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Ward 86 Management Recommendations

Management of HIV-Infected Patients Who Use Methamphetamine

updated September 2017

Contributors: Paula J. Lum, MD, MPH
Jacqueline P. Tulsky, MD
John Baker, MD
Valerie Gruber, PhD, MPH

In industrialized countries and, increasingly, in resource-limited settings, stimulant use, especially the use of methamphetamine (MA), is common among people infected with HIV and accounts for substantial morbidity and mortality. Methamphetamine use is a driving force in HIV transmission among men who have sex with men (MSM), more than doubling the probability both of engaging in high-risk sexual behavior and of acquiring sexually transmitted infections (including HIV and hepatitis C).

MA is a psychostimulant and sympathomimetic that causes direct presynaptic release of monoamine neurotransmitters (dopamine, norepinephrine, and serotonin), indirectly blocks their reuptake at the presynaptic transporters, and is neurotoxic to the brain's dopaminergic and serotonergic circuits.(1) MA can be ingested orally, but when smoked, snorted, or injected, higher concentrations are rapidly achieved in the brain. Increased extracellular concentrations of monoamines activate the cardiovascular and central nervous systems with surges in dopamine, mediating the reinforcing effects that can lead to MA addiction.(2)

In addition to MA's acute effects on the sympathetic branch of the autonomic nervous system (hypertension, tachycardia, hyperthermia, increased respiratory rate, blood vessel constriction), MA use can cause severe hypertension, arrhythmias, myocardial infarction, stroke, cardiomyopathy, pulmonary hypertension, rhabdomyolysis, acute renal failure, severe dental caries, and dyskinesias.(3) Neurocognitive and behavioral effects can be characterized across a spectrum of use, and by acute and chronic withdrawal syndromes (see Table 1). In a 2007 metaanalysis of studies examining the effects of chronic MA use on neuropsychiatric and neurologic function, the most frequently reported deficits were in episodic memory, executive function, and motor function, and the largest impairments were in episodic memory, executive function, and information processing speed.(3) Given the number and severity of MA-related health effects, training in how to elicit a history of stimulant use, how to characterize the nature of stimulant use in the medical record, and how to use tools and techniques to manage this disorder are important for providers who treat HIV-infected individuals and those at risk of acquiring HIV infection.

Table 1. Cognitive, Behavioral, and Emotional Effects of Methamphetamine Use over Stages of Use(3)

Acute UseBinge UseTweakingWithdrawal Syndrome
Euphoria, enhanced energy and alertness, feelings of increased physical and mental capacity, surge in productivity, elevated self-esteem, increased libidoIncrease in sexual behaviors and repetitive, focused activities (cleaning, skin picking), sleeplessness, heightened anxiety, paranoia, hallucinations, deliriumIncreased anxiety, irritability, insomnia, confusionDysphoria, depression, irritability, anxiety, poor concentration, hypersomnia, fatigue, paranoia, akathisia, drug craving

Screening for Methamphetamine Use

  • Asking HIV-infected patients and those at high-risk of acquiring HIV infection about drug use should be part of the every initial medical history. The following validated, single-question drug screening tool helps the clinician determine which patients need further substance use assessment: "How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?" A response of just 1 or more is considered to be positive.(4) Those who screen positive for MA use should be assessed further for unhealthy use and for a diagnosis of stimulant use disorder. (See Appendix 1 for more details.)

  • Since patients often experience shame about their substance use, questions about MA should be introduced matter-of-factly and nonjudgmentally (in the same manner one might present the rationale for colon cancer screening to a patient) in order to create a productive working relationship and to reduce the stigma of substance use in an already heavily stigmatized patient population.

  • Unhealthy substance use occurs when it increases a person's risk of health consequences (hazardous use) or has already led to health consequences (harmful use).(5) A stimulant use disorder may be diagnosed when MA use leads to clinically significant distress and impairment in 4 broad areas: hazardous or harmful use, social problems, impaired control, and pharmacologic symptoms (eg, tolerance and withdrawal). (See Appendix 1 for specific DSM-5 diagnostic criteria).

Treatment for Methamphetamine Use

  • For patients diagnosed with a mild stimulant use disorder (DSM-4) or unhealthy use not meeting criteria for stimulant use disorder, brief counseling interventions during office visits may help them to reduce MA use or stop altogether (see Appendix 1 for counseling hints). For patients diagnosed with moderate to severe stimulant use disorder (DSM-5), higher levels of care are indicated, including intensive outpatient individual or group behavioral therapy, medically supervised withdrawal management, and rehabilitation in a residential treatment setting. Off-label trials of medication management may be considered, with caveats (see below).

  • For patients who are not ready to make changes in their drug use, patient-centered counseling at office visits can be used to explore ambivalence about their drug use, build motivation, and strengthen commitment to change. Providers may find that conversations about change are most productive using Motivational Interviewing, "a collaborative conversation style for strengthening a person's own motivation and commitment to change."(6)

  • Once a patient demonstrates readiness and commitment to change, it's time to proceed to an action plan, which may include office-based treatment or referral to more specialized treatment. The choice depends on what the patient is ready for and what is clinically indicated for the severity of the patient's substance use.

Behavioral therapies are currently the only evidence-based treatment for MA use disorders. These therapies can be resource intensive, and their cost-effectiveness has not been well characterized. The Matrix Model is one example of an effective treatment for stimulant use disorder.(7) This intervention consists of engaging the patient in cognitive-behavioral therapy (CBT) and psychoeducation, including early recovery and relapse-prevention groups, education groups (for patients as well as supportive family members), social support groups, individual counseling, and urine and/or breath drug screening delivered over a 16-week period. For MSM, CBT tailored to MSM has been found to have a greater effect than general CBT. An example of a behavioral treatment program in San Francisco that offers harm reduction-based individual or group counseling, treatment, and support services for gay men, transmen who have sex with men, and other MSM who are having issues with drugs or alcohol can be found on the Stonewall Project website.

Contingency management is another effective behavioral treatment. An example of a 12-week contingency management program in San Francisco that uses positive reinforcement to support people who choose to stop using MA without the use of groups or meetings can be found on the Stonewall Project website. A metaanalysis of 13 randomized trials of behavioral interventions has shown that CBT such as Matrix combined with contingency management is more effective than CBT alone in reducing stimulant use.(8)

Medical therapy

Preliminary encouraging results have been seen in small trials testing naltrexone, sustained-release methylphenidate, bupropion, and sustained-release mirtazapine in combination with behavioral therapy for the management of MA use disorder.(9,10,11,12,13) These trials have been limited by small sample sizes, high dropout rates, disagreement about outcomes, and relatively short-term follow-up. Moreover, they generally have been conducted in specific patient subgroups (eg, patients with less-severe dependence at baseline or MSM), and few have been conducted with subjects living with HIV disease, limiting the generalizability of their findings. With the caveat that larger, definitive trials are required to establish efficacy, these 4 medications are described below for the HIV clinician who is considering their off-label use (see Appendix 2 for details about these clinical trials).

  • Antagonist medications: Antagonist medications can eliminate or attenuate the acute positive reinforcing effects of MA intoxication by blocking the action of MA. Antagonists, including naltrexone, haloperidol, risperidone, quetiapine, and the partial antagonist, aripiprazole, have been studied as pharmacotherapies for MA use, but only the trials of naltrexone suggest potential efficacy.

    • Naltrexone is an opioid receptor antagonist that can partially modulate or blunt the reinforcing dopaminergic effects of methamphetamine and amphetamine. Naltrexone is well tolerated in patients who do not require opioids for medical reasons and is FDA approved for the treatment of alcohol and opioid use disorders. Naltrexone can be initiated at a dosage of 12.5 to 25 mg once daily for the first week to reduce the risk of its most common side effect, gastrointestinal distress, then increased to 50 mg once daily. Because hepatotoxicity can be an adverse effect of this drug, oral naltrexone should be used cautiously in patients who have laboratory evidence of hepatic impairment. It is an FDA pregnancy category C medication.

    Psychostimulant medications: Agonist medications, such as nicotine and methadone, are evidence-based pharmacotherapies for the treatment of tobacco use disorder and opioid use disorder, respectively. An effective agonist medication for the treatment of MA use disorder would promote early abstinence by binding and mimicking the action of MA on brain receptors, as well as minimize withdrawal and other negative affective symptoms. Psychostimulants, such as dextroamphetamine, methylphenidate, bupropion, and modafinil, have agonist properties. Of these, only methylphenidate and bupropion have suggested some efficacy in subgroups of patients with less-severe MA use disorder.(14)

    • Methylphenidate is a mild CNS stimulant that is FDA approved for the treatment of attention deficit disorder and narcolepsy. While its precise pharmacological mechanism of action in persons with MA use disorder is unknown, methylphenidate's activity as an inhibitor of dopamine uptake at the dopamine transporter (may prevent dopamine release by MA and consequently prevent the euphoria and reinforcing effects of MA.(2) Sustained-release methylphenidate in titrated doses of 18 to 54 mg/day has been studied in clinical trials. Methylphenidate is a controlled substance that may cause anxiety, agitation, tolerance, withdrawal, and addiction, and it may cause sudden death, heart attack, or stroke in adults. It is an FDA pregnancy category C medication.
    • Bupropion is an antidepressant approved by the FDA for the treatment of major depressive disorder and seasonal affective disorder, and as a nonnicotine aid to smoking cessation. It is a weak, nonselective inhibitor of dopamine and norepinephrine transporters and an antagonist at nicotinic acetylcholine receptors.(15) By increasing dopamine transmission and restoring depleted dopamine, bupropion acts as a stimulating antidepressant that may alleviate the cravings and dysphoria experienced during MA withdrawal and may help to prevent relapse.(16,17) Sustained-release bupropion in 150 mg twice daily dosing has been studied. Bupropion may cause drowsiness, dizziness, blurred vision, or neuropsychiatric symptoms. It is associated with an increased risk of seizures, especially in persons with eating disorders and those who use alcohol in excess. It may cause a false-positive result for the presence of amphetamine in urine drug screens. It is an FDA pregnancy category C medication.

    HIV clinicians may encounter patients who request psychostimulant medications for the treatment of MA use disorder or to prevent MA withdrawal symptoms. Given the potential for cardiovascular adverse effects, lack of clear effectiveness in the current literature, and risk of liability if patients misuse the medications, controlled psychostimulant medications probably should be administered for the treatment of MA use disorder only in a closely monitored clinical trial. Exceptions may occur. For instance, methylphenidate and dextroamphetamine are effective for treatment of attention deficit disorders and treatment-refractory depression that can complicate recovery from MA use disorders. Expert consultation with a psychiatrist is recommended when such comorbidities are in the differential diagnosis for complicated patients. As of 2017, the NIDA Clinical Trials Network is recruiting adults with moderate or severe MA use disorder from multiple U.S. sites for a double-blind, placebo-controlled, randomized clinical trial of 380 mg of extended-release injectable naltrexone combined with extended-release oral bupropion (450 mg/day).

    Serotonergic medications: MA acts also on serotonin (5HT) neurotransmitter systems, and 5HT reuptake inhibitors have been proposed as potential agents to decrease the reinforcing effects of MA and its neurotoxic effects in monoaminergic neurons. Imipramine, fluoxetine, paroxetine, sertraline, ondansetron, and mirtazapine have been evaluated, and only mirtazapine has shown promise.

    • Mirtazapine is a novel noradrenergic and specific serotonergic antidepressant that facilitates the release of norepinephrine, serotonin, and dopamine in the areas of the brain involved in drug reward, craving, and drug-seeking behavior. Mirtazapine typically is initiated at a dose of 15 mg at bedtime for 1 week, then titrated to 30 mg at bedtime. Adverse effects include somnolence, increased appetite, weight gain, dry mouth, and angle-closure glaucoma. It is an FDA pregnancy category C medication.
  • Clinical urine drug testing (UDT) for MA. With patient consent, testing urine for the presence of methamphetamine and amphetamine can be a useful clinical tool during treatment with psychostimulant medications, in order to evaluate possible use of MA in the previous 2-5 days. As a feedback component of counseling or other behavioral treatments, UDT may help patients reflect on their frequency or patterns of use. UDT also can provide the patient with a measurable goal to work toward (ie, increasing the number or ratio of confirmed MA-negative urine test results in a given time period). MA-negative results can help medical providers advocate on behalf of patients who are doing well. Of note, screening immunoassays for amphetamine and methamphetamine are highly cross-reactive; false positives can be caused by use of bupropion, trazodone, sildenafil, some bath salts, and other drugs. Confirmatory testing of positive results by liquid/gas chromatography and mass spectroscopy therefore is essential when using UDT in clinical practice.

  • Management of MA withdrawal and relapse prevention
    • Patients who stop using methamphetamine may show the following symptoms of acute withdrawal: feelings of fatigue and unrest, irritability, long but troubled sleep, intense hunger, and moderate to severe depression (see Table 1). These symptoms may be observed for up to 2 weeks after discontinuing use. Intense craving for MA may persist for weeks to months after stopping use.

    • People who stop using methamphetamine experience a reduction in brain concentrations of dopamine that may reach their lowest point after several months of abstinence. The neurotoxic effects of MA on the brain's dopamine terminals have been associated with a significant loss of dopamine transporters in the thalamus and striatum. Positron emission tomography studies conducted after short (<6 month) and protracted (12- to 17-month) periods of abstinence have shown partial recovery of DAT metabolism in only some areas of the brain, and these were associated with improved motor and verbal memory tests; these improvements, however, may take a year or more to achieve.(14)

    • Depression is a common feature during both acute and subacute withdrawal. Patients can benefit from being informed about this effect, as delayed-onset depression may increase the risk of relapse.

    • Providers should develop a plan with each patient for addressing possible depression (eg, nutrition, exercise, psychiatric consultation, antidepressant therapy). Mental health and other support services may be important for months after abstinence begins.

  • Other considerations

    For persons who use MA, auditory memory is more negatively impacted and (in those who quit) returns more slowly than visual memory. This may have important implications for HIV clinicians, who often convey important information verbally. Providers should write down instructions, HIV treatment plans, and appointment dates; they should visually review treatment plans, schedules, and medications; and use medi-sets or pillboxes as adherence reminders.

    Stimulant-induced psychoses commonly include auditory and tactile hallucinations, ideas of reference, and paranoid delusions. These symptoms often are worsened by sleep deprivation and can cause profound distress, impairment, violence, and disability. While typically transient, resolving on average within a week of MA cessation, acute agitation and delusions may require crisis team management and psychiatric hospitalization. Acute symptoms often are treated with antipsychotic medications (eg, risperidone, olanzapine), short-term anxiolytics (eg, benzodiazepines), sleep medications for insomnia, and behavioral therapies that target psychosis, such as CBT. Psychotic symptoms, however, may recur or persist in a subset of persons, even in the absence of MA intoxication or withdrawal, and create a diagnostic challenge to differentiate stimulant-induced psychosis from a primary psychotic disorder (eg, paranoid schizophrenia). Consultation and comanagement with an experienced psychiatrist and behavioral therapist is recommended. Glasner-Edwards and Mooney have written an excellent review on MA psychosis.(18)

  • Appendix 1. Assessment of methamphetamine use and diagnosis of stimulant use disorders for patients who screen positive for at-risk methamphetamine use.

    1. For patients who screen positive for MA use, an assessment can provide a specific diagnosis and inform the type of treatment that is most appropriate for an individual. Assessment done in a patient-centered manner also can be therapeutic and create a context for brief intervention or more specialized treatment. The type and depth of assessment can vary depending on time constraints and patient presentation.
      1. We recommend starting with an open-ended, nonjudgmental question: "Using drugs affects people's health and lives differently. In the last year, how has using crystal meth affected you?"
      2. Ask about whether the patient injects drugs and about patterns of injecting, because injecting drug use is associated with increased risk of addiction, infections, and higher levels of other drug-related problems.
        1. "Have you ever used a needle to inject a drug?""Where?"
        2. "Can you get enough sterile equipment to use a new syringe/rig for every injection?"
        3. "What are you doing to prevent abscesses or other skin infections?" (eg, prepping skin with alcohol, rotating injection sites)
      3. In order to determine the most effective intervention or treatment, assess whether the patient meets DSM-5 diagnostic criteria for a diagnosis of "stimulant use disorder" (mild, moderate, severe).

        Stimulant Use Disorder (DSM-5):

        • Two or more of the following substance use disorder criteria within a 12-month period: 1) risk of bodily harm; 2) relationship trouble; 3) role failure; 4) tolerance; 5) withdrawal; 6) used larger amounts/longer; 7) repeated attempts to quit/control use; 8) much time spent using; 9) gave up other meaningful activities; 10) physical/psychological problems related to use; 11) craving.
        • Mild = 2-3; Moderate = 4-5; Severe ≥6 substance use disorder criteria
          • Mild: ICD-10 code F15.1, Other stimulant abuse (DSM-IV terminology)
          • Moderate or severe: ICD-10 code F15.2, Other stimulant dependence (DSM-IV terminology)
    2. Assess for medical complications and medication interactions that can exacerbate health risks:

      1. Concurrent use of methamphetamines with sildenafil or other phosphodiesterase inhibitors, which has been associated with increased risk of STDs, especially syphilis as well as HIV transmission to high-risk HIV-negative individuals

      2. Use of ritonavir, which can increase amphetamine levels

      3. ART nonadherence

      4. Stimulant-induced disorders (eg, psychosis, anxiety, sleep disturbance, sexual dysfunction)
    3. Elicit patients' perspectives about their use. Few patients are not ambivalent about their drug use.
    4. Provide patients with feedback on the results of their screening and assessment--this can be a valuable tool for building motivation to change and assessing their readiness for change. Engage patients in an interactive discussion regarding the severity and the health implications of their use.
      • ELICIT: What do you think might be the medical recommendation regarding your methamphetamine use?
      • PROVIDE: You meet criteria for the diagnosis of a moderate stimulant use disorder. The best treatment for this problem is to cut down or stop altogether, and I'm willing to help.
      • ELICIT: What do you make of this? How does this affect your thinking about your use?
    5. At every follow-up visit, ask about recent methamphetamine use and its consequences. Explore patients' values and goals as a way of learning what motivates them. For patients who have stopped use, ask about cravings or triggers, how they managed them, and if they could use some extra support. Always look for opportunities to recognize, support, and encourage the patient's strengths and efforts. This is considered "strength-based" counseling--you reflect back to the patient their prior achievements or current strengths that can help them in their situation now. It can be helpful to refer patients to social work, case management, or behavioral health providers who can continue these motivational conversations with patients and refer them the appropriate level of care for substance use disorders when patients are ready.

    Appendix 2. Summary of clinical trials of promising medications for the treatment of methamphetamine use disorder.

    • Antagonist medication

      Naltrexone: In a trial conducted in Sweden, where amphetamine use is more prevalent than MA use, 80 treatment-seeking individuals who met the older DSM-IV criteria for amphetamine dependence were randomized to 12 weeks of double-blind naltrexone (50 mg/day) or placebo.(9) All subjects received 60 minutes of individualized relapse prevention counseling weekly by a licensed psychologist. A significantly higher mean number of amphetamine-negative urine samples and higher continuous abstinence rates were observed in the group treated with naltrexone compared with the placebo group. Cravings and self-reported consumption also were lower in the naltrexone-treated group. Notably, the trial required a 2-week period of abstinence prior to enrollment. Similar to findings in alcohol research, a greater period of abstinence prior to initiating medication selects patients likely to achieve better outcomes. Medication adherence (63%) was strongly related to treatment outcomes. Thus, this study showed that naltrexone, when combined with weekly counseling, may be an effective medication for reducing amphetamine relapse.

      A smaller pilot study completed in 2014 in San Francisco evaluated the feasibility, acceptability, and tolerability of oral naltrexone for targeted administration (ie, during craving or in anticipation of MA or alcohol use).(13) Thirty nondependent MA-using and binge-drinking MSM were randomized to naltrexone (50 mg/day) or placebo for 8 weeks. Persons with HIV infection were included if their CD4 counts were >200 cells/µL. All participants received substance use counseling and behavioral assessments every 2 weeks. This intervention was found to be feasible, acceptable, and well-tolerated. While intention-to-treat analyses showed no differences in MA use or drinking, a subgroup analysis found that naltrexone was associated with a significant reduction in drug use among those who reported at least weekly MA use at baseline.

      In contrast to a targeted administration approach, long-acting naltrexone formulations that improve medication adherence also have been studied. In a trial to prevent amphetamine relapse following an initial 7-10 day period of residential treatment, 100 persons who met DSM-IV criteria for amphetamine dependence were randomized to receive 6 monthly injections (380 mg) of extended-release naltrexone (XR-NTX) or matching placebo before entering intensive outpatient treatment in Reykjavik, Iceland.(19) Less than half (39%) of those randomized to XR-NTX completed 4 or more injections, and XR-NTX had no effect on weekly amphetamine-positive tests, treatment retention, or other outcomes. Better outcomes were associated instead with longer duration of outpatient treatment.

      Finally, in a 10-week randomized, double-blind, placebo-controlled trial in Russia, 100 persons meeting DSM-IV criteria for concurrent amphetamine and opioid dependence were randomized to receive a subcutaneous naltrexone implant or a placebo implant.(20) The sustained-release naltrexone implant contains 1,000 mg of naltrexone and can block opioid effects for 8-10 weeks. The study did enroll persons living with HIV, 48% in the naltrexone arm and 77% in the placebo arm (p = .004). While the investigators observed more drug-free urine specimens (38% vs 16%; p = .01) and higher treatment retention (52% vs 28%; p = .01) in the naltrexone group compared with the placebo group at week 10, the naltrexone implant arm did not produce more amphetamine-negative urine samples when compared with placebo.

    • Psychostimulant medications

      A 2013 Cochrane systematic review of studies published between 1966 and 2012 evaluated the efficacy and safety of these medications for persons meeting DSM-IV criteria for amphetamine abuse or dependence.(21) With 11 studies included in the review (791 participants), the authors reported no significant differences in any efficacy outcomes (eg, use, cravings, sustained abstinence) between psychostimulants and placebo, and most studies were limited by low overall retention (50%). A more recent systematic review in 2016 of 17 studies (1,387 participants) also detected no effect of psychostimulants for end-of-study abstinence (5 studies) or treatment retention (14 studies).(22) In an excellent comprehensive review, Brensilver et al evaluated 21 randomized clinical trials of pharmacotherapies for MA- or amphetamine-type stimulants.(14) Among the agonist candidates, only methylphenidate and bupropion suggested some efficacy in subgroups of patients with less severe disease.

      Methylphenidate: In a 20-week, randomized, double-blind, placebo-controlled trial of aripiprazole, methylphenidate, or placebo for persons who met DSM-IV criteria for intravenous MA dependence in Finland, Tiihonen et al observed that persons assigned to receive 54 mg/day of slow-release methylphenidate had significantly fewer amphetamine-positive urine samples than persons assigned to placebo (odds ratio [OR] = 0.46; 95% confidence interval [CI] = 0.26-0.81).(23) The trial was stopped prematurely, however, because of safety concerns in the aripiprazole arm. Another trial by some of the same authors conducted in Finland and New Zealand was limited by high study dropout in the placebo arm and could not replicate the earlier methylphenidate result.(24)

      In a subsequent randomized, double-blind, placebo-controlled trial in Los Angeles and Honolulu, Ling et al randomized 110 persons who met DSM-IV criteria for MA dependence to sustained-release methylphenidate vs placebo for 10 weeks (active phase) combined with CBT and motivational incentives.(12) There was no difference between treatment groups in the primary outcome of self-reported days of MA use during the last 30 days of the active phase (p = .22) or in other outcomes (eg, MA-positive urine samples, cravings as determined by the Visual Analogue Scale (VAS), treatment adherence, retention, satisfaction). However, in a planned secondary outcomes analyses, persons assigned to the methylphenidate arm had lower craving scores and reported fewer MA use days from baseline through the active phase compared with persons assigned to placebo (p = .05). In another 10-week, randomized, double-blind, placebo-controlled study conducted in Iran, 56 persons with MA dependence were randomized to titrated doses (18 to 54 mg/day) of sustained-released methylphenidate or placebo.(25) The primary outcome was MA craving measured weekly by VAS. At the end of treatment, persons assigned to the methylphenidate group reported significantly less MA craving and fewer depressive symptoms, and they had fewer MA-positive urine specimens compared with persons in the placebo arm.

      Bupropion: In a 12-week, double-blind, placebo-controlled trial in the conducted in the United States, 151 treatment-seeking persons who met DSM-IV criteria for MA dependence were randomized to sustained-release bupropion 150 mg twice daily or placebo.(26) Participants were seen in an outpatient addiction treatment clinic 3 times weekly for assessments, urine drug screens, and 90-minute group psychotherapy sessions. There was no difference between groups in the primary outcome of change in proportion of participants having an MA-free week. In a preplanned subgroup analysis, however, bupropion had a significant effect compared with placebo among depressed and nondepressed male participants with a lower level (<19 days in past month) of baseline MA use (OR = 1.39 and 1.34, respectively; NLMM [nonlinear mixed effect model (NLMM)], both p < .0001). These data suggest that bupropion combined with behavioral therapy can increase the number of weeks of MA abstinence in men with low-to-moderate MA dependence regardless of comorbid depression.

      Combination pharmacotherapies are now under investigation for the treatment of MA use disorders. In the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT) study, a 2-stage, open-label pilot study to assess the safety and preliminary efficacy of combined agonist and antagonist, 20 initial subjects from California, Hawaii, or Texas received 380 mg of extended-release injectable naltrexone at weeks 1 and 5 plus extended-release oral bupropion (450 mg/day) for a period of 8 weeks.(27) Eligible subjects met DSM-5 criteria for severe MA use disorder, reported at least 20 days of MA use in the previous 30 days, and submitted at least 3 MA-positive urine specimens during the screening period. The treatment response outcome was defined by at least 6 of 8 MA-negative urine drug specimens during the last 4 weeks of medication, including the final urine drug screen at week 8. A predetermined minimum of 3 or more responders was required for the study to advance to a second stage of enrolling an additional 29 subjects, and a cumulative total of 9 or more responders from the 49 subjects in both stages was required to justify further investigation. With 11 responders, investigators in the NIDA Clinical Trials Network are currently (2017) recruiting 370 adults with moderate or severe MA-use disorder from multiple U.S. sites for a double-blind, placebo-controlled, randomized clinical trial (CTN-0068).

    • Serotonergic medication

      Mirtazapine was tested in a 12-week randomized, placebo-controlled trial in 60 MA-dependent MSM in San Francisco; participants were instructed to take 15 mg nightly for 1 week and then 30 mg nightly for the remainder of the study period. Persons living with HIV were included.(8) In addition to the medication, both treatment groups received 30 minutes of substance use counseling weekly and medication adherence counseling monthly. In the mirtazapine group, there were significantly fewer MA-positive urine specimens as well as a reduction in high-risk sexual behavior despite low medication adherence. A second, randomized, controlled trial is currently under way to determine whether mirtazapine's efficacy can be replicated in a larger study population (n = 120) and sustained over a longer period of time (24 weeks).

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