Amphetamine-Related Psychiatric Disorders

Back

Background

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

  1. Amphetamine-induced anxiety disorder
  2. Amphetamine-induced mood disorder
  3. Amphetamine-induced psychotic disorder with delusions
  4. Amphetamine-induced psychotic disorder with hallucinations
  5. Amphetamine-induced sexual dysfunction
  6. Amphetamine-induced sleep disorder
  7. Amphetamine intoxication
  8. Amphetamine intoxication delirium
  9. Amphetamine withdrawal
  10. 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.[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 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.

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.

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.

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 everyday 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]

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.

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 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.[5]

Postmarketing 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.[6]

International

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.

Race

Amphetamine-related psychiatric disorders most commonly occur in white individuals.

Sex

Age

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-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).

Physical

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

Causes

Laboratory Studies

Imaging Studies

In the presence of neurologic impairments, CT or MRI helps in evaluating for subarachnoid and intracranial hemorrhage.

Other Tests

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.

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.

Consultations

Activity

Patients intoxicated with amphetamines are dangerous, and their activity should be limited (eg, no driving) until their symptoms have resolved.

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.

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.[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.

Haloperidol (Haldol)

Clinical Context:  Provides rapid sedation of agitated anxious patient; available PO and IM, allowing for flexible, emergency administration.

Thiothixene (Navane)

Clinical Context:  Blocks postsynaptic blockade of CNS dopamine receptors, inhibiting dopamine-mediated effects. PO and IM forms allow for rapid tranquilization.

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.

Lorazepam (Ativan)

Clinical Context:  Provides rapid onset and efficacy in sedating aggressive patient; flexible administration in emergency situation.

Chlordiazepoxide (Librium, Libritabs, Mitran)

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.

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.

Naloxone (Narcan)

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.

Class Summary

These drugs inhibit the action of opiates.

Propranolol (Inderal)

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.

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.

Ammonium chloride (Quelidrine)

Clinical Context:  Commonly used as OTC expectorant; acidifies urine at high doses. Safe and easy to use.

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.

Activated charcoal suspension (Actidose-aqua, Inst-Aqua, Liquid-Char)

Clinical Context:  Bottles and tubes. Use long after amphetamine ingestion can reduce systemic levels by adsorbing amphetamines recirculating through gastric mucosa.

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.

Further Inpatient Care

Further Outpatient Care

Inpatient & Outpatient Medications

Transfer

Deterrence/Prevention

Complications

Prognosis

Author

Michael F Larson, DO, Clinical Instructor, Department of Child and Adolescent Psychiatry, Harvard Medical School; Psychiatrist, Harvard Vanguard Medical Associates and Private Practice

Disclosure: Nothing to disclose.

Specialty Editors

Denis F Darko, MD, Executive Director, Clinical Research and Development, Global Neuroscience, AstraZeneca

Disclosure: AstraZeneca Salary Management position

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Harold H Harsch, MD, Program Director of Geropsychiatry, Department of Geriatrics/Gerontology, Associate Professor, Department of Psychiatry and Department of Medicine, Froedtert Hospital, Medical College of Wisconsin

Disclosure: Novartis Honoraria Speaking and teaching; Sunovion Honoraria Speaking and teaching; Otsuke Grant/research funds reseach; Merck Honoraria Speaking and teaching

Chief Editor

Eduardo Dunayevich, MD, Adjunct Assistant Professor, Department of Psychiatry, University of Cincinnati College of Medicine; Clinical Research Physician, Neuroscience, Lilly Research Laboratories

Disclosure: Nothing to disclose.

References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000.
  2. Pardo-Lozano R, Farré M, Yubero-Lahoz S, O'Mathúna B, Torrens M, Mustata C, et al. Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT). PLoS One. 2012;7(10):e47599. [View Abstract]
  3. Carhart-Harris RL, King LA, Nutt DJ. A web-based survey on mephedrone. Drug Alcohol Depend. Oct 1 2011;118(1):19-22. [View Abstract]
  4. Thirthalli J, Benegal V. Psychosis among substance users. Curr Opin Psychiatry. May 2006;19(3):239-45. [View Abstract]
  5. Substance Abuse and Mental Health Services Administration. (2006). Results from the 2005 National Survey on Drug Use and Health: National Findings. Rockville, MD: Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Office of Applied Studies; September 2006.
  6. Mosholder AD, Gelperin K, Hammad TA, Phelan K, Johann-Liang R. Hallucinations and other psychotic symptoms associated with the use of attention-deficit/hyperactivity disorder drugs in children. Pediatrics. Feb 2009;123(2):611-6. [View Abstract]
  7. Alem A, Kebede D, Kullgren G. The prevalence and socio-demographic correlates of khat chewing in Butajira, Ethiopia. Acta Psychiatr Scand Suppl. 1999;397:84-91. [View Abstract]
  8. Shen W, Liu Y, Li L, Zhang Y, Zhou W. Negative moods correlate with craving in female methamphetamine users enrolled in compulsory detoxification. Subst Abuse Treat Prev Policy. Oct 30 2012;7:44. [View Abstract]
  9. Bramness JG, Gundersen ØH, Guterstam J, Rognli EB, Konstenius M, Løberg EM, et al. Amphetamine-induced psychosis--a separate diagnostic entity or primary psychosis triggered in the vulnerable?. BMC Psychiatry. Dec 5 2012;12:221. [View Abstract]
  10. McKetin R, Lubman DI, Baker AL, Dawe S, Ali RL. Dose-related psychotic symptoms in chronic methamphetamine users: evidence from a prospective longitudinal study. JAMA Psychiatry. Mar 2013;70(3):319-24. [View Abstract]
  11. Jayaram-Lindström N, Hammarberg A, Beck O, Franck J. Naltrexone for the treatment of amphetamine dependence: a randomized, placebo-controlled trial. Am J Psychiatry. Nov 2008;165(11):1442-8. [View Abstract]
  12. Payer DE, Lieberman MD, London ED. Neural correlates of affect processing and aggression in methamphetamine dependence. Arch Gen Psychiatry. Mar 2011;68(3):271-82. [View Abstract]
  13. Anderson BB, Chen G, Gutman DA, Ewing AG. Dopamine levels of two classes of vesicles are differentially depleted by amphetamine. Brain Res. Mar 30 1998;788(1-2):294-301. [View Abstract]
  14. Brown ES, Nejtek VA, Perantie DC, et al. Cocaine and amphetamine use in patients with psychiatric illness: a randomized trial of typical antipsychotic continuation or discontinuation. J Clin Psychopharmacol. Aug 2003;23(4):384-8. [View Abstract]
  15. Cooper N. Inappropriate prescription of methylphenidate. N Z Med J. Oct 10 2003;116(1183):U636. [View Abstract]
  16. Drug Enforcement Agency. Drug Enforcement Agency: Khat. [Drug Enforcement Administration Web site].
  17. Farber NB, Hanslick J, Kirby C, et al. Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity. Neuropsychopharmacology. Jan 1998;18(1):57-62. [View Abstract]
  18. Galanter M, Kleber DH, eds. American Psychiatric Press Textbook of Substance Abuse Treatment. 2nd ed. Arlington, VA: American Psychiatric Press; 1999.
  19. Guze BH, Ferng HK, Szuba MP, Richeimer SH. The Psychiatric Drug Handbook. St Louis, Mo: Mosby-Year; 1995:184-260.
  20. Kaplan HI, Sadock BJ. Comprehensive Textbook of Psychiatry. Baltimore, Md: Lippincott Williams & Wilkins; 1995:792-798.
  21. Kaplan HI, Sadock BJ. Pocket Handbook of Emergency Psychiatric Medicine. Baltimore, Md: Lippincott Williams & Wilkins; 1993:108-110.
  22. Leamon MH, Gibson DR, Canning RD, Benjamin L. Hospitalization of patients with cocaine and amphetamine use disorders from a psychiatric emergency service. Psychiatr Serv. Nov 2002;53(11):1461-6. [View Abstract]
  23. Methamphetamine abuse and addiction. Research Report Series. National Institute of Health, National Institue on Drug Abuse; January, 2002.
  24. Sekine Y, Minabe Y, Ouchi Y, et al. Association of dopamine transporter loss in the orbitofrontal and dorsolateral prefrontal cortices with methamphetamine-related psychiatric symptoms. Am J Psychiatry. Sep 2003;160(9):1699-701. [View Abstract]
  25. Sills TL, Greenshaw AJ, Baker GB, Fletcher PJ. Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction. Psychopharmacology (Berl). Feb 1999;141(4):421-7. [View Abstract]
  26. Srisurapanont M, Jarusuraisin N, Jittiwutikan J. Amphetamine withdrawal: II. A placebo-controlled, randomised, double-blind study of amineptine treatment. Aust N Z J Psychiatry. Feb 1999;33(1):94-8. [View Abstract]
  27. Thirthalli J, Benegal V. Psychosis among substance users. Curr Opin Psychiatry. May 2006;19(3):239-45. [View Abstract]