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David L. Ginsberg, MD

  Primary Psychiatry. 2007;14(6):19-22

Dr. Ginsberg is vice-chair of clinical initiatives in the Department of Psychiatry at New York University Medical Center in New York City.

Disclosures: Dr. Ginsberg receives honoraria for lectures, papers, and/or teaching from AstraZeneca and GlaxoSmithKline; and receives research support from Cyberonics.


 

Aripiprazole-Induced Hyponatremia

Previous Psychopharmacology Reviews have discussed the association between serotonin reuptake inhibitors (SRIs)1-6 and the syndrome of inappropriate antidiuretic hormone secretion (SIADH), which is characterized by the sustained release of antidiuretic hormone (ADH) from the posterior pituitary gland. The norepinephrine reuptake inhibitor reboxetine, approved in Europe for the treatment of depression, has also been associated with SIADH.7 Other medications associated with SIADH include tricyclic antidepressants (TCAs),8 bupropion,9 neuroleptics, carbamazepine, sodium divalproex,10 vincristine, and cyclophosphamide.11

Non-medication causes of SIADH include central nervous system disorders, pulmonary disease, cardiac failure, renal disease, and neoplasia. Affected patients have a reduced ability to excrete dilute urine and as a consequence, they retain ingested fluid, which results in expansion of the extracellular fluid. Clinical symptoms are often nonspecific and may include weakness, lethargy, headache, anorexia, nausea, and weight gain. Associated laboratory signs are hyponatremia, serum hypoosmolality, and a less than maximally diluted urine. Treatment involves fluid restriction and intravenous hypertonic saline. If untreated, the syndrome may progress to confusion, convulsions, coma, and death.

Aripiprazole is an atypical neuroleptic indicated for the treatment of schizophrenia and for acute and maintenance phase treatment of manic and mixed episodes associated with bipolar I disorder. A potent dopamine partial agonist, aripiprazole acts as an antagonist at dopamine (D)2 receptors under hyperdopaminergic conditions and as a D2 agonist under hypodopaminergic conditions. It has been theorized that dopamine partial agonists may be able to stabilize the dopaminergic system without inducing a hypodopaminergic state, thereby reducing risk of side effects associated with pure blockade of dopamine receptors. In addition to these effects, aripiprazole also acts as a partial agonist at serotonin (5-HT)1A and as an antagonist at 5-HT2A receptors. The most commonly reported side effects in association with aripiprazole use include insomnia, anxiety, headaches, nausea, vomiting, and somnolence.12 There is now a report of aripiprazole-induced hyponatremia.13

A 69-year-old man with diabetes mellitus and bipolar disorder had a history of two prior manic episodes in 2001 and 2003. Treated with sodium valproate 1,000 mg/day for his bipolar disorder, he was also taking metformin 1,000 mg/day, glibenclamide 5 mg/day, and thyroxine supplements 100 µg/day for hypothyroidism. In August 2005, the man presented with relapse of manic symptoms for 1 week. Aripiprazole 10 mg/day was added. Two days later, he developed persistent hiccups. A comprehensive clinical examination revealed no neurologic deficits. Laboratory testing revealed glucose levels of 97 mg/dL, serum sodium levels of 122 mEq/L, and serum potassium levels of 4.5 mEq/L. Thyroid and renal function tests and lipid profiles were normal. Urine specific gravity was 1.010 (ie, no ketonuria).

It was discovered that the patient had been drinking 3–4 liters of water per day for the past 3 weeks. Immediate water restriction to 1.5 L/day was initiated. Because of its temporal association with hiccoughs, aripiprazole was withheld. Sodium levels stabilized to 133 mEq/L (all sampling done at 6AM). Two days later, aripiprazole 10 mg/day was restarted. The next day, sodium levels again dropped to 120 mEq/L and aripiprazole was discontinued. Quetiapine was started and increased to 400 mg/day over 2 weeks. Subsequently, 1 week later, sodium levels gradually increased and reached normal levels of 135 mEq/L. The hiccoughs spontaneously subsided with correction of sodium levels. At this time, fluid restriction was discontinued. Over the next 8 months of follow-up, the patient maintained euthymia with normal sodium levels.

The temporal sequence of described events supports an association in this patient between use of aripiprazole with the development of hyponatremia. Persistent hiccoughs are a frequent manifestation of hyponatremia. A decrease in sodium levels of 10 mEq/L can increase the incidence of hiccough 17 times.14 Excessive water intake is not the likely etiology. For water intake to be the sole basis for hyponatremia, typically a person has to drink >10 liters/day.15 In addition, water intake could not be the basis for hyponatremia as the fall in sodium levels persisted despite fluid restriction and the patient did not develop hyponatremia in the prior episodes, despite increased fluid intake of similar quantity.

In general, the risk of hyponatremia with psychotropic medications is greatest during the first 2 weeks of treatment and is unrelated to drug dose.16 Withdrawing aripiprazole in this patient led to stabilization of sodium levels within 1 week, which corresponds to the washout period of aripiprazole. Clinicians who prescribe aripiprazole should be mindful of the potential for precipitating the acute onset of SIADH. Based on reports with other psychotropic drugs, such as SRIs, women, the elderly, and those with comorbid medical conditions appear to be at highest risk. PP

 

References

1. Hwang AS, Magraw RM. Syndrome of inappropriate secretion of antidiuretic hormone due to fluoxetine. Am J Psychiatry. 1989;146(3):399.
2. Goddard C, Patton C. Hyponatremia associated with paroxetine. BMJ. 1992;305(6865):1332.
3. Crews JR, Potts NL, Schreiber J, Lipper S. Hyponatremia in a patient with sertraline. Am J Psychiatry. 1993;150(10):1564.
4. Baliga RR, McHardy KC. Syndrome of inappropriate antidiuretic hormone secretion due to fluvoxamine therapy. Br J Clin Pract. 1993;47(2):62-63.5. Gupta AK, Saravay SM. Venlafaxine-induced hyponatremia. J Clin Psychopharmacol. 1997;17(3):223-225.
6. Safdieh JE, Rudominer R. A case of hyponatremia induced by duloxetine. J Clin Psychopharmacol. 2006;26(6):675-676.
7. Ranieri P, Franzoni S, Trabucchi M. Reboxetine and hyponatremia. N Engl J Med. 2000;342(3):215-216.
8. Anfinson TJ, Kathol RG. Laboratory and neuroendocrine assessment in medical-psychiatric patients. In: Stoudemire A, Fogel BS, eds. Psychiatric Care of the Medical Patient. New York, NY: Oxford University Press; 1993:117.
9. Bagley SC, Yaeger D. Hyponatremia associated with bupropion, a case verified by rechallenge. J Clin Psychopharmacol. 2005;25(1):98-99.
10. Branten AJ, Wetzels JF, Weber AM, Koene RA. Hyponatremia due to sodium valproate. Ann Neurol. 1998;43(2):265-267.
11. Kinzie BJ. Management of the syndrome of inappropriate secretion of antidiuretic hormone. Clin Pharm. 1987;6(8):625-633.
12. Swainston Harrison T, Perry CM. Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder. Drugs. 2004;64(15):1715-1736.
13. Behere RV, Venkatasubramanian G, Naveen MN, Gangadhar BN. Aripiprazole-induced hyponatremia: a case report. J Clin Psychiatry. 2007;68(4):640-641.
14. George J, Thomas K, Jeyaseelan L, Peter JV, Cherian AM. Hyponatremia and hiccups. Natl Med J India. 1996;9(3):107-109.
15. Tierney LM Jr, McPhee SJ, Papadakis MA. Current Medical Diagnosis & Treatment 2004. 43rd ed. New York, NY: McGraw-Hill; 2003:837.
16. Madhusoodanan S, Bogunovic OJ, Moise D, Brenner R, Markowitz S, Sotelo J. Hyponatremia associated with psychotropic medications. A review of the literature and spontaneous reports. Adverse Drug React Toxicol Rev. 2002;21(1-2):17-29.

 

Disulfiram-Induced Manic Psychosis

For years, disulfiram has been used for the treatment of alcohol dependence. Its main effect is to produce an extremely unpleasant reaction in any patient who ingests even a small amount of alcohol while disulfiram is in their system. An aldehyde dehydrogenase inhibitor, disulfiram interferes with the metabolism of alcohol by producing a marked increase in blood acetaldehyde levels. This accumulation, in some cases upwards of 10 times higher than normal, produces an array of unpleasant effects sometimes referred to as the disulfiram alcohol reaction. These effects include nausea, throbbing headache, vomiting, hypertension, flushing, sweating, thirst, dyspnea, tachycardia, chest pain, vertigo, and blurred vision. Typically, reactions occur almost immediately after the ingestion of one drink and may last up to 30 minutes.

Via one of its metabolites, disulfiram also inhibits dopamine b-hydroxylase, which converts dopamine to norepinephrine. Therefore, it has the potential to cause psychotic or mood symptoms, including mania.1-5 Now comes a report of disulfiram-induced manic psychosis in an individual with no past personal or family history of any mood or psychotic disorder.6

A 34-year-old man was brought by his family to the psychiatric emergency room of a Turkish hospital in May 2005. For the prior 3 days, the patient had suffered from insomnia, talked too much, and exhibited increased psychomotor activity. He claimed that God talked to him and told him that he was special. Upon admission, further evaluation revealed excessive alcohol consumption for 15 years. On average, he drank 5–7 standard units of alcohol per weekend. Recently, he had been arguing more frequently with his wife over his lack of financial support for his family. In the absence of exhibiting a withdrawal syndrome, he was diagnosed with alcohol abuse. Three weeks prior to the present admission, he began taking—on his own without a prescription—500 mg/day of disulfiram in an effort to give up alcohol. In Turkey, disulfiram tablets can be obtained from pharmacies without a doctor’s prescription. One week later, after consuming three standard units of alcohol, the patient experienced a disulfiram reaction with headache, flushing, and respiratory difficulty. This reaction had resulted in an overnight admission to the emergency room. Over the next 2 weeks, as confirmed by his wife, the patient refrained from drinking alcohol and maintained disulfiram at doses between 500 and 1,500 mg/day.

Mental status examination revealed that the patient had auditory hallucinations (God talked to him). He also had mystic and megalomaniac delusions (he claimed to be on a mission by God and that he was a preeminent and special person commissioned to call people upon religion). Also evident were increased speed and pressure of speech with accelerated associations. While spontaneous attention was increased, voluntary attention was diminished. Orientation to place, time, and person was normal. There was no memory disorder. Family psychiatric history was unremarkable. Laboratory tests, including complete blood count, chemistries, and thyroid function tests, were normal. Urine test for psychoactive substances was negative. Electroencephalography (EEG) was normal.

Diagnosed with manic psychosis, the patient was started on haloperidol 20 mg/day, chlorpromazine 100 mg/day, and biperiden 10 mg/day. Within 2 days, the auditory hallucinations disappeared, mystic and megalomanic delusions improved, and insight was restored. On day 6 of hospitalization, the patient was discharged with prescriptions for chlorpromazine 100 mg/day and carbamazepine 400 mg/day. One week later, chlorpromazine was discontinued. Carbamazepine was maintained to reduce his tendency to drink alcohol. However, 1 month later, the patient stopped taking carbamazepine on his own. At a follow-up outpatient visit 9 months later, the patient did not exhibit any symptoms or signs of psychosis or mood disorder.

In typical practice, disulfiram is initiated at a dose of 500 mg/day then 1 or 2 weeks later decreased to a maintenance dose of 250 mg/day. The temporal sequence of events described above, including a 12-day alcohol-free period in the context of use of higher than normal doses of disulfiram, supports an association between disulfiram and emergence of manic psychosis. Interestingly, it appears that there are more reports of disulfiram-related psychiatric complications in eastern countries. Whether this reflects reporting bias, greater use of unpure forms of disulfiram in these regions, increased genetic susceptibility to this adverse event among certain ethnic populations, or some other combination of factors is unknown. PP

References

1. Liddon SC, Satran R. Disulfiram (Antabuse) psychosis. Am J Psychiatry. 1967;123(10):1284-1289.
2. Lacoursiere RB, Swatek R. Adverse interaction between disulfiram and marijuana: a case report. Am J Psychiatry. 1983;140(2):243-244.
3. Bakish D, Lapierre YD. Disulfiram and bipolar affective disorder: a case report. J Clin Psychopharmacol. 1986;6(3):178-180.
4. Daniel DG, Swallows A, Wolff F. Capgras delusion and seizures in association with therapeutic dosages of disulfiram. South Med J. 1987;80(12):1577-1579.
5. Larson EW, Olincy A, Rummans TA, Morse RM. Disulfiram treatment of patients with both alcohol dependence and other psychiatric disorders: a review. Alcohol Clin Exp Res. 1992;16(1):125-130.
6. Ceylan ME, Turkcan A, Mutlu E, Onal O. Manic episode with psychotic symptoms associated with high dose of disulfiram: a case report. J Clin Psychopharmacol. 2007;27(2):224-225.

Alopecia Associated With Quetiapine

Alopecia involves the loss of some or all of the hair from the head and sometimes from other parts of the body. Many psychotropic medications have been associated with the development of alopecia, including selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), lithium, sodium valproate, and the atypical antipsychotics olanzapine and risperidone.1,2

Quetiapine is a second-generation antipsychotic indicated for the treatment of schizophrenia; as monotherapy for the acute treatment of manic episodes as well as an adjunct to treatment with lithium or divalproex for bipolar I disorder; and for bipolar depression. Pharmacologically, it is an antagonist at serotonin (5-HT)1A and 5-HT2, dopamine (D)1 and D2, histamine (H)1, and adrenergic a1 and a2 receptors.3 Derived from the New Zealand Intensive Medicines Monitoring Programme, there are now the first published reports of alopecia in association with quetiapine.4

In the first report, a 34-year-old woman with a history of psychotic depression commenced citalopram 20 mg/day and quetiapine 25 mg/day, with the latter titrated up to 100 mg/day. Approximately 6 weeks later, she noticed significant hair loss, involving whole strands. One week after onset, quetiapine was withdrawn. The hair loss resolved. At last follow-up, the patient remained on citalopram.

In the second report, another 34-year-old woman with a history of bipolar disorder was taking quetiapine 300 mg/day, zopiclone 7.5–15 mg/day, clonazepam 1 mg as needed, and salbutamol inhaler as needed. Approximately 3 weeks after beginning quetiapine at a dosage of 300 mg/day, she reported increasing hair loss. In the past, the patient had experienced a similar reaction to sodium valproate. Quetiapine was discontinued. Subsequently, her alopecia resolved.

The World Health Organization database contains 15 other reports of alopecia associated with quetiapine. Of these, seven reports contained sufficient information for an assessment of causality, with one of these also providing dechallenge information, as were present in the previous reports.

There are two main mechanisms presumed to underlie drug-induced alopecia. Normally, each hair follicle grows following a three-phase cycle: anagen (growth phase) lasting between 4–8 years in the adult scalp; catagen (transitional phase) lasting approximately 2 weeks; followed by telogen (resting phase) that lasts approximately 100 days before hair is shed.5 One mechanism, which is characteristic of antineoplastic drugs, appears to affect anagen. As a result, mitosis ceases and hair is shed within days to weeks.5 Other medications, including psychotropics, appear to act by inducing hair follicles to enter a premature telogen phase (telogen effluvium) that results in hair loss occurring 2–4 months after beginning the treatment.5-7 While the mechanism is unknown, it has been suggested that these medications may chelate zinc and selenium, which are believed to be necessary for hair growth.

Typically, medication-induced alopecia is reversible upon dosage reduction or discontinuation of the offending drug.6,7 Other options for managing this side effect include waiting for accomodation to occur or the use of zinc and selenium.8 Whether the patients described here were genetically predisposed to this effect is not known. Nevertheless, when alopecia does occur, it is important to treat as its occurrence has been associated with elevated rates of depression and anxiety,9 as well as medication noncompliance. PP

References

1. Kimyai-Asadi A, Harris JC, Nousari HC. Critical overview: adverse cutaneous reactions to psychotropic medications. J Clin Psychiatry. 1999;60(10):714-725.
2. Leung M, Wrixon K, Remick RA. Olanzapine-induced hair loss. Can J Psychiatry. 2002;47(9):891-892.
3. Seroquel [package insert]. London, England: AstraZeneca Pharmaceuticals; 2006.
4. McLean RM, Harrison-Woolrych M. Alopecia associated with quetiapine. Int Clin Psychopharmacol. 2007;22(2):117-119.
5. Tosi A, Misciali C, Piraccini BM, Peluso AM, Bardazzi F. Drug-induced hair loss and hair growth. Incidence, management and avoidance. Drug Saf. 1994;10(4):310-317.
6. Mercke Y, Sheng H, Khan T, Lippmann S. Hair loss in psychopharmacology. Ann Clin Psychiatry. 2000;12(1):35-42.
7. Gautam M. Alopecia due to psychotropic medications. Ann Pharmacother. 1999;33(5):631-637.
8. Fatemi SH, Calabrese JR. Treatment of valproate-induced alopecia. Ann Pharmacother. 1995;29(12):1302.
9. Hunt N, McHale S. The psychological impact of alopecia. BMJ. 2005;331(7522):951-953.

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Methamphetamines: What the Primary Care Physician Needs to Know

W. R. Murray Bennett, MD, FRCPC, and Peter Roy-Byrne, MD

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Primary Psychiatry. 2007;14(5):67-73

Dr. Bennett is assistant professor and Dr. Roy-Byrne is professor and vice-chair of the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine at Harborview Medical Center in Seattle. 

Disclosures: Dr. Bennett reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Roy-Byrne is a consultant to Alexza, Jazz, and Solvay; and receives honoraria from Forest and Wyeth.

Please direct all correspondence to: W. R. Murray Bennett, MD, FRCPC, Assistant Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Box 359930, 325 9th Ave, Seattle, WA 98104; Tel: 206-731-1190; Fax: 206-731-5109; E-mail: mbennett@u.washington.edu.

Focus Points

• Methamphetamine dependence has a devastating affect on society, healthcare, and the environment.

• Methamphetamine intoxification results in prolonged euphoria and disinhibition associated with impulsivity and risk-taking behavior.

• Methamphetamine dependence has cognitive effects as shown by neuro-anatomical and neurophysiologic changes, and demonstrated by neuropsychologic testing.

• Chronic methamphetamine users show an increased risk of cardiovascular events and dental decay.

• Healthcare providers should use a non-judgmental, empathic, direct approach with patients, first assessing and treating medical and psychiatric complications before utilizing addiction treatment options.

• There are few effective treatments for methamphetamine dependence; however, newer behavioral treatments are showing promising results.

Abstract

The prevalence of methamphetamine abuse in the United States has increased and caused devastating effects on society, healthcare, and the environment as well as the court and prison system. Primary care physicians are often the first point of contact for dependent patients, who frequently present with medical and psychiatric symptoms. Methamphetamine use poses significant risk of medical and dental complications as well as impairment from psychiatric and cognitive effects. This article describes the pharmacologic properties of methamphetamine and its immediate effects on the central nervous system; characteristic clinical presentation and medical sequelae of methamphetamine abuse; psychiatric complications, cognitive effects, and their neurobiologic correlates; important elements of the clinical assessment of the methamphetamine abuser; and current treatment options, both pharmacologic and behavioral.

Introduction

Twelve million people across the United States have taken methamphetamine on 1 occasion in their lives,1 comprising a large proportion of the estimated 35 million international methamphetamine users. These rates are in contrast with the approximately 15 million cocaine users and 10 million opiate abusers around the world.2 Methamphetamine abuse and dependence has spread across the United States from rural to urban populations as well as across racial and class barriers. The impact of methamphetamine on society, healthcare, and the environment as well as the court and prison system is often difficult to appreciate. Parents who are methamphetamine users are often incarcerated or deceased, which leaves a generation of abandoned, neglected children and disintegrating families. During the history of methamphetamine use in this country, emergency departments, burn units, and medical inpatient wards have become familiar with the multiple medical consequences of its use. In addition, methamphetamine laboratories have left unanticipated environmental consequences due to toxic ingredients and by-products involved in its manufacture.

Primary care physicians (PCPs) are often the point of first contact for these patients, who frequently present with both medical and psychiatric symptoms. This article outlines the pharmacologic properties and immediate effects of methamphetamine on the central nervous system (CNS); characteristic clinical presentations, psychiatric complications, cognitive effects, stages of addiction and recovery, neurobiologic correlates, and medical sequelae of methamphetamine abuse; important elements of the clinical assessment of the methamphetamine abuser; and current treatment options both pharmacologic and behavioral. 

Pharmacologic Properties and Subjective Effects

Methamphetamine subjective effect duration is typically 8–24 hours and its half-life—the time for 50% of the substance to be removed from the body—is 12 hours. The high lipid solubility of methamphetamine facilitates rapid transfer of the drug across the blood-brain barrier. In comparison, cocaine has an effect duration of 1–2 hours and a half-life of 1 hour. Methamphetamine is also more potent than cocaine and utilizes a synergistic combination of mechanisms to augment dopaminergic neurotransmission, thus creating a more intense euphoria. These mechanisms include stimulating release of newly synthesized catecholamine in the CNS; reversing transport of neurotransmitters through plasma membrane transporters; reducing expression of dopamine transporters at the cell surface; partially blocking pre-synaptic reuptake of these neurotransmitters; and increasing activity and expression of dopamine synthesizing enzyme tyrosine hydroxylase.3-8 Euphoria as described by methamphetamine users lasts for several hours and increases the sensory perception of pleasurable experiences. Many patients who have abused substances describe enhanced sexual thoughts, feelings, and behaviors with methamphetamine use in comparison to other drugs.9 Increased sexual activity noted by users is often characterized by an increase in the number of sexual partners among heterosexual men and women as well as men who have sex with men10,11 and elevated gonorrhea infection rates.12 Other users report an improved sense of confidence, diminished social anxiety, greater assertiveness, and inhibition resolution as well as the facilitation of sustained, enhanced sexual activity.13 Patient descriptions of experiences on methamphetamine confirm that these subjective effects largely account for their motivation to use.13-15

Increased confidence and assertiveness, and the resolution of inhibitions can translate to increased impulsivity, carelessness, risk taking, and violence. Of the women using illicit drugs, 50% are in the childbearing age group.16 Prevalence of in utero methamphetamine damage with prenatal complications, including low birth weight, growth restriction, cardiac defects, cleft palate, placental abruption, and intraventricular hemorrhage, is increasing.17-20 Other studies have suggested lower intelligence quotients and aggressive behavior among children exposed to methamphetamines during pregnancy.21-28 During law enforcement seizures of maufacturing laboratories, children found have been shown to have been exposed to toxic levels of the precursors and byproducts of methamphetamine.29 Violence is associated with the intoxication phase of use and is commonly noted during emergency department visits.30-32 The inhibitions of users are also lowered concerning needle sharing or engaging in unprotected sexual intercourse among high-risk populations, such as men who have sex with men. Such behaviors make methamphetamine use a major contributor to the spread of human immunodeficiency virus (HIV) infection in this patient population.33-37

Clinical Presentation 

Patients who chronically use methamphetamine may present to PCPs in a number of ways. Intoxicated patients may be restless, agitated, and diaphoretic with tachycardia, elevated blood pressure, and dilated pupils. Gum chewing or teeth grinding may also be present. More often, patients will present in the immediate recovery phase of methamphetamine use (described as “the crash”) or with medical and psychiatric sequelae of chronic use. While recovering from methamphetamine use, patients commonly complain of hypersomnia, anergia, increased appetite, anhedonia, and mood lability, becoming easily tearful. Patients may have clear evidence of injection drug use with abscesses at injection sites or excoriated lesions on the face and arms. These lesions result from the patient’s response to formication, a sensation of bugs crawling under the skin when “coming down” from drug effects. A chronic user may demonstrate weight loss or complain of problems sleeping, jaw pain, or dental problems.38 Erectile dysfunction is also a common side effect of methamphetamine use, and often leads male patients to request medications, such as Viagra (sildenafil), from PCPs.39

Medical Effects

Short-term medical effects of methamphetamine include tachycardia, insomnia, hyperthermia, dehydration, and rhabdomyolosis in severe cases. Long-term medical effects include elevated risk of stroke, cardiomyopathy, myocardial infarction, lethal cardiac arrhythmias, aortic dissection, and pulmonary hypertension.40-43 Xerostomia from ongoing methamphetamine use also leads to tooth decay, resulting in the common presentation of edentulous 30-year-old methamphetamine addicted patients.44-46 

Psychiatric Effects

The immediate recovery phase following methamphetamine use is associated with symptoms mimicking significant clinical major depressive disorder (MDD) that are typically resolved within 7–10 days following withdrawal. Patients may complain of irritability, melancholia, marked dysphoria, carbohydrate craving, anxiety, and hypersomnia as well as an intense craving for the drug. Less well described is the abstinence phase of withdrawal, which is characterized by prolonged anhedonia. As persistent use of methamphetamine depletes dopamine, the body is no longer able to produce the neurotransmitter in reaction to pleasurable stimuli. This anhedonic effect lasts for 12 months. Gradual partial improvement correlates with findings demonstrating partial resolution of neurocognitive and neuroanatomical changes during the same 12-month period.47 However, for some patients, MDD symptoms may last longer and potentially be permanent.48

Women reported difficulty in controlling violent behavior more often than men in a sample of patients in the Methamphetamine Treatment Project at the University of California at Los Angeles. However, because men more often find violence and aggression as justifiable, fewer men may believe this is a problem. Clinicians must consider risk for violence and aggression to be increased in this patient population.31,48 

Methamphetamine, as in other psychoactive stimulants, can trigger a psychotic or manic episode in patients with pre-existing diagnosis or a predisposition to bipolar or psychotic disorders.49,50 Unique to methamphetamine is its ability to directly cause chronic psychotic disorders that do not resolve upon withdrawal of the substance.51-57 Research has shown a link between the duration of drug use and the persistence and severity of psychotic symptoms.50

Cognitive Effects 

Acute use of methamphetamines will improve performance on cognitive tasks in the short term. However, methamphetamine is potentially neurotoxic and long-term exposure may lead to neurologic damage. Consequently, chronic methamphetamine-dependent patients are at an increased risk of cognitive effects to a much greater extent than was initially suspected. Cognitive deficits have been reported in 40% of chronic methamphetamine users,58 severity correlating with duration and frequency of use in a dose-dependent fashion. Deficit areas are widespread and global, including attention and memory deficits,59,60 impaired learning, delayed recall, and slowed processing speeds.61 More prominent deficits demonstrated on neuropsychological testing are associated with speed of processing information. Tasks that combine these skills with visuomotor scanning are particularly challenging for chronic methamphetamine users as these tasks involve shifts in executive function,61 including abstract reasoning, planning, and behavioral flexibility. Selective inattention deficits or reduced cognitive inhibition—the inability to suppress irrelevant distracting information—result from the areas affected.62,63 This may contribute to impulsive decision making, which increases the difficulty for patients to process and apply cognitive elements of effective addiction treatment. Cognitive impairment characterized by attention-deficit/hyperactivity disorder (ADHD) parallels deficits due to methamphetamine use, which confounds the clinical assessment of methamphetamine-dependent patients alleging ADHD symptoms.

Stages of Addiction and Recovery 

Poly-drug abuse is common in patient substance use and PCPs should note this fact when assessing patients who abuse methamphetamine. Patients progress through various stages during the addition recovery process, and will benefit most if engaged in a treatment program, either inpatient or outpatient. Patients should be encouraged by their PCP to follow through with treatment referrals. 

The stages of addiction described in this article include: (I) intoxication, which describes patients presenting under the direct influence of the substance—patients are often agitated, potentially psychotic, and can be violent; (II) the “crash,” which encompasses the first 2 weeks of acute withdrawal; (III) abstinence, which describes the first 90 days of the return to everyday behaviors and habits; and (IV) recovery, which outlines the process of maintaining abstinence during the first 3–12 months.

Patients in stage I present most often to emergency departments for help with agitation, psychosis, or suicidal ideation. Measures to address these presenting symptoms may be taken after examination, such as administering anxiolytic, sedative-hypnotic, or antipsychotic medications. Emergency department protocol for the management of such patients accounts for these concerns as well as addresses the likelihood of polydrug use. Patients in Stage II are encouraged to rest, sleep, and eat, and should be informed to expect mood swings, anenergia, and a sense of grieving. Some patients may also experience persistent symptoms of psychosis or suicidal ideation in abstinence. These symptoms should be treated with antidpressant and/or antipsychotic medications with consideration of psychiatric hospitalization for the patient’s safety. Patients in Stage III should expect to gain some of the weight they lost while using methamphetamine. Cravings for the drug will also persist and patients should keep an active, established routine as a helpful distraction. Patients who have had 30 days of abstinence may benefit from treatment of comorbid mood or anxiety symptoms and may be started on an antidepressant or anxiolytic medication. Stage IV marks the transition of resuming usual activities. Cravings for the drug will gradually subside and triggers for relapse should be identified. The emphasis should be on behavioral activation, involvement with groups, socialization, and exercise. 

Neurobiologic Correlates

Neuroanatomical changes in methamphetamine-dependent patients have been well demonstrated by neuroimaging. The subcortical region as well as the temporal and frontal cortical areas show evidence of hypometabolism and perfusion deficits on single photon emission computed tomography.64-66 Neuronal damage in the basal ganglia and in frontal white and gray matter have been demonstrated on magnetic resonance spectroscopy,67 magnetic resonance imaging,68,69 and positron emission tomography (PET).70,71 The mechanism for striatal damage has been hypothesized to be a change in cerebral blood flow or a loss of dopamine terminals and transporters with consequent lower levels of dopamine in the nucleus accumbens, caudate, and putamen.70,72 

Decreased density of dopaminergic axon terminals revealed by PET in the caudate and putamen,47,70,71 has correlated with slowed motor activities and impaired memory. Bilaterally reduced volume of the hippocampus has also been observed,73 correlating with poor memory performance on neuropsychological testing. Global brain serotonin transporter density was found to be decreased amongst methamphetamine-dependent patients noted for aggression.74 The depletion of dopaminergic neurons and transporter systems correlates with subjective patient reports of persistent anhedonia in methamphetamine withdrawal. Furthermore, methamphetamine users in early abstinence also demonstrate global metabolic activity consistent with MDD, with complaints of dysphoria and anhedonia.75 However, gradual partial improvement of these subjective complaints after 12 months of abstinence also correlates with gradual recovery of dopamine transporters, a marker for likely combination of re-innervation, axonal sprouting on spared terminals, and increased dopamine transporters on spared terminals, shown on PET scans.47 

Guidelines for Assessment

PCP awareness of clinical manifestations can increase vigilance for signs of methamphetamine use. Discussions with patients suspected of drug use require a non-judgmental, empathic, direct, yet diplomatic approach. Expressing concern about potential and current effects of methamphetamine use for the patient, including medical, psychiatric, and cognitive effects, is more effective than an emphasis on the recreational use of an illicit substance. Considering the patient’s potential cognitive deficits, it may be effective to fully explain these concerns. PCPs should encourage an open dialogue and reassure the patient that the intent is treatment of medical and psychiatric complications regardless of the patient’s success in abstaining from methamphetamine use. 

Patients’ medical risk for infection, dental decay, and cardiovascular complications should be evaluated and followed by a discussion on how the patient can minimize these risks. Ensuring that a patient is alive and healthy is not akin to aiding or supporting drug use. Instead, from a harm reduction approach, PCPs can build trust with the patient, who may begin to talk about their addiction with the knowledge that help will be available. Serious psychiatric presentations, such as psychosis, severe MDD, or suicidality merit direct treatment, however, mild-to-moderate dysphoria and anxiety may be managed with supportive, rather than somatic, treatment.

PCPs should establish with the patient his or her desire for good health and the wish to avoid medical, psychiatric, and cognitive complications from methamphetamine abuse so as to begin to identify discrepancies between these desires and the patient’s actions.

Treatments

Obstacles to achieving sobriety are considerable. Patients may endure 12 months of anhedonia during recovery whilst resisting potent relapse triggers.13 Treatment options include traditional complete abstinence, 12-step programs, harm reduction, and cognitive-behavioral approaches as well as treatments that combine approaches.76 The Matrix Model is a 4-month manualized intensive outpatient treatment program that combines cognitive-behavioral therapy (CBT), 12-step meetings, family education, and behavioral positive reinforcement.77 The model was validated for use in treatment of cocaine dependence over 15 years ago. Contingency management has also shown promising results and is particularly applicable in treating methamphetamine addiction due to cognitive deficits caused by chronic use of the drug.78 Contingency management uses either a voucher-based or a prize-based format.79,80 Each approach is structured to reward abstinence, confirmed by negative urine toxicology screens, on an escalating schedule. Thus, a greater period of confirmed abstinence earns a greater reward. Voucher-based contingency management has been shown to be effective in achieving abstinence in methamphetamine-dependent patients with benefits also shown at 1-year follow up.81 Prize-based adaptations of contingency management are a cost-effective alternative to effective yet costly voucher-based programs. Rather than earning vouchers of increasing value with greater periods of abstinence from methamphetamine use, patients earn additional chances to win a prize. Of note, researchers also studied whether an increase in gambling is found with this approach. However, no objective increase in gambling addiction has been recorded among study participants.82

Medication

As with most pharmacologic treatments for addiction, finding an effective treatment agent has been difficult and recent approaches have been disappointing for researchers. Randomized controlled trials have been conducted for a range of psychotropic agents including several antidepressants. Selective serotonin reuptake inhibitors fluoxetine83 and sertraline84 and tricyclic antidepressants imipramine85 and nortriptyline86 have all failed to demonstrate any benefit. A sertraline trial had poor enough results for researchers to recommend that it be avoided in methamphetamine-dependent patients. However, the noradrenergic antidepressant bupropion has demonstrated some efficacy in reducing subjective and cue-induced cravings.87 

Due to success with other γ-aminobutyric acid (GABA)-ergic medications in the treatment of cocaine dependence,88,89 research with such agents to stop methamphetamine use has been conducted. While gabapentin did not demonstrate significant benefit, baclofen, a GABA-β receptor agonist with a short half-life, showed a promising data trend.90 With a longer half-life,91 γ-vinyl-GABA has been shown to be safe and efficacious in a small open-label study.92 Novel agents have also been evaluated and produced mixed results. The calcium-channel antagonist amlodipine was not found to be effective,93 but another such agent, isradipine, reduced methamphetamine-induced positive subjective and reinforcing effects.94 A trial of serotonin (5-HT)3 antagonist ondansetron failed to show any benefit over placebo.95 Antipsychotics haloperidol and risperidone were not found to be beneficial,96 but a retrospective chart review of patients admitted to a residential rehabilitation program suggested that quetiapine reduced craving and anxiety amongst alcohol- and methamphetamine-dependent patients.97 Modafinil, a novel alerting agent that combats daytime drowsiness and has an US Food and Drug Administration indication for narcolepsy and sleep-wake disruption caused by shift work, has been used to target cognitive effects found with chronic methamphetamine use,98 based on preliminary evidence in the treatment of cocaine dependence. In stimulant-dependent patients, modafinil showed decreased craving of both amphetamines and cocaine,99,100 minimal abuse liability,99,101 and reports of subjective dampening of drug euphoria.102 Neuropsychological testing shows that modafinil has been found to improve performance by decreasing impulsivity, allowing the respondent time to use other cognitive processes before making a decision.103,104 Moreover, modafinil is believed to treat anergia and anhedonia found with stimulant withdrawal,98 however, additional research evaluating the effects of modafinil on methamphetamine-dependent patients is necessary. Based on research as well as common clinical medication uses, doses of modafinil 100–200 mg/day, bupropion 150–200 mg BID, or quetiapine 50–300 mg/day would be sensible for the treatment of methamphetamine dependence.

The National Institute on Drug Abuse (NIDA) is sponsoring several trials evaluating novel treatments for methamphetamine abuse and dependence.105 Bupropion is being investigated in conjunction with CBT and contingency management. Topiramate, an anticonvulsant found to be effective for treatment of alcohol and cocaine dependence in previous research, is being studied at a multi-site NIDA trial. The University of Texas Southwestern Medical Branch in Dallas is the site of a trial evaluating citicoline, a nutritional supplement with some data to suggest that it may stabilize mood, decrease drug use and craving, and improve memory.105 Research has produced some promising results with citicoline in patients with bipolar disorder and cocaine dependence. Another nutritional supplement studied, lobeline, may inhibit the action of amphetamine and functionally act as an indirect dopamine receptor antagonist through a combination of mechanisms. Other NIDA trials105 are evaluating perindopril, used for hypertension treatment, and rivastigmine, an acetylcholinesterase inhibitor that increases the level of acetycholine in the brain and may improve cognition in treatment of Alzheimer’s-related dementia. Since angiotensin converting enzyme (ACE) inhibitors have the potential to reverse methamphetamine’s neurotoxic effects, this class of medications may be useful treatment. Perindopril demonstrates greater activity in the CNS than other ACE inhibitors. This study will attempt to determine whether perindopril modifies cardiovascular responses and adverse events during methamphetamine administration and whether perindopril alters methamphetamine pharmacokinetics and its reinforcing effects.105 These medication trials may take an innovative approach to the study of methamphetamine abuse pharmacotherapy and reveal an agent with clear benefit for patients.

Conclusion

Methamphetamine is a recreationally abused, highly-addictive stimulant with an impact on society on various levels. Users suffer significant cognitive, mood, and psychotic effects, and users’ children and families are often neglected and/or abused. Emergency departments, burn units, and hospital wards deal with medical and psychiatric consequences of drug use; the court and prison systems handle the criminal impact on communities; and clean-up from methamphetamine laboratories leaves residual impact on the environment. Assessment of methamphetamine-dependent patients requires an empathic, non-judgmental, direct approach, considering their overall health needs and the goal of beginning addiction treatment. Advances in behavioral treatment suggest a contingency management model in addition to the manualized multi-disciplinary Matrix Model. Adjunctive pharmacologic agents suggest using bupropion and modafinil as treatments. Further research into the effect of methamphetamine and addiction treatment is necessary. PP

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W. R. Murray Bennett, MD, FRCPC, and Peter Roy-Byrne, MD
 

Primary Psychiatry. 2007;14(5):67-73

Dr. Bennett is assistant professor and Dr. Roy-Byrne is professor and vice-chair of the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine at Harborview Medical Center in Seattle. 

Disclosures: Dr. Bennett reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Roy-Byrne is a consultant to Alexza, Jazz, and Solvay; and receives honoraria from Forest and Wyeth.

Please direct all correspondence to: W. R. Murray Bennett, MD, FRCPC, Assistant Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine at Harborview Medical Center, Box 359930, 325 9th Ave, Seattle, WA 98104; Tel: 206-731-1190; Fax: 206-731-5109; E-mail: mbennett@u.washington.edu.

Focus Points

• Methamphetamine dependence has a devastating affect on society, healthcare, and the environment.

• Methamphetamine intoxification results in prolonged euphoria and disinhibition associated with impulsivity and risk-taking behavior.

• Methamphetamine dependence has cognitive effects as shown by neuro-anatomical and neurophysiologic changes, and demonstrated by neuropsychologic testing.

• Chronic methamphetamine users show an increased risk of cardiovascular events and dental decay.

• Healthcare providers should use a non-judgmental, empathic, direct approach with patients, first assessing and treating medical and psychiatric complications before utilizing addiction treatment options.

• There are few effective treatments for methamphetamine dependence; however, newer behavioral treatments are showing promising results.

Abstract

The prevalence of methamphetamine abuse in the United States has increased and caused devastating effects on society, healthcare, and the environment as well as the court and prison system. Primary care physicians are often the first point of contact for dependent patients, who frequently present with medical and psychiatric symptoms. Methamphetamine use poses significant risk of medical and dental complications as well as impairment from psychiatric and cognitive effects. This article describes the pharmacologic properties of methamphetamine and its immediate effects on the central nervous system; characteristic clinical presentation and medical sequelae of methamphetamine abuse; psychiatric complications, cognitive effects, and their neurobiologic correlates; important elements of the clinical assessment of the methamphetamine abuser; and current treatment options, both pharmacologic and behavioral.

Introduction

Twelve million people across the United States have taken methamphetamine on 1 occasion in their lives,1 comprising a large proportion of the estimated 35 million international methamphetamine users. These rates are in contrast with the approximately 15 million cocaine users and 10 million opiate abusers around the world.2 Methamphetamine abuse and dependence has spread across the United States from rural to urban populations as well as across racial and class barriers. The impact of methamphetamine on society, healthcare, and the environment as well as the court and prison system is often difficult to appreciate. Parents who are methamphetamine users are often incarcerated or deceased, which leaves a generation of abandoned, neglected children and disintegrating families. During the history of methamphetamine use in this country, emergency departments, burn units, and medical inpatient wards have become familiar with the multiple medical consequences of its use. In addition, methamphetamine laboratories have left unanticipated environmental consequences due to toxic ingredients and by-products involved in its manufacture.

Primary care physicians (PCPs) are often the point of first contact for these patients, who frequently present with both medical and psychiatric symptoms. This article outlines the pharmacologic properties and immediate effects of methamphetamine on the central nervous system (CNS); characteristic clinical presentations, psychiatric complications, cognitive effects, stages of addiction and recovery, neurobiologic correlates, and medical sequelae of methamphetamine abuse; important elements of the clinical assessment of the methamphetamine abuser; and current treatment options both pharmacologic and behavioral. 

Pharmacologic Properties and Subjective Effects

Methamphetamine subjective effect duration is typically 8–24 hours and its half-life—the time for 50% of the substance to be removed from the body—is 12 hours. The high lipid solubility of methamphetamine facilitates rapid transfer of the drug across the blood-brain barrier. In comparison, cocaine has an effect duration of 1–2 hours and a half-life of 1 hour. Methamphetamine is also more potent than cocaine and utilizes a synergistic combination of mechanisms to augment dopaminergic neurotransmission, thus creating a more intense euphoria. These mechanisms include stimulating release of newly synthesized catecholamine in the CNS; reversing transport of neurotransmitters through plasma membrane transporters; reducing expression of dopamine transporters at the cell surface; partially blocking pre-synaptic reuptake of these neurotransmitters; and increasing activity and expression of dopamine synthesizing enzyme tyrosine hydroxylase.3-8 Euphoria as described by methamphetamine users lasts for several hours and increases the sensory perception of pleasurable experiences. Many patients who have abused substances describe enhanced sexual thoughts, feelings, and behaviors with methamphetamine use in comparison to other drugs.9 Increased sexual activity noted by users is often characterized by an increase in the number of sexual partners among heterosexual men and women as well as men who have sex with men10,11 and elevated gonorrhea infection rates.12 Other users report an improved sense of confidence, diminished social anxiety, greater assertiveness, and inhibition resolution as well as the facilitation of sustained, enhanced sexual activity.13 Patient descriptions of experiences on methamphetamine confirm that these subjective effects largely account for their motivation to use.13-15

Increased confidence and assertiveness, and the resolution of inhibitions can translate to increased impulsivity, carelessness, risk taking, and violence. Of the women using illicit drugs, 50% are in the childbearing age group.16 Prevalence of in utero methamphetamine damage with prenatal complications, including low birth weight, growth restriction, cardiac defects, cleft palate, placental abruption, and intraventricular hemorrhage, is increasing.17-20 Other studies have suggested lower intelligence quotients and aggressive behavior among children exposed to methamphetamines during pregnancy.21-28 During law enforcement seizures of maufacturing laboratories, children found have been shown to have been exposed to toxic levels of the precursors and byproducts of methamphetamine.29 Violence is associated with the intoxication phase of use and is commonly noted during emergency department visits.30-32 The inhibitions of users are also lowered concerning needle sharing or engaging in unprotected sexual intercourse among high-risk populations, such as men who have sex with men. Such behaviors make methamphetamine use a major contributor to the spread of human immunodeficiency virus (HIV) infection in this patient population.33-37

Clinical Presentation 

Patients who chronically use methamphetamine may present to PCPs in a number of ways. Intoxicated patients may be restless, agitated, and diaphoretic with tachycardia, elevated blood pressure, and dilated pupils. Gum chewing or teeth grinding may also be present. More often, patients will present in the immediate recovery phase of methamphetamine use (described as “the crash”) or with medical and psychiatric sequelae of chronic use. While recovering from methamphetamine use, patients commonly complain of hypersomnia, anergia, increased appetite, anhedonia, and mood lability, becoming easily tearful. Patients may have clear evidence of injection drug use with abscesses at injection sites or excoriated lesions on the face and arms. These lesions result from the patient’s response to formication, a sensation of bugs crawling under the skin when “coming down” from drug effects. A chronic user may demonstrate weight loss or complain of problems sleeping, jaw pain, or dental problems.38 Erectile dysfunction is also a common side effect of methamphetamine use, and often leads male patients to request medications, such as Viagra (sildenafil), from PCPs.39

Medical Effects

Short-term medical effects of methamphetamine include tachycardia, insomnia, hyperthermia, dehydration, and rhabdomyolosis in severe cases. Long-term medical effects include elevated risk of stroke, cardiomyopathy, myocardial infarction, lethal cardiac arrhythmias, aortic dissection, and pulmonary hypertension.40-43 Xerostomia from ongoing methamphetamine use also leads to tooth decay, resulting in the common presentation of edentulous 30-year-old methamphetamine addicted patients.44-46 

Psychiatric Effects

The immediate recovery phase following methamphetamine use is associated with symptoms mimicking significant clinical major depressive disorder (MDD) that are typically resolved within 7–10 days following withdrawal. Patients may complain of irritability, melancholia, marked dysphoria, carbohydrate craving, anxiety, and hypersomnia as well as an intense craving for the drug. Less well described is the abstinence phase of withdrawal, which is characterized by prolonged anhedonia. As persistent use of methamphetamine depletes dopamine, the body is no longer able to produce the neurotransmitter in reaction to pleasurable stimuli. This anhedonic effect lasts for 12 months. Gradual partial improvement correlates with findings demonstrating partial resolution of neurocognitive and neuroanatomical changes during the same 12-month period.47 However, for some patients, MDD symptoms may last longer and potentially be permanent.48

Women reported difficulty in controlling violent behavior more often than men in a sample of patients in the Methamphetamine Treatment Project at the University of California at Los Angeles. However, because men more often find violence and aggression as justifiable, fewer men may believe this is a problem. Clinicians must consider risk for violence and aggression to be increased in this patient population.31,48 

Methamphetamine, as in other psychoactive stimulants, can trigger a psychotic or manic episode in patients with pre-existing diagnosis or a predisposition to bipolar or psychotic disorders.49,50 Unique to methamphetamine is its ability to directly cause chronic psychotic disorders that do not resolve upon withdrawal of the substance.51-57 Research has shown a link between the duration of drug use and the persistence and severity of psychotic symptoms.50

Cognitive Effects 

Acute use of methamphetamines will improve performance on cognitive tasks in the short term. However, methamphetamine is potentially neurotoxic and long-term exposure may lead to neurologic damage. Consequently, chronic methamphetamine-dependent patients are at an increased risk of cognitive effects to a much greater extent than was initially suspected. Cognitive deficits have been reported in 40% of chronic methamphetamine users,58 severity correlating with duration and frequency of use in a dose-dependent fashion. Deficit areas are widespread and global, including attention and memory deficits,59,60 impaired learning, delayed recall, and slowed processing speeds.61 More prominent deficits demonstrated on neuropsychological testing are associated with speed of processing information. Tasks that combine these skills with visuomotor scanning are particularly challenging for chronic methamphetamine users as these tasks involve shifts in executive function,61 including abstract reasoning, planning, and behavioral flexibility. Selective inattention deficits or reduced cognitive inhibition—the inability to suppress irrelevant distracting information—result from the areas affected.62,63 This may contribute to impulsive decision making, which increases the difficulty for patients to process and apply cognitive elements of effective addiction treatment. Cognitive impairment characterized by attention-deficit/hyperactivity disorder (ADHD) parallels deficits due to methamphetamine use, which confounds the clinical assessment of methamphetamine-dependent patients alleging ADHD symptoms.

Stages of Addiction and Recovery 

Poly-drug abuse is common in patient substance use and PCPs should note this fact when assessing patients who abuse methamphetamine. Patients progress through various stages during the addition recovery process, and will benefit most if engaged in a treatment program, either inpatient or outpatient. Patients should be encouraged by their PCP to follow through with treatment referrals. 

The stages of addiction described in this article include: (I) intoxication, which describes patients presenting under the direct influence of the substance—patients are often agitated, potentially psychotic, and can be violent; (II) the “crash,” which encompasses the first 2 weeks of acute withdrawal; (III) abstinence, which describes the first 90 days of the return to everyday behaviors and habits; and (IV) recovery, which outlines the process of maintaining abstinence during the first 3–12 months.

Patients in stage I present most often to emergency departments for help with agitation, psychosis, or suicidal ideation. Measures to address these presenting symptoms may be taken after examination, such as administering anxiolytic, sedative-hypnotic, or antipsychotic medications. Emergency department protocol for the management of such patients accounts for these concerns as well as addresses the likelihood of polydrug use. Patients in Stage II are encouraged to rest, sleep, and eat, and should be informed to expect mood swings, anenergia, and a sense of grieving. Some patients may also experience persistent symptoms of psychosis or suicidal ideation in abstinence. These symptoms should be treated with antidpressant and/or antipsychotic medications with consideration of psychiatric hospitalization for the patient’s safety. Patients in Stage III should expect to gain some of the weight they lost while using methamphetamine. Cravings for the drug will also persist and patients should keep an active, established routine as a helpful distraction. Patients who have had 30 days of abstinence may benefit from treatment of comorbid mood or anxiety symptoms and may be started on an antidepressant or anxiolytic medication. Stage IV marks the transition of resuming usual activities. Cravings for the drug will gradually subside and triggers for relapse should be identified. The emphasis should be on behavioral activation, involvement with groups, socialization, and exercise. 

Neurobiologic Correlates

Neuroanatomical changes in methamphetamine-dependent patients have been well demonstrated by neuroimaging. The subcortical region as well as the temporal and frontal cortical areas show evidence of hypometabolism and perfusion deficits on single photon emission computed tomography.64-66 Neuronal damage in the basal ganglia and in frontal white and gray matter have been demonstrated on magnetic resonance spectroscopy,67 magnetic resonance imaging,68,69 and positron emission tomography (PET).70,71 The mechanism for striatal damage has been hypothesized to be a change in cerebral blood flow or a loss of dopamine terminals and transporters with consequent lower levels of dopamine in the nucleus accumbens, caudate, and putamen.70,72 

Decreased density of dopaminergic axon terminals revealed by PET in the caudate and putamen,47,70,71 has correlated with slowed motor activities and impaired memory. Bilaterally reduced volume of the hippocampus has also been observed,73 correlating with poor memory performance on neuropsychological testing. Global brain serotonin transporter density was found to be decreased amongst methamphetamine-dependent patients noted for aggression.74 The depletion of dopaminergic neurons and transporter systems correlates with subjective patient reports of persistent anhedonia in methamphetamine withdrawal. Furthermore, methamphetamine users in early abstinence also demonstrate global metabolic activity consistent with MDD, with complaints of dysphoria and anhedonia.75 However, gradual partial improvement of these subjective complaints after 12 months of abstinence also correlates with gradual recovery of dopamine transporters, a marker for likely combination of re-innervation, axonal sprouting on spared terminals, and increased dopamine transporters on spared terminals, shown on PET scans.47 

Guidelines for Assessment

PCP awareness of clinical manifestations can increase vigilance for signs of methamphetamine use. Discussions with patients suspected of drug use require a non-judgmental, empathic, direct, yet diplomatic approach. Expressing concern about potential and current effects of methamphetamine use for the patient, including medical, psychiatric, and cognitive effects, is more effective than an emphasis on the recreational use of an illicit substance. Considering the patient’s potential cognitive deficits, it may be effective to fully explain these concerns. PCPs should encourage an open dialogue and reassure the patient that the intent is treatment of medical and psychiatric complications regardless of the patient’s success in abstaining from methamphetamine use. 

Patients’ medical risk for infection, dental decay, and cardiovascular complications should be evaluated and followed by a discussion on how the patient can minimize these risks. Ensuring that a patient is alive and healthy is not akin to aiding or supporting drug use. Instead, from a harm reduction approach, PCPs can build trust with the patient, who may begin to talk about their addiction with the knowledge that help will be available. Serious psychiatric presentations, such as psychosis, severe MDD, or suicidality merit direct treatment, however, mild-to-moderate dysphoria and anxiety may be managed with supportive, rather than somatic, treatment.

PCPs should establish with the patient his or her desire for good health and the wish to avoid medical, psychiatric, and cognitive complications from methamphetamine abuse so as to begin to identify discrepancies between these desires and the patient’s actions.

Treatments

Obstacles to achieving sobriety are considerable. Patients may endure 12 months of anhedonia during recovery whilst resisting potent relapse triggers.13 Treatment options include traditional complete abstinence, 12-step programs, harm reduction, and cognitive-behavioral approaches as well as treatments that combine approaches.76 The Matrix Model is a 4-month manualized intensive outpatient treatment program that combines cognitive-behavioral therapy (CBT), 12-step meetings, family education, and behavioral positive reinforcement.77 The model was validated for use in treatment of cocaine dependence over 15 years ago. Contingency management has also shown promising results and is particularly applicable in treating methamphetamine addiction due to cognitive deficits caused by chronic use of the drug.78 Contingency management uses either a voucher-based or a prize-based format.79,80 Each approach is structured to reward abstinence, confirmed by negative urine toxicology screens, on an escalating schedule. Thus, a greater period of confirmed abstinence earns a greater reward. Voucher-based contingency management has been shown to be effective in achieving abstinence in methamphetamine-dependent patients with benefits also shown at 1-year follow up.81 Prize-based adaptations of contingency management are a cost-effective alternative to effective yet costly voucher-based programs. Rather than earning vouchers of increasing value with greater periods of abstinence from methamphetamine use, patients earn additional chances to win a prize. Of note, researchers also studied whether an increase in gambling is found with this approach. However, no objective increase in gambling addiction has been recorded among study participants.82

Medication

As with most pharmacologic treatments for addiction, finding an effective treatment agent has been difficult and recent approaches have been disappointing for researchers. Randomized controlled trials have been conducted for a range of psychotropic agents including several antidepressants. Selective serotonin reuptake inhibitors fluoxetine83 and sertraline84 and tricyclic antidepressants imipramine85 and nortriptyline86 have all failed to demonstrate any benefit. A sertraline trial had poor enough results for researchers to recommend that it be avoided in methamphetamine-dependent patients. However, the noradrenergic antidepressant bupropion has demonstrated some efficacy in reducing subjective and cue-induced cravings.87 

Due to success with other γ-aminobutyric acid (GABA)-ergic medications in the treatment of cocaine dependence,88,89 research with such agents to stop methamphetamine use has been conducted. While gabapentin did not demonstrate significant benefit, baclofen, a GABA-β receptor agonist with a short half-life, showed a promising data trend.90 With a longer half-life,91 γ-vinyl-GABA has been shown to be safe and efficacious in a small open-label study.92 Novel agents have also been evaluated and produced mixed results. The calcium-channel antagonist amlodipine was not found to be effective,93 but another such agent, isradipine, reduced methamphetamine-induced positive subjective and reinforcing effects.94 A trial of serotonin (5-HT)3 antagonist ondansetron failed to show any benefit over placebo.95 Antipsychotics haloperidol and risperidone were not found to be beneficial,96 but a retrospective chart review of patients admitted to a residential rehabilitation program suggested that quetiapine reduced craving and anxiety amongst alcohol- and methamphetamine-dependent patients.97 Modafinil, a novel alerting agent that combats daytime drowsiness and has an US Food and Drug Administration indication for narcolepsy and sleep-wake disruption caused by shift work, has been used to target cognitive effects found with chronic methamphetamine use,98 based on preliminary evidence in the treatment of cocaine dependence. In stimulant-dependent patients, modafinil showed decreased craving of both amphetamines and cocaine,99,100 minimal abuse liability,99,101 and reports of subjective dampening of drug euphoria.102 Neuropsychological testing shows that modafinil has been found to improve performance by decreasing impulsivity, allowing the respondent time to use other cognitive processes before making a decision.103,104 Moreover, modafinil is believed to treat anergia and anhedonia found with stimulant withdrawal,98 however, additional research evaluating the effects of modafinil on methamphetamine-dependent patients is necessary. Based on research as well as common clinical medication uses, doses of modafinil 100–200 mg/day, bupropion 150–200 mg BID, or quetiapine 50–300 mg/day would be sensible for the treatment of methamphetamine dependence.

The National Institute on Drug Abuse (NIDA) is sponsoring several trials evaluating novel treatments for methamphetamine abuse and dependence.105 Bupropion is being investigated in conjunction with CBT and contingency management. Topiramate, an anticonvulsant found to be effective for treatment of alcohol and cocaine dependence in previous research, is being studied at a multi-site NIDA trial. The University of Texas Southwestern Medical Branch in Dallas is the site of a trial evaluating citicoline, a nutritional supplement with some data to suggest that it may stabilize mood, decrease drug use and craving, and improve memory.105 Research has produced some promising results with citicoline in patients with bipolar disorder and cocaine dependence. Another nutritional supplement studied, lobeline, may inhibit the action of amphetamine and functionally act as an indirect dopamine receptor antagonist through a combination of mechanisms. Other NIDA trials105 are evaluating perindopril, used for hypertension treatment, and rivastigmine, an acetylcholinesterase inhibitor that increases the level of acetycholine in the brain and may improve cognition in treatment of Alzheimer’s-related dementia. Since angiotensin converting enzyme (ACE) inhibitors have the potential to reverse methamphetamine’s neurotoxic effects, this class of medications may be useful treatment. Perindopril demonstrates greater activity in the CNS than other ACE inhibitors. This study will attempt to determine whether perindopril modifies cardiovascular responses and adverse events during methamphetamine administration and whether perindopril alters methamphetamine pharmacokinetics and its reinforcing effects.105 These medication trials may take an innovative approach to the study of methamphetamine abuse pharmacotherapy and reveal an agent with clear benefit for patients.

Conclusion

Methamphetamine is a recreationally abused, highly-addictive stimulant with an impact on society on various levels. Users suffer significant cognitive, mood, and psychotic effects, and users’ children and families are often neglected and/or abused. Emergency departments, burn units, and hospital wards deal with medical and psychiatric consequences of drug use; the court and prison systems handle the criminal impact on communities; and clean-up from methamphetamine laboratories leaves residual impact on the environment. Assessment of methamphetamine-dependent patients requires an empathic, non-judgmental, direct approach, considering their overall health needs and the goal of beginning addiction treatment. Advances in behavioral treatment suggest a contingency management model in addition to the manualized multi-disciplinary Matrix Model. Adjunctive pharmacologic agents suggest using bupropion and modafinil as treatments. Further research into the effect of methamphetamine and addiction treatment is necessary. PP

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