The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) describes the following 11 amphetamine-related psychiatric disorders:
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. 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 mephedro’e'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.
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. 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.
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.
A 36-year-old white male who works as a real estate agent arrives at your office, depressed, disheveled, and slightly agitated. He is very guarded and reluctant to talk about his work history or relationships. After a period of time he describes how his coworkers are manipulating his clock to read 9:11, and the police drive by with their sirens on every day at 4:20. He refuses to open his mail, because he read secondary messages by rearranging letters. He admits to spending most of his time at home alone fixing his computer, sometimes all night long. His sleep cycle is reversed on the weekends, he is depressed most of the time, isolated, lost 25 lbs in the last 3 months, and has pale skin. Only when asked about the burn mark on his hand did he admit to "smoking some T." On further questioning he disclosed a 5-month period of crystal methamphetamine use.
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 inhibition of the dopamine transporter in the striatum and nucleus accumbens. The longer the duration of use, the greater the magnitude of dopamine reduction. Methamphetamine has been suggested to induce psychosis through inhibiting the dopamine transporter, with a resultant increase in dopamine in the synaptic cleft.
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.
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 use of methamphetamine did not change from 2011 to 2013, remaining at approximately 0.2%. However, this does represent a nearly two-fold increase from the percentage of the population surveyed who had used in the last month in 2010 (0.1%). In 2013, an estimated 144,000 people became new users of methamphetamine, which is consistent with the new user initation rates of the preceding five years.
Post-marketing studies of amphetamines prescribed to children and adolescents revealed a total of 865 unique case reports describing signs and/or symptoms of psychosis or mania, with nearly half reported in children 10 years or younger.
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. Khat dependency has been associated with people of Muslim religion and with people of low socioeconomic status.
Khat is also used to cope with the trauma of war in Somalia. One study showed that 36.4% of Somali combatants used khat 1 week prior to being interviewed.
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-5 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).
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.
Two issues are emphasized:
The patient's history of amphetamine abuse is the most important factor and is determined by asking the following questions:
Substance abuse history
Potentially abused substances include the following:
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-5 criteria for stimulant intoxication are as follows:
The DSM-5 criteria for stimulant withdrawal are as follows:
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:
A mental status expected for a patient with amphetamine psychosis is as follows:[9, 10]
A mental status for a patient withdrawing form amphetamines is as follows:
Causes may include the following:
The purpose of the workup is to exclude complications of amphetamine abuse and other causes of psychosis and altered mental status.
Laboratory evaluation should include the following tests:
In the presence of neurologic impairments, CT or MRI helps in evaluating for subarachnoid and intracranial hemorrhage.
Perform ECG to evaluate for cardiac involvement.
Perform EEG if a seizure disorder is considered possible.
Use of the brief psychotic rating scale (BPRS), Beck Depression Scale, violence and suicide assessment, and other measures may be helpful.
If persistent psychiatric conditions are noted, neuropsychological testing can be beneficial to assess levels of psychosocial and neurologic function to guide treatment and to assess the need for placement.
Results of projective testing, such as the Rorschach test and the Thematic Apperception Test, can help in clarifying thought disorders.
During amphetamine intoxication, the Mini-Mental State Examination (MMSE) can be helpful in measuring cognitive change.
Repeated exposure to amphetamines is theorized to alter the morphology of dendrites in the prefrontal cortex and in the nucleus accumbens. Amphetamines may increase the length of dendrites for longer than 1 month. These alterations may help explain the behavioral cravings and psychosis that long-term abuse of amphetamines produces.
Initial treatment should include medically stabilizing the patient's condition by assessing his or her respiratory, circulatory, and neurologic systems. The offending substance may be eliminated by means of gastric lavage and acidification of the urine. Psychotropic medication can be used to stabilize an agitated patient with psychosis. Because most cases of amphetamine-related psychiatric disorders are self-limiting, removal of the amphetamines should suffice.
Induced emesis, lavage, or charcoal may be helpful in the event of overdose.
The excretion of amphetamines can be accelerated by the use of ammonium chloride, given either IV or orally (PO).
Consultations with a neurologist, internal medicine specialist, psychiatrist, or social services may prove helpful.
Consult a psychiatrist for inpatient substance abuse treatment or further psychiatric stabilization.
Social services coordinate outpatient services, such as Alcoholics Anonymous and Narcotics Anonymous meetings and sober houses, and provide appointments. Some large metropolitan areas have groups that specifically focus on crystal methamphetamine abuse in the gay population.
Patients intoxicated with amphetamines are dangerous, and their activity should be limited (eg, no driving) until their symptoms have resolved.
Several psychiatric conditions can be associated with amphetamine intoxication and withdrawal, all of which may require different management strategies. However, amphetamine-related psychiatric disorders are typically self-limited and usually remit on their own.
Amphetamine-related psychiatric disorders occur most often during intoxication; therefore, treatment should focus on controlling medical and psychiatric symptoms while eliminating the offending substance. Medical therapy involves stabilizing agitation and minimizing psychosis. Gastric lavage directly removes the amphetamines before they have an opportunity to be absorbed. Medication and charcoal eliminate amphetamines from the gastrointestinal and circulatory systems.
If the induced disorders persist and interfere with the patient's social and occupational functioning, treatment should be related to the remaining psychiatric symptoms. Antidepressants, such as sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa), can be used to treat depression. Antimanic agents, such as valproic acid (Depakote), carbamazepine (Tegretol), and lithium carbonate, can be used to treat mania. Anxiety can be treated with nonbenzodiazepine drugs, such as beta-blockers and antimanic agents.
Data from recent studies suggest typical antipsychotics (haloperidol thioridazine, Thorazine, etc) may increase amphetamine and cocaine cravings in patients with dual diagnoses of amphetamine and cocaine abuse. Typical antipsychotics should be used for acute stabilization with the intention of switching to an atypical antipsychotic drug (eg, risperidone, quetiapine, olanzapine, aripiprazole, and ziprasidone) for long-term use.
Some evidence suggests that naltrexone might be helpful in treating those addicted to amphetamines.
For the purposes of this discussion, specific treatment of amphetamine toxicity is reviewed. For further information, please refer to the articles on Depression, Substance-Induced Mood Disorder, Depressed Type, Bipolar Affective Disorder, Schizophrenia, Anxiety Disorders, and Sleeping Disorders.
Clinical Context: Provides rapid sedation of agitated anxious patient; available PO and IM, allowing for flexible, emergency administration.
Clinical Context: Blocks postsynaptic blockade of CNS dopamine receptors, inhibiting dopamine-mediated effects. PO and IM forms allow for rapid tranquilization.
Clinicians should select a high-potency antipsychotic that is available in tablet, liquid, and IM forms for administration in emergency situations. Antipsychotics help control psychotic symptoms and provide rapid tranquilization of the agitated and psychotic patient.
Clinical Context: Provides rapid onset and efficacy in sedating aggressive patient; flexible administration in emergency situation.
Clinical Context: Depresses all levels of CNS, including limbic and reticular formation, possibly by increasing activity of gamma-aminobutyric acid (GABA) activity, major inhibitory neurotransmitter.
These drugs are primarily used to sedate agitated patients. Availability in PO, IV, and IM forms allowing the drug to be used in emergency situations. Caution must be used in the violent, aggressive patient because benzodiazepines may cause disinhibition.
Clinical Context: Used to treat concurrent opiate toxicity. Consider in patients with altered mental status due to opiate overdose. Poorly absorbed PO route and should be administered IM or IV. Available in IV, IM, and SC forms. Use caution to avoid precipitating acute opioid withdrawal in patient using opioids long term.
These drugs inhibit the action of opiates.
Clinical Context: Antihypertensive agent useful in psychiatry to treat anxiety and impulse control. Often well tolerated with minimal effect on hemodynamics of blood pressure and pulse.
Propranolol (Inderal) is useful in patients who are agitated, anxious, and hyperarousable because of amphetamines. They are temporarily used until the amphetamine is eliminated from the patient's system. For some patients, anxiety can be prolonged, and nonaddictive beta-blockers may be helpful.
Clinical Context: Commonly used as OTC expectorant; acidifies urine at high doses. Safe and easy to use.
Expectorants are used to acidify the urine and increase amphetamine excretion when intoxication from amphetamines has resulted in psychiatric and medical complications. These agents are available in PO form, and the patient must be able to swallow or receive a nasogastric tube.
Clinical Context: Bottles and tubes. Use long after amphetamine ingestion can reduce systemic levels by adsorbing amphetamines recirculating through gastric mucosa.
These agents, given through a nasogastric tube into the stomach, absorb intentionally and accidentally ingested substances to prevent their further absorption into the systemic circulation.
The patient should be monitored closely for recurring psychosis, depression, mania, anxiety, sleep disturbances, and relapse of amphetamine abuse.
Psychiatric follow-up care should occur within, at most, 2 weeks of the initial evaluation to ensure compliance.
Depending on the complications of amphetamine abuse in the specific patient, consider a follow-up examination with a neurologist and an internal medicine specialist.
Admit the patient for observation in the event of mania, severe depression, psychosis, delirium, or if he or she is suicidal or homicidal.
A patient who is in a state of delirium should be placed in a quiet, cool (not cold), dimly lit (not dark) room and, if uncontrollable, placed in restraints.
If psychosis persists after the offending substance is eliminated, use of an atypical antipsychotic (risperidone, quetiapine, olanzapine, aripiprazole, ziprasidone) may be considered. No single atypical antipsychotic has been proven to be more beneficial than the others in managing prolonged amphetamine-induced psychosis.
Antimanic agents may be continued if mania persists longer than 2 weeks.
Antidepressants can be useful if depression persists for 2 weeks after withdrawal. Antidepressants alone may not be as effective as other options in amphetamine-induced depression due to neuronal damage. Medication regimens for treatment-resistant organic mood disorders are the applicable approach.
If anxiety persists longer than 2 weeks, consider the use of nonbenzodiazepine drugs. Medications such as beta-blockers, valproic acid, carbamazepine, or gabapentin have shown promise in patients with substance abuse who also have anxiety.
Sleep medication may help patients adjust their circadian rhythm and can be used for approximately 1-2 weeks. If sleep medication is required for long periods, a referral to a sleep clinic is recommended.
If psychiatric conditions persist, causing social and occupational impairment, inpatient treatment may be required.
Medical or neurologic complications require treatment in an inpatient medical or neurologic unit.
Abstinence prevents disorders and is the primary treatment.
Relapse prevention occurs though patient education, individual psychotherapy, appropriate medical treatment of continuing psychiatric illness (eg, major depression, panic disorder), and attendance at substance abuse meetings.
Mandatory weekly urine drug screens help prevent relapse or expose relapse early so that aggressive treatment intervention can be pursued.
If psychiatric conditions arise during prescription amphetamine use for ADHD, lower doses may be tried and/or nonamphetamine treatments can be pursued, such as bupropion (Wellbutrin), desipramine, venlafaxine (Effexor), or clonidine. Please refer to the Attention Deficit Hyperactivity Disorder article for a full discussion of treatment options.
Early medication treatments have been tried with desipramine and lithium ; aripiprazole vs. methylphenidate vs. placebo ; bupropion ; and naltrexone.
The most recent published study at the time of this review assessed the efficacy of extended-release methylphenidate. The intention-to-treat analysis failed to demonstrate statistical difference between extended-release methylphenidate (n=40) compared with placebo (n=39). The authors noted that the study was limited by significantly higher dropout rates in the placebo arm.
Currently, there are no medications that are routinely prescribed as standard-of-care or approved by the FDA for the treatment of amphetamine use disorder.
Complications include an increased risk of the following:
If amphetamine abuse and amphetamine-related psychiatric disorders occur in the context of 1 or more personality disorders, the amphetamine-related disorder is more difficult to successfully treat than it is in other contexts.
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 present.
Instruct the patient to abstain from alcohol and illicit drugs, especially because dual diagnosis is a real issue. The only effective treatment is abstinence.
Patients should be in a support group.
The family must be educated about the patient's addiction and its dangers.
Refer the patient for psychosocial counseling.
Hospitalize the patient if he or she is suicidal or homicidal.
Refer the patient for substance abuse counseling.
Helpful Web sites include the following
For excellent patient and family education resources, see eMedicineHealth's patient education articles Drug Dependence and Abuse and Substance Abuse.