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The purpose of this review article is to summarize published studies that examined a treatment for methamphetamine dependence and/or withdrawal and included anxiety as an outcome measure.
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Pharmacological, psychosocial and exercise studies were reviewed.
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Pharmacological studies noted a reduction in symptoms of anxiety and percent positive methamphetamine urine drug screens and an exercise study noted a reduction in symptoms of anxiety.
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Studies had small sample sizes and pharmacological studies had higher rates of attrition.
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Anxiety was measured using a variety of tools.
Abstract
Rates of anxiety disorders among individuals who use methamphetamine are estimated to be as high as 30.2%. The presence of an anxiety disorder in methamphetamine users is associated with higher rates of relapse, non-adherence to treatment and poorer outcomes relative to methamphetamine users without an anxiety disorder. A review investigating current treatment options for methamphetamine dependence or withdrawal from methamphetamine was conducted using PubMed, CINAHL and PsycINFO. The focus of the review was trials that utilized an intervention and collected anxiety as an outcome measure. Seven studies were included in the review, and five of these studies examined a pharmacotherapy option, one studied a psychosocial intervention and one study investigated exercise as an intervention. Some of the pharmacotherapy studies and the study of exercise were associated with improvements in mood and/or a reduction in methamphetamine use. Concerns of sample size and measurement of anxiety were raised. Future well-designed research with large sample sizes is warranted to examine how to manage anxiety among methamphetamine users.
). For example, in a study that examined the relationship between anxiety disorders, substance use and functional outcomes, at a 3-year follow-up interview, individuals with a diagnosed anxiety disorder (n = 138) had significantly greater odds of being hospitalized over the past 12 months relative to those without an anxiety disorder (n = 388;
). Additionally, the presence of an anxiety disorder was associated with greater self-reported methamphetamine use during the follow-up period, poorer treatment adherence, as well as more than triple the odds of having a lifetime suicide attempt compared to individuals without a diagnosis of an anxiety disorder (
Symptoms of anxiety in a methamphetamine-using population may be explained by a primary anxiety disorder or substance-induced anxiety or due to withdrawal from methamphetamine. According to the Diagnostic Statistical Manual of Mental Disorders Fifth Edition (DSM-5), the differential diagnosis depends on the onset and course of anxiety symptoms, in addition to other factors related to substance use. For example, a primary diagnosis of an anxiety disorder requires that symptoms of anxiety precede the onset of substance use or symptoms of anxiety persist for a month or longer after discontinuation of a substance (
). Distinguishing a primary anxiety disorder from substance-induced anxiety can be problematic in individuals with years of chronic methamphetamine use and recurring relapses.
Despite the differential diagnosis of anxiety, little attention has been paid to the treatment of anxiety disorders in methamphetamine users. In fact, to my knowledge, there are not any published studies that have evaluated an intervention for the treatment of an anxiety disorder among methamphetamine users. Most of the published studies that evaluate treatment options among methamphetamine users are focused on managing methamphetamine dependence or withdrawal. Thus, as an initial step to understanding if treatment options that have been studied for methamphetamine dependence or withdrawal have an impact on anxiety, the purpose of this article is to summarize published studies that examined a treatment for methamphetamine dependence and/or withdrawal and included anxiety as an outcome measure. The clinical course of anxiety may be different in methamphetamine users seeking treatment for methamphetamine dependence compared with individuals receiving pharmacological treatment for acute withdrawal. However, because comorbid anxiety disorders and methamphetamine dependence threaten treatment outcomes (
), this review focuses on both treatment for methamphetamine dependence and withdrawal to gain a broad understanding of anxiety outcomes in intervention studies of methamphetamine dependence and withdrawal. Further, considering that the severity of dependence and treatment outcomes may vary by route of administration (
), route of administration and its relationship to study outcomes were reviewed in each study.
2. Methods
A review of the literature was conducted by searching the databases PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PsycINFO. These databases were selected based on relevancy of the topic and their comprehensive coverage of content. The initial search used “methamphetamine,” “anxiety” and “treatment” as search terms. A second search was performed with the search terms “methamphetamine,” “dependence” and “treatment” to include studies of methamphetamine dependence with anxiety as an outcome measure.
The initial search produced 146 articles (PubMed =130, CINAHL =14, PsycINFO =2). After pre-clinical studies (n = 34), articles in a language other than English (n = 3) and duplicate titles (n = 10) were omitted, 99 articles were screened for inclusion. The second search yielded 642 articles (PubMed =542, CINAHL =50, PsycINFO =50). After pre-clinical studies (n = 61), articles in a language other than English (n = 43) and duplicate titles (n = 72) were removed, and 466 articles were considered for inclusion. Thus, collectively between the two separate searches further eligibility criteria were applied to 565 articles.
To be considered for inclusion, studies were required to be an intervention study for the treatment of methamphetamine dependence or withdrawal. However, there were two studies noted that focused on treating comorbid depression (
) among methamphetamine users and utilized a tool for measuring anxiety. Even though these were not studies of treatment for methamphetamine dependence or withdrawal, they were included in this review because they reported changes in anxiety severity. Considering that an integrative review that summarizes treatment strategies for comorbid depression and methamphetamine use disorders was recently published (
), the current review did not expand the search to include studies that target depression among methamphetamine users. An exclusion based on year published was not used because I was interested in reviewing all published articles on this topic. Review articles (n = 37), case studies (n = 2), commentaries (n = 1) and non-relevant articles (n = 459) were excluded from reading titles and abstracts. The remaining full-text articles (n = 66) were reviewed, and additional studies were excluded because they were lacking an intervention (n = 3) or the study was not an investigation for the treatment of methamphetamine dependence or withdrawal (n = 1). Finally, 55 studies were excluded because an instrument for evaluating anxiety was not utilized, resulting in a final sample of seven studies (see Fig. 1).
Of the seven studies that were included, one of them was a study that evaluated an intervention for the treatment of mood symptoms in recently abstinent methamphetamine users, one was an examination of an intervention for comorbid depression and methamphetamine dependence, four of them were an investigation of an intervention for methamphetamine dependence and included anxiety as an outcome measure and one study examined an intervention for the management of methamphetamine withdrawal and measured anxiety (see Table 1). Over half (n = 4) of the studies employed a randomized controlled trial study design, whereas the remaining studies used an open-label (i.e., uncontrolled) design. There were five studies of pharmacotherapy, one study that evaluated a psychosocial intervention and one study that examined exercise as an intervention. A variety of tools were used to measure anxiety symptoms, such as the Hamilton Anxiety Rating Scale, Addiction Severity Index, Addiction Severity Index Lite, Brief Psychiatric Rating Scale, Depression Anxiety-Stress Scale and Beck Anxiety Inventory. The following sections outline the study findings by intervention type, in addition to reporting how anxiety was measured in each study. Finally, there is a section below that describes adverse events that were reported in studies of medications.
Table 1Results of systematic review of studies investigating treatment options for methamphetamine dependence or withdrawal or to manage mood symptoms.
14 METH dependent females with comorbid depression
Not reported
Open label
Oral creatine monohydrate 5 g/day
Manage mood symptoms
Secondary
Beck Anxiety Inventory
8 weeks
Beck Anxiety Inventory scores were significantly reduced as early as week 2 (p = 0.01) compared to baseline of creatine treatment, and this improvement was maintained through study completion.
There was a significant effect of exercise on reducing the severity of anxiety (p = 0.001) and depression (p = 0.001) over the 8-week intervention period compared to a health education control group.
Scores on the Hamilton Anxiety Rating Scale ranged from 1 to 16 at the beginning of the study and decreased as the study progressed (t = −2.50, df = 29, p = 0.018).
Brief Psychiatric Rating Scale and Addiction Severity Index—Lite
8 weeks
The psychiatric composite of the Addiction Severity Index—Lite was significantly reduced at week 4 (p = 0.013) but not at week 8. Anxiety/depression on the Brief Psychiatric Rating Scale decreased over time but these findings were not significant (p = 0.06).
). In an open-label trial of 25 mg of intramuscular risperidone, 34 participants were enrolled and 12 participants completed the four injections that were outlined in the treatment protocol (
). Of relevance, individuals with concurrent mental health treatment were excluded from the study, and even though the Structured Clinical Interview for DSM-IV Disorders (SCID) was listed as a study procedure, the prevalence of comorbid mood disorders was not reported.
The results of the study indicated that methamphetamine use, measured by urine toxicology and self-reported use, and craving were reduced during the 8-week trial (
). Psychiatric symptoms, measured by the Addiction Severity Index (ASI) Lite improved at week 4 but were not sustained through treatment completion, and, further, anxiety/depression on the Brief Psychiatric Rating Scale (BPRS) decreased during the treatment period but did not reach statistical significance (
). The authors did not assess treatment outcomes by route of administration. Notably, fewer participants used methamphetamine intravenously (7%) compared with smoking (11%) and 4% of the sample preferred nasal insufflation.
3.1.2 Non-amphetamine stimulant
The non-amphetamine psychostimulant modafinil has been studied in a randomized controlled trial (
) for the treatment of methamphetamine dependence. Modafinil is an effective wake-promoting medication, but its mechanism of action differs from traditional stimulants by increasing dopamine through dopamine transporters (
). In addition to modafinil, participants received cognitive behavioral therapy and contingency management. The SCID was administered at baseline; however, the authors failed to report if participants met diagnostic criteria for an anxiety disorder. The Hamilton Anxiety Rating Scale (HAMA) was used as a measure of severity of anxiety, and baseline scores ranged from 1 to 16, suggesting that participants had mild to moderate anxiety (
). Hamilton Anxiety Rating Scale scores and self-reported methamphetamine use decreased during the 6-weeks of treatment, but there was no change in the percent of positive urine drug screens for methamphetamine (
). The authors did not assess treatment outcomes by route of administration; however, they did report that three participants were intravenous users and four participants preferred smoking methamphetamine.
In a randomized controlled trial of 200 mg daily, 400 mg of daily modafinil or matching placebo, 210 participants were randomized and 112 completed the 12-week study (
). Thrice weekly 90-minute group cognitive behavioral therapy was also offered to all participants. Individuals with a psychiatric disorder requiring medication were excluded, and the only SCID diagnosis that was reported was Attention Deficit Hyperactivity Disorder (ADHD). Therefore, it is not known if the sample included individuals with comorbid anxiety disorders and methamphetamine dependence. The ASI-Lite was used to measure psychiatric symptoms during treatment, and the results indicated no differences in ASI-Lite domains between the modafinil groups and placebo (
). Further, there were no differences between groups noted in methamphetamine use, based on urine toxicology, and participants who were the most compliant (defined as >85% of urine toxicology positive for modafinil), had a statistically significant difference in maximum duration of abstinence compared with medication non-compliant participants (
). The authors did not report frequencies for route of administration nor did they assess treatment outcomes by route of administration.
3.1.3 Antidepressants
Mirtazapine, a nonadrenergic and specific serotonergic antidepressant, has been studied for the management of methamphetamine withdrawal. Sleep disturbances, depression and anxiety are prominent symptoms of acute methamphetamine withdrawal (
). Participants were randomized to 15 mg daily of mirtazapine for 2 days followed by 30 mg daily for 12 days. In addition, all participants were offered weekly 45-minute narrative therapy sessions for 5 weeks. The researchers did not assess for DSM disorders, resulting in uncertainty regarding the prevalence of anxiety disorders among the sample. Symptoms of anxiety were measured using the Depression–Anxiety–Stress Scale (DASS), and the results of data analysis indicated no differences in improving methamphetamine withdrawal symptoms between placebo and mirtazapine (
). The authors did not assess treatment outcomes by route of administration; however, they did report frequencies by route of administration: oral: 3.2%; smoking: 41.9%; and intravenous: 54.8%.
3.1.4 Dietary supplements
The dietary supplement creatine monohydrate (“creatine”) has been studied as a treatment option for comorbid depression and methamphetamine dependence in females. There is evidence of creatine being an effective adjunctive treatment for major depressive disorder in adolescent (
Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: A 31-phosphorus magnetic resonance spectroscopy study.
A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive dsorder.
) females without methamphetamine dependence. Oral supplementation with creatine has been found to increase the cerebral reservoir of phosphocreatine (
Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate.
Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate.
Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: A 31-phosphorus magnetic resonance spectroscopy study.
A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive dsorder.
). Results of administering the SCID as a screening study procedure indicated that 28.6% of the participants currently met the diagnostic criteria for substance-induced anxiety, 7.1% met the diagnostic criteria for social phobia, 7.1% met the criteria for post-traumatic stress disorder and severity of anxiety was measured using the Beck Anxiety Inventory (BAI). The authors noted a reduction in BAI scores, as early as the second week of creatine treatment and maintained through study completion, in addition to a decrease in methamphetamine positive urine drug screens after 6 weeks of treatment (
). The authors did not report frequencies for route of administration nor did they assess treatment outcomes by route of administration.
3.2 Psychosocial interventions
Motivational interviewing (MI) has been examined as a treatment option for substance use disorders across a range of populations and it has been shown to be effective for both alcohol and illicit substance use disorders (
). In a randomized controlled trial of IMI versus a single session of standard MI plus eight nutrition education sessions, 217 participants were randomized and 201 participants completed the study through 6 months of follow-up (
). A diagnostic interview for mental disorders was not conducted at study entry and, therefore, the prevalence of anxiety disorders among study participants is not known. Anxiety was measured using the ASI Lite, as well as examining the number of days in the past 30 days that the participant subjectively experienced anxiety. The results of the study revealed no differences in methamphetamine use or anxiety between the two groups (
). An 8-week randomized controlled trial of thrice-weekly 60-minute sessions of progressive aerobic and resistance exercise training program versus health education (i.e., the control group) was conducted in recent abstinent methamphetamine users to evaluate the impact of exercise on depression and anxiety (
). Out of 138 randomized participants, 135 completed the intervention trial. A DSM diagnostic interview was not administered at baseline and, therefore, it is not known if the study participants met the diagnostic criteria for an anxiety disorder. The BAI was used to assess for symptoms of anxiety, and the average baseline BAI score for the exercise group was 16.5 ± 6.0 and 11.9 ± 5.1 for the control group, with higher scores representing a higher intensity of symptoms (
). The authors noted a statistically significant reduction in BAI scores at the 8-week time point compared to baseline in the exercise group but not in the control group (
). Methamphetamine use data were not collected, but participants resided in a residential treatment facility, and the facility enforced a drug abstinence policy that was monitored by random urine drug screens. There were a total of two participants, one from the treatment group and one from the control group, who were excluded from data analyses because they were dismissed from the treatment facility for positive random urine drug screens (
). The authors did not report frequencies for route of administration nor did they assess treatment outcomes by route of administration.
3.4 Adverse events in medication trials
In studies that examined a pharmacotherapy option, the results of adverse event monitoring were reported in 5 of the 7 studies. There were no adverse events reported for mirtazapine. It was unclear if the authors simply did not collect adverse events or if they simply did not report the events. Table 2 outlines the adverse events reported in each study and the frequency of each adverse event reported. The authors of the open-label creatine study (
) indicated which events were probably related to study participation (i.e., gastrointestinal and muscle cramping), and the authors of the open-label modafinil study (
) indicated that there were three events that were probably related to study participation but they did not specify which ones. In the remaining studies that reported adverse events, it was not clear if any of the events were a result of the study medication.
Table 2Adverse events reported in trials of pharmacotherapies.
In the randomized controlled trial of modafinil, adverse events were only reported for events that occurred more frequently with modafinil than placebo and at a rate of >5%.
Headache
3
Arthralgia
15
Fatigue
24
Nausea
1
27
Insomnia
6
29
Depressed mood
5
15
Diarrhea
4
Cold/flu symptoms
10
Dizziness
3
20
Suicidal ideation
1
Chest pain
1
Ischemic injury
1
Cellulitis
1
Tachycardia
2
Dry mouth
6
13
Nervousness
1
Musculoskeletal
7
Anxiety
5
18
Excessive salivation
5
Restlessness
5
Sexual dysfunction
5
Gastrointestinal
4
Decreased appetite
3
Disorientation
3
Dermatological
3
Joint stiffness
3
Muscle stiffness
3
Indigestion
1
11
Flank pain
1
Polydipsia
1
Swelling in hands
4
Stomach discomfort
3
Numbness and tingling in hands
1
Muscle cramps
2
Blurry vision
1
Lightheaded
1
Cough
31
Neck pain
9
Other
13
Bold text indicates that 1 or more serious adverse events occurred.
a In the randomized controlled trial of modafinil, adverse events were only reported for events that occurred more frequently with modafinil than placebo and at a rate of >5%.
Three different intervention categories have been examined for the treatment of methamphetamine dependence or methamphetamine withdrawal, and in these intervention studies, anxiety was a variable of interest. These interventions included: pharmacotherapy, psychological approaches and exercise. Study findings across and among interventions were inconsistent. The study that investigated a psychosocial approach for the treatment of methamphetamine dependence reported no differences in anxiety status between the two randomized groups (
). Of relevance, only one study reported the prevalence of an anxiety disorder among the sample.
Results from pharmacotherapy studies for the treatment of methamphetamine dependence or withdrawal were variable. For example, risperidone and creatine were associated with a reduction in percent of positive urine drug screens for methamphetamine (
). However, in an open-label trial of risperidone, anxiety symptoms were improved only temporarily using one measure of anxiety and no improvements were noted using a second measure of anxiety (
]) and the study designs were open-label, which raises concerns of generalizability and efficacy. Also, it is possible that anxiety severity improved as a result of reduced methamphetamine use in the two studies that reported both a reduction in methamphetamine use and anxiety scores (
) poses the question to the participant about experiencing serious anxiety in the past 30 days rather than a careful review of symptoms associated with anxiety, and considering that the BPRS was developed to assess psychopathology in patients with schizophrenia (
), these tools may not have adequately captured anxiety symptoms in individuals dependent on methamphetamine. Similarly, even though the BAI has established reliability and validity in a psychiatric population (
), there is no documentation of reliability and validity in a methamphetamine-using population.
In an open-label study of the non-amphetamine psychostimulant modafinil, anxiety symptoms were noted as reduced throughout the course of treatment, but there was no effect on methamphetamine use (
). In contrast, the results of a randomized controlled trial of modafinil found no changes in anxiety or methamphetamine use, with the exception of participants compliant with modafinil treatment demonstrating a longer duration of abstinence than non-compliant participants (
). In an open-label modafinil trial the HAMA was used to measure anxiety, whereas the randomized controlled trial utilized the ASI-Lite. The differences between these two measures might explain the discrepancy in findings, but other considerations such as study design, length of treatment and sample size may also play a role. For example, the open-label modafinil trial's treatment period consisted of 6-weeks (n = 4 completers), and the randomized controlled trial investigated modafinil for 12 weeks (n = 112 completers).
Another explanation for the differences in findings across pharmacotherapy studies is the classification of the pharmacotherapies investigated. The trials included an antipsychotic (risperidone), a dietary supplement (creatine), an antidepressant (mirtazapine) and a non-amphetamine psychostimulant (modafinil). Given the bidirectional relationship between methamphetamine use and mood symptoms (
), it is possible that treating mood symptoms resulted in a reduction in methamphetamine use, or conversely, a decrease in methamphetamine use led to improvements in mood symptoms, and perhaps risperidone and creatine were more effective in accomplishing this relative to mirtazapine and modafinil, although, the nature of the open-label study designs in the risperidone and creatine studies warrant caution when interpreting the study results.
Exercise for the management of depression and anxiety among recent abstinent methamphetamine users was shown to be an effective treatment for improving symptoms of anxiety (
). Data are limited, though, with regard to the use of exercise as an intervention for the treatment of methamphetamine dependence and/or mood symptoms associated with methamphetamine use, as there was only one exercise study included in this review. Interestingly, compared with the other intervention types, retention was higher in the exercise study. For example, the retention rates ranged from 35% to 79% in pharmacotherapy investigations, 92% in a study of a psychosocial intervention, 50% to 70% in pharmacotherapy plus psychosocial studies and 98% in the study of exercise. The participants enrolled in the exercise study were residents of a residential treatment center (
). Easy access to study visits at the residential treatment facility likely contributed to the high retention rate in the exercise study.
There are several limitations noted in these studies. For example, the sample sizes in the pharmacotherapy studies are small, which limits generalizability. Further, an open-label design was used in three of the studies that evaluated a medication, and the lack of a control group limits the conclusion of efficacy of an intervention. There was also a paucity of report rates of anxiety. With the single study that did report rates of anxiety, substance-induced anxiety was the most common anxiety disorder (
), and thus, the study findings are not generalizable to methamphetamine users with a primary anxiety disorder. In addition, reporting the frequencies of route of administration was not consistent. Three out of the seven studies reported the number of participants who used by the different routes of administration, but none of these studies reported treatment outcomes by route. Previous research demonstrates that there are differences in measures of mental health between individuals who inject methamphetamine compared with those who use other routes of administration (
). Therefore, assessing treatment outcomes by the various routes of administration would provide useful information with regard to treatment plans. Finally, there are concerns of reliability and validity with the tools that were used to measure anxiety.
There are also limitations to this review that are important to consider. Because I sought to gain a broad understanding of how anxiety is treated in methamphetamine users, the clinical implications may be difficult to discern. For example, considering that there are differences in the clinical course of anxiety between methamphetamine users seeking treatment and those in acute withdrawal, it may have been more appropriate to conduct separate reviews. Moreover, this review included studies that did not report anxiety diagnoses. Thus, it is not known if the interventions studied had the potential to address anxiety syndromes or if only symptoms of anxiety were targeted.
5. Conclusions
While research suggests that rates of anxiety disorders among methamphetamine users are high (
), there is no published evidence that indicates how to manage anxiety disorders or symptoms of anxiety in a methamphetamine using population. Given that the comorbidity of anxiety disorders and methamphetamine dependence confounds treatment outcomes (
), studies investigating treatment options for this comorbidity are warranted. Further, standardizing methods for collecting anxiety severity would be an important methodology step for interpreting results. To this end, studies of interventions for methamphetamine dependence and withdrawal should consider using reliable and valid tools for measuring anxiety, as well as a standard reporting of prevalence of anxiety disorders, in an effort to understand if treatment modalities have an impact on anxiety disorders or symptoms of anxiety. Finally, future well-designed studies would benefit from large sample sizes to increase generalizability and eliminate concerns of efficacy.
Acknowledgments
The College of Nursing and Vice President for Research at Montana State University supported this work.
References
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Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: A 31-phosphorus magnetic resonance spectroscopy study.
Multinuclear magnetic resonance spectroscopy of high-energy phosphate metabolites in human brain following oral supplementation of creatine-monohydrate.
A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive dsorder.
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