine-induced sleep disorder
Amphetamine intoxication
Amphetamine intoxication delirium
Amphetamine withdrawal
Amphetamine-related disorder not otherwise specified

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, weight loss, and some depression can be treated with amphetamines. However, because of their addicting potential, these drugs are no longer used for weight loss. 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. 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.

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 disord ers 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. Absence of first-rank Schneiderian symptoms, including anhedonia, avolition, amotivation, and flat affect, further suggests amphetamine-induced psychosis. 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.

Amphetamine-related disorder not otherwise specified 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.


The pathophysiology of amphetamine-related psychiatric disorders is difficult to establish, because amphetamines influence multiple neural systems. In general, chronic amphetamine abuse may cause psychiatric symptoms due to dopamine depletion in the striatum.

Amphetamine-induced psychosis often results after increased or large 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 may be causally related to psychotic symptoms because the use of D2-blocking agents (eg, haloperidol) often ameliorates these 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 into the neuron. 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). Serotonergic damage has been suggested to lead to cognitive impairment.

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 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.
United States

Psychosis, delirium, mood symptoms, anxiety, insomnia, and sexual dysfunction are considered rare adverse effects of therapeutic doses of prescription amphetamines. Dextroamphetamine has a slightly increased rate of these adverse effects because of its increased CNS stimulation.

Data about the frequency of amphetamine-related psychiatric disorders are unreliable because of comorbid primary psychiatric illnesses.

Intravenous (IV) use occurs more frequently in people of low socioeconomic status than in those of high socioeconomic status.

The rates for past month and past year use of methamphetamine did not change from 2004 to 2005, but the lifetime rate declined from 4.9% to 4.3%. Comparing 2002 with 2005, decreases were seen in lifetime use (5.3% to 4.3%) and past year use (0.7% to 0.5%), but not past month use (0.3% in 2002 vs 0.2% in 2005). Although the number of past month users has remained steady since 2002, the number of methamphetamine users who were dependent on or abused some illicit drug did rise significantly during this period, from 164,000 in 2002 to 257,000 in 2005.2


The first amphetamine epidemic occurred after World War II in Japan, when leftover supplies intended to counteract fatigue in pilots were made available to the general public. This even resulted in many cases of amphetamine psychosis. Of interest, both German and American troops used these preparations during World War II, as did Japanese kamikaze pilots.

Khat, which is primarily used in Ethiopia for cultural and religious purposes, has been well studied. A house-to-house survey of 10,468 adults showed a lifetime prevalence of khat use of 55.7%. Daily use occurred among 17.4%, and 80% indicated they used khat to increase concentration during prayer.3 Khat dependency has been associated with people of Muslim religion and with people of low socioeconomic status.

The Drug Abuse Warning Network (DAWN) Annual Medical Examiner Data for 2005 showed 10% of all drug-related hospital emergency department visits were stimulant-related. DAWN data indicated that 26% of all drug-related deaths in Oklahoma City were due to methamphetamine, making it the city’s most frequent drug-related cause of death in 1998.

In high doses, prescription amphetamines can produce cardiovascular collapse, myocardial infarction, stroke, seizures, renal failure, ischemic colitis, and hepatotoxicity. Death related to MDMA can occur from malignant hyperthermia, which leads to kidney failure and cardiovascular collapse. Heart attacks, seizures, subarachnoid and 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 psychogenic than cocaine.
Amphetamine withdrawal is consistent with a major depressive episode, though lasting less then 2 weeks and involving decreased energy, increased appetite, craving for sleep, and suicidal ideation.


Amphetamine-related psychiatric disorders most commonly occur in white individuals.
With IV use, amphetamine-related psychiatric disorders most commonly occur in men, with a male-to-female ratio of 3-4:1.
With non-IV use, amphetamine-related psychiatric disorders occur equally in men and women.
Amphetamine-related psychiatric disorders most frequently occur in people aged 20-39 years who are inclined to abuse amphetamine derivatives at rave parties and dance clubs.
Adolescents have developed a method for abusing prescription amphetamines in which prescription tablets are crushed into a powder and inhaled nasally.

Amphetamine-related psychiatric disorders can be confused with psychiatric disorders caused by organic, medical, neurologic, and/or psychological etiologies. The causes of amphetamine-related psychiatric disorders usually can be determined by assessing the patient’s history and the family’s genealogy.

The DSM-IV-TR provides criteria helpful for determining if the patient is in a state of intoxication or withdrawal. The criteria helps clinicians distinguish disorders occurring during intoxication (eg, psychosis, delirium, mania, anxiety, insomnia) from those occurring during withdrawal (eg, depression, hypersomnia).
Developmental history: The developmental history provides information about the patient’s in utero exposure to medications, illicit drugs, alcohol, pathogens, and trauma.
As children, patients may have had prodromal symptoms of psychiatric disorders, such as social isolation, deteriorating school performance, mood liability, amotivation, avolition, anhedonia, sleep disturbances, sexual paraphilias, poor interest, psychomotor retardation, demoralization, social isolation, and suicidal thoughts and behaviors.
Delinquency, truancy, educational failure, early use of drugs and alcohol, oppositional behavior associated with conduct disorder, and participation in the rave party scene are developmental behaviors that suggest an amphetamine-related psychiatric disorder.
Psychiatric history: Two issues are emphasized:
Determine whether a psychiatric disorder or symptoms ever occurred when the patient was not exposed to amphetamines.
Determine whether the patient ever had a psychiatric disorder or symptoms similar to the present symptoms in relation to any other drug or medication.
Recent history: The patient’s history of amphetamine abuse is the most important factor and is determined by asking the following questions:
When did the patient’s amphetamine use start?
How often does the patient use amphetamines?
How much does he or she use?
Is the patient currently intoxicated or in withdrawal from amphetamines?
Does the patient frequently attend rave parties?
Has the patient recently increased his or her amphetamine use or started to binge?
Substance abuse history: Potentially abused substances include the following:
Lysergic acid diethylamide (LSD)
OTC sympathomimetics
Family history: A family history of a psychiatric disorder may suggest a primary psychiatric disorder. A diagnosis of amphetamine-related psychiatric disorder might still be possible if the patient has no family history of psychiatric disorder.
The DSM-IV-TR criteria for amphetamine intoxication are as follows:
The patient has recently used an amphetamine or related substance, such as methylphenidate.
Clinically significant maladaptive behavioral or psychological changes developed during or shortly after the patient used amphetamines or a related substance. Such changes include the following:
Euphoria or affective blunting
Changes in sociability
Interpersonal sensitivity
Anxiety, tension, or anger
Stereotyped behaviors
Impaired judgment
Impaired social or occupational functioning
Two or more of the following conditions develop during or shortly after the patient used amphetamines or a related substance:
Tachycardia or bradycardia
Pupillary dilatation
Elevated or lowered blood pressure
Perspiration or chills
Nausea or vomiting
Evidence of weight loss
Psychomotor agitation or retardation
Muscular weakness, respiratory depression, chest pain, or cardiac arrhythmias
Disorientation and memory loss, seizures, dyskinesias, dystonias, or coma
The symptoms are not due to a general medical condition, and another mental disorder does not account for them better than amphetamine intoxication does.
The DSM-IV-TR criteria for amphetamine withdrawal are as follows:
The patient has recently ceased or reduced heavy or prolonged use of amphetamines or related substances.
A dysphoric mood and 2 or more of the following physiologic changes develop within a few hours to several days after the patient ceases or reduces his or her use:
Vivid, unpleasant dreams
Insomnia or hypersomnia
Increased appetite
Psychomotor retardation or agitation
A complete mental status examination must be performed, with an emphasis on hallucinations, delusions, suicide and/or homicide, orientation, memory, and judgment.
The aforementioned symptoms cause clinically significant distress or impairment in terms of social, occupational, or other important areas of functioning.
The symptoms are not due to a general medical condition, and another mental disorder does not account for them better than amphetamine withdrawal does.

Full physical and neurologic examination should be performed. Initially assess patients for medical stability and then for level of danger.

During physical examination, assess the patient for medical complications of amphetamine abuse, including hyperthermia, dehydration, renal failure, and cardiac complications.
During neurologic examination, assess the patient for neurologic complications of amphetamine abuse, including subarachnoid and intracranial hemorrhage, delirium, and seizures.
Mental status examination should emphasize delusions, hallucinations, suicide, homicide, orientation, insight and judgment, and affect. The mental status examination can be very different for intoxication and psychosis.
A mental status expected for a patient with amphetamine intoxication is as follows:
Appearance and behavior: Unusually friendly, scattered eye contact, buccal oral gyrations, overly talkative and verbally intrusive
Speech: Increased rate
Thought process: Tangential, circumstantial over inclusive and disinhibited
Thought content: Paranoid
Mood: Anxious, hypomanic
Affect: Anxious and tense
Insight and judgment: Poor
A mental status expected for a patient with amphetamine psychosis is as follows:
Appearance and behavior: Disheveled, suspicious, paranoid, difficult to engage, and poor eye contact
Speech: Decreased and rapid
Thought process: Guarded and internally preoccupied
Thought content: Paranoid; possible auditory hallucinations
Mood: Anxious
Affect: Paranoid and fearful
Insight and judgment: Poor

Amphetamine intoxication, binge pattern use, and long-term exposure
Comorbid psychiatric disorders
Abuse of other substances such as alcohol, OTC sympathomimetics, and illicit drugs
Fluoxetine (Prozac) - Increases CNS concentrations of amphetamine and potentiates its effects

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