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Overview
Background
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) describes the
following 11 amphetamine-related psychiatric disorders:[1]
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.[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.
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.
Case study
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.
Pathophysiology
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.[4]
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.
Epidemiology
Frequency
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 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.[5]
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.[7] 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.
Mortality/Morbidity
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 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.
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.
Presentation
History
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).
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
Recent history
The patient's history of amphetamine abuse is the most important factor and is determined by
asking the following questions:
Alcohol
Marijuana
Cocaine
Lysergic acid diethylamide (LSD)
OTC sympathomimetics
Steroids
Family history
Physical
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.
A mental status expected for a patient with amphetamine psychosis is as follows:[9, 10]
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; no suicidal or homicidal
thoughts
Mood: Anxious
Affect: Paranoid and fearful
Insight and judgment: Poor
Orientation: Has no concept of purpose, though understands place and person;
perspective of time is disorganized.
Appearance and behavior: Disheveled, psychomotor slowing, poor eye contact, pale
appearance to skin
Speech: Decreased tone and volume
Thought processes: Decreased content, guarded
Thought content: No auditory, visual hallucinations; suicidal thoughts present, but no
homicidal thoughts
Mood: depressed
Affect: Flat and withdrawn
Insight and judgment: Poor
Orientation: Oriented to person, place, and purpose
Causes
Causes may include the following:
DDx
Differential Diagnoses
Cannabis-Related Disorders
Cocaine-Related Psychiatric Disorders
Delirium
Depression
Hallucinogen Use
Hyperthyroidism and Thyrotoxicosis
Hypothyroidism
Inhalant-Related Psychiatric Disorders
Insomnia
Opioid Abuse
Phencyclidine (PCP)-Related Psychiatric Disorders
Schizophrenia
Toxicity, Heroin
Toxicity, Mushroom
Wernicke-Korsakoff Syndrome
Workup
Workup
Laboratory Studies
The purpose of the workup is to exclude complications of amphetamine abuse and other causes
of psychosis and altered mental status.
Imaging Studies
In the presence of neurologic impairments, CT or MRI helps in evaluating for subarachnoid and
intracranial hemorrhage.
Other Tests
Perform ECG to evaluate for cardiac involvement.
Use of the brief psychotic rating scale (BPRS), Beck Depression Scale, violence and suicide
assessment, and other measures may be helpful.
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.
Histologic Findings
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.
Treatment
Medical Care
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.
The excretion of amphetamines can be accelerated by the use of ammonium chloride, given
either IV or orally (PO).
Amphetamine intoxication can be treated with ammonium chloride, often found in OTC
expectorants, such as ammonium chloride (Quelidrine), baby cough syrup, Romilar, and
P-V-Tussin.
The recommended dose to acidify the urine is ammonium chloride 500 mg every 2-3
hours.
The ingredients in OTC cough syrups vary, and the clinician should become familiar with
1 or 2 stock items for use in the emergency department.
Ammonium chloride (Quelidrine), an OTC expectorant, can be used in the absence of
liver or kidney failure.
Administer IV fluids to provide adequate hydration.
If the patient is psychotic or if he or she is in danger of harming him or herself or others,
a high-potency antipsychotic, such as haloperidol (Haldol), can be used. Exercise caution
because of the potential for extrapyramidal symptoms, such as acute dystonic reactions,
and neuroleptic malignant syndrome.
Agitation also can be treated cautiously with benzodiazepines PO, IV, or intramuscularly
(IM). Lorazepam (Ativan) and chlordiazepoxide (Librium) are commonly used.
Administer naloxone (Narcan) in the event of concurrent opiate toxicity. Use caution to
avoid precipitation of acute opioid withdrawal in a patient who has used high doses of
opioid on a long-term basis.
Beta-blockers, such as propranolol (Inderal), can be used in the event of elevated blood
pressure and pulse. They also may be helpful with anxiety or panic.
Psychiatric hospitalization may be necessary when psychosis, aggression, and suicidality
cannot be controlled in a less restrictive environment.
If serotonin syndrome is suspected, stop all SSRI and SNRI medications.
Consultations
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.
Activity
Patients intoxicated with amphetamines are dangerous, and their activity should be limited (eg,
no driving) until their symptoms have resolved.
Medication
Medication Summary
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.
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.[11]
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.
Antipsychotics
Class Summary
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.
Haloperidol (Haldol)
Provides rapid sedation of agitated anxious patient; available PO and IM, allowing for flexible,
emergency administration.
Thiothixene (Navane)
Benzodiazepines
Class Summary
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.
Lorazepam (Ativan)
Provides rapid onset and efficacy in sedating aggressive patient; flexible administration in
emergency situation.
Depresses all levels of CNS, including limbic and reticular formation, possibly by increasing
activity of gamma-aminobutyric acid (GABA) activity, major inhibitory neurotransmitter.
Opiate antagonists
Class Summary
Naloxone (Narcan)
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.
Beta-blockers
Class Summary
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.
Propranolol (Inderal)
Antihypertensive agent useful in psychiatry to treat anxiety and impulse control. Often well
tolerated with minimal effect on hemodynamics of blood pressure and pulse.
Expectorants
Class Summary
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.
Commonly used as OTC expectorant; acidifies urine at high doses. Safe and easy to use.
Adsorbents
Class Summary
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.
Bottles and tubes. Use long after amphetamine ingestion can reduce systemic levels by adsorbing
amphetamines recirculating through gastric mucosa.
Follow-up
Further Outpatient Care
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.
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 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.
Transfer
If psychiatric conditions persist, causing social and occupational impairment, inpatient treatment
may be required.
Deterrence/Prevention
Abstinence prevents disorders and is the primary treatment.
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[12] ; aripiprazole vs.
methylphenidate vs. placebo[13] ; bupropion[14] ; and naltrexone.[15]
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.[16]
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
Complications include an increased risk of the following:
Psychosis
Depression
Anxiety disorder
Sleep disturbance
Memory impairment
Medical complications
Neurologic complications
Abuse of another or several substances
Psychosocial impairment
Affect dysregulation and aggression[17]
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.
Patient Education
Instruct the patient to abstain from alcohol and illicit drugs, especially because dual diagnosis is
a real issue. The only effective treatment is abstinence.
The family must be educated about the patient's addiction and its dangers.
For excellent patient and family education resources, see eMedicineHealth's patient education
articles Drug Dependence and Abuse and Substance Abuse.
References