Sustained-release methylphenidate in methamphetamine dependence treatment: a double-blind and placebo-controlled trial

Background

The objective of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of sustained-release methylphenidate (MPH-SR) in treatment of methamphetamine dependence.

Methods

Fifty-six individuals who met DSM-IV-TR criteria for methamphetamine dependence participated in this 10-week trial. The participants were randomly allocated into two groups and received 18 to 54 mg/day sustained-released methylphenidate or placebo for 10 weeks. Craving was evaluated by a visual analogue craving scale every week. Urinary screening test for methamphetamine was carried out each week. The Beck Depression Inventory-II (BDI-II) was used to monitor participant depressive symptoms at baseline and bi-weekly during the treatment period.

Results

At the end of the trial, the MPH-SR group was less methamphetamine positive compared to the placebo group and the difference was significant (p = 0.03). By the end of the study, MPH-SR group showed significantly less craving scores compared to the placebo group [MD (95% CI) = -10.28(0.88-19.18), t(54) = 2.19, p = 0.03]. There was greater improvement in the depressive symptoms scores in the intervention group compared to the placebo group [MD (95% CI) =2.03(0.31-3.75), t (54) =2.37, p = 0.02].

Conclusion

Sustained-released methylphenidate was safe and well tolerated among active methamphetamine users and significantly reduced methamphetamine use, craving and depressive symptoms.

Trial registration

IRCT201202281556N38     

Randomized, placebo-controlled trial of bupropion for the treatment of methamphetamine dependence

OBJECTIVE: To compare bupropion to placebo for reducing methamphetamine (MA) use, increasing retention, and reducing the severity of depressive symptoms and MA-cravings. A secondary objective compared bupropion to placebo for reducing cigarette smoking among MA dependent participants. METHODS: Following a 2-week, non-medication baseline screening period, 73 treatment-seeking MA dependent participants were randomly assigned to bupropion sustained release (150 mg twice daily; N=36) or placebo (twice daily; N=37) for 12-weeks under double-blind conditions. Participants attended clinic thrice weekly to provide urine samples analyzed for MA-metabolite, to complete research measures and assessments, and to receive contingency management and weekly cognitive behavioral therapy sessions. RESULTS: There were no statistically significant effects for bupropion relative to placebo on MA use verified by urine drug screens, for reducing the severity of depressive symptoms or MA-cravings, or on study retention. In a post hoc analysis, there was a statistically significant effect of bupropion treatment on MA use among participants with lighter (0-2 MA-positive urines), but not heavier (3-6 MA-positive urines) MA use during baseline (OR=2.81, 95% CI=1.61-4.93, p<0.001 for MA-free week with bupropion among light users). Bupropion treatment was also associated with significantly reduced cigarette smoking, by almost five cigarettes per day (p=0.0002). CONCLUSION: Bupropion was no more effective than placebo in reducing MA use in planned analyses, though bupropion did reduce cigarette smoking. Post hoc findings of an effect for bupropion among baseline light, but not heavy, MA users suggests further evaluation of bupropion for light-MA users is warranted.     

Pharmacotherapeutic agents in the treatment of methamphetamine dependence

Introduction: Methamphetamine use is a serious public health concern in many countries and is second to cannabis as the most widely abused illicit drug in the world. Effective management for methamphetamine dependence remains elusive and the large majority of methamphetamine users relapse following treatment.

Areas covered: Progression in the understanding of the pharmacological basis of methamphetamine use has provided us with innovative opportunities to develop agents to treat dependence. The current review summarizes relevant literature on the neurobiological and clinical correlates associated with methamphetamine use. We then outline agents that have been explored for potential treatments in preclinical studies, human laboratory phase I and phase II trials over the last ten years.

Expert opinion: No agent has demonstrated a broad and strong effect in achieving MA abstinence in Phase II trials. Agents with novel therapeutic targets appear promising. Advancement in MA treatment, including translation into practice, faces several clinical challenges.     

Patterns of treatment utilization and methamphetamine use during first 10 years after methamphetamine initiation

The study examined joint trajectories of methamphetamine (MA) use and substance abuse treatment utilization and identified differences among pattern groups for a sample of 348 treated for MA use. Results from group-based trajectory modeling showed that treatment utilization during the first 10 years after initiation of MA use could be categorized into three distinctive patterns: about half the MA users have a pattern of low treatment utilization; one-fourth follow a quicker-to-treatment trajectory with higher probability of treatment during the first 5 years of MA use and less treatment in the next 5 years; and one-fourth have a slower-to-treatment trajectory with more treatment during the second half of the 10-year period. Four MA use patterns were identified: consistently low use, moderate, and high use, as well as a decreasing use pattern. Periods of greater likelihood of treatment participation were associated with periods of decreasing or lower frequency of MA use.     

A placebo-controlled trial of mirtazapine for the management of methamphetamine withdrawal

Introduction and Aims. As an antidepressant with sedative and anxiolytic properties, mirtazapine may be an appropriate pharmacotherapy for methamphetamine withdrawal. This study sought to examine whether mirtazapine improves retention and alleviates methamphetamine withdrawal symptoms in an out-patient setting. Design and Methods. An out-patient double-blind, randomised placebo-controlled trial of mirtazapine for the treatment of methamphetamine withdrawal was conducted (15 mg nocte for 2 days, 30 mg nocte for 12 days). Both groups were offered narrative therapy counselling. Measures recorded on days 0, 3, 7, 14 and 35 included: treatment retention, Amphetamine Cessation Symptoms Assessment, the Athens Insomnia Scale, the Brief Symptom Inventory, the Depression - Anxiety - Stress Scale (DASS), Severity of Dependence scale and the Opiate Treatment Index Drug Use subscale. Results. Thirty-one participants were recruited (18 placebo, 13 mirtazapine) and 52% completed the 2-week medication phase. No significant differences between the mirtazapine and placebo groups in retention, or any symptom measure were observed, except greater DASS - anxiety and longer sleep duration were measured at baseline among the mirtazapine group. Discussion and Conclusions. Results suggest that mirtazapine does not facilitate retention or recruitment in out-patient methamphetamine withdrawal treatment, although recruitment may have been insufficient to identify a significant treatment effect. The potential role of narrative therapy for methamphetamine dependent patients deserves further exploration. [Cruikshank CC, Montebello ME, Dyer KR, Quigley A, Blaszczyk J, Tomkins S, Shand D. A placebo-controlled trial of mirtazapine for the management of methamphetamine withdrawal. Drug Alcohol Rev 2008;27:326-333]     

Gray-matter volume in methamphetamine dependence: Cigarette smoking and changes with abstinence from methamphetamine

Background

Group differences in brain structure between methamphetamine-dependent and healthy research participants have been reported, but findings in the literature present discrepancies. Although most methamphetamine-abusing individuals also smoke cigarettes, the effects of smoking on brain structure have not been distinguished from those of methamphetamine. Changes with abstinence from methamphetamine have also been relatively unexplored. This study, therefore, attempted to account for effects of smoking and brief abstinence from methamphetamine on gray-matter measures in methamphetamine-dependent research participants.

Methods

Gray matter was measured using voxel-based morphometry in three groups: 18 Control Nonsmokers, 25 Control Smokers, and 39 Methamphetamine-dependent Smokers (methamphetamine-abstinent 4–7 days). Subgroups of methamphetamine-dependent and control participants (n = 12/group) were scanned twice to determine change in gray matter over the first month of methamphetamine abstinence.

Results

Compared with Control Nonsmokers, Control Smokers and Methamphetamine-dependent Smokers had smaller gray-matter volume in the orbitofrontal cortex and caudate nucleus. Methamphetamine-dependent Smokers also had smaller gray-matter volumes in frontal, parietal and temporal cortices than Control Nonsmokers or Smokers, and smaller gray-matter volume in insula than Control Nonsmokers. Longitudinal assessment revealed gray matter increases in cortical regions (inferior frontal, angular, and superior temporal gyri, precuneus, insula, occipital pole) in methamphetamine-dependent but not control participants; the cerebellum showed a decrease.

Conclusions

Gray-matter volume deficits in the orbitofrontal cortex and caudate of methamphetamine-dependent individuals may be in part attributable to cigarette smoking or pre-morbid conditions. Increase in gray matter with methamphetamine abstinence suggests that some gray-matter deficits are partially attributable to methamphetamine abuse.     

奥氮平与利培酮治疗酒精所致精神障碍对照研究

目的：比较奥氮平与利培酮治疗酒精所致精神障碍的疗效及不良反应。方法：63例患者按住院号奇数和偶数分为两组,分别服用奥氮平或利培酮6周,分别在治疗0,1,2,4,6周用阳性症状-9阴性症状量表（PANSS）和副反应量表（TESS）评定疗效和不良反应,0、6周检查心脑电图和肝肾功能、空腹血糖、血催乳素和甘油三酯（TG）、胆固醇（TC）。结果：奥氮平组治愈率为76．66％（23／30）,利培酮组治愈率为70．97％（22／31）,两组的治愈率相当（P值〉0．05）,奥氮平组PANSS减分率在第1周末高于利培酮组（P值〈0．05）,奥氮平组TESS分在第2、4、6周末低于利培酮组（P值均〈0．01）,很少引起血催乳素升高,利培酮会显著升高血催乳素水平,均会导致甘油三酯升高。结论：奥氮平、利培酮对酒精所致精神障碍的治疗均安全有效,应根据不同的个体需要,选择奥氮平或利培酮治疗。     

A controlled trial of imipramine for the treatment of methamphetamine dependence

At the Drug Detoxification Program of the Haight Ashbury Free Clinics, we conducted a randomized clinical trial of imipramine in the treatment of methamphetamine dependence. The purposes of the trial were to test the efficacy of imipramine as a treatment for methamphetamine dependence and to establish the feasibility of conducting a controlled clinical trial at the Clinic. Thirty-two subjects were randomly assigned to receive either 10 or 150 mg/day of imiprine for 180 days. Imipramine 10 mg/day was the control. Subjects received intensive counseling. Retention in treatment was significantly longer for subjects who were treated with 150 mg of imipramine compared to control (median days: 33.0 vs. 10.5). There were no consistent differences in percent of urine samples positive for methamphetamine, Beck Depression Inventory scores, or craving. Determination of the full extent of imipramine's utility in the treatment of methamphetamine dependence awaits a larger trial.     

Effects of MDMA, methamphetamine and methylphenidate on repeated acquisition and performance in rats

Repeated-acquisition procedures that include performance controls for effects not specific to acquisition permit the assessment of drug effects on learning on a within-subject, within-session basis. Despite the advantages of this methodology, few studies have examined effects of psychomotor stimulants on repeated acquisition in rodents. The purpose of the present study was to investigate the effects of methylenedioxymethamphetamine (MDMA, 0.3–10 mg/kg), methamphetamine (MA, 0.1–3 mg/kg) and methylphenidate (MPD,1–17 mg/kg) using repeated-acquisition procedures with performance controls in rats using a touch-screen apparatus. Rats were presented a 2 × 3 array of stimuli using a computer touch-screen and nose-pokes to target locations within the array were reinforced. In the acquisition component, the correct location changed across sessions, whereas during the performance component, the correct location was constant across sessions. All three drugs reduced accuracy of responding to target locations in a dose-dependent fashion. None of the compounds enhanced learning at any dose. MPD and MA produced significant disruptions of acquisition accuracy only at doses that also disrupted performance, but the 3 mg/kg dose of MDMA impaired acquisition of target responding without affecting performance. The selective impairment of acquisition found in the present study adds to the evidence of learning and memory disruption produced by acute MDMA administration and raise questions about the mechanisms for these actions.     

Naltrexone vs. nefazodone for treatment of alcohol dependence. A placebo-controlled trial.

This study compared the effects of nefazodone, a serotonergic antidepressant, with the opioid antagonist naltrexone, and an inactive placebo in 183 alcohol-dependent subjects receiving weekly relapse prevention psychotherapy. Following a single-blind, placebo lead-in period, subjects were randomly assigned to receive study medication, which they took under double-blind conditions for 11 weeks. Naltrexone treatment was associated with significantly more adverse neuropsychiatric and gastrointestinal effects, poorer compliance, and a greater rate of treatment attrition. There were no reliable between-group differences in drinking behavior. These results indicate that nefazodone is not efficacious for treatment of alcohol dependence. Furthermore, the clinical utility of naltrexone seems to be limited by its adverse effects, a finding that has important implications for efforts to develop medications to treat alcohol dependence.     

A tale of two stimulants: Mentholated cigarettes may play a role in cocaine,but not methamphetamine,dependence

Background

Research suggests that mentholated cigarettes may play a role in cocaine dependence. The purpose of the present study was to expand upon the research on mentholated cigarettes and cocaine dependence and to evaluate the role of mentholated cigarettes in methamphetamine dependence.

Methods

Secondary analysis of a multisite, randomized trial evaluating the impact of smoking-cessation treatment in stimulant-dependent outpatients (N = 538). Participants’ reasons for concurrent use of cigarettes and illicit stimulants were assessed via self-report. Stimulant-abstinence was measured by self-report and urine drug screens. Smoking cessation was assessed via self-report and carbon monoxide levels.

Results

Of the 301 cocaine-dependent participants, 201 (67%) were menthol and 100 (33%) were non-menthol cigarette smokers. Cocaine-dependent participants who smoked menthol, compared to non-menthol, cigarettes were significantly more likely to report that cigarettes prolong their cocaine high (X²(1) = 16.3, p < .0001, OR = 3.58 [95% CI: 1.88–6.79]) and were less likely to be stimulant abstinent during active treatment (W = 3.6, p < 0.001, d = .39 [95% CI: 0.16–0.62]), at 3-month follow-up (X²(1) = 14.4, p < 0.001, OR = .32 [95% CI: 0.17–0.58]), and at 6-month follow-up (X²(1) = 4.6, p = 0.03, OR = .53 [95% CI: 0.29–0.95]). No parallel differences were found between menthol and non-menthol methamphetamine-dependent smokers. The prevalence of Caucasian menthol smokers was significantly greater in the cocaine-dependent participants (37.2%) than in the methamphetamine-dependent participants (17.61%), (X²(1) = 14.4, p < .001, OR = 2.77 [95% CI:1.62–4.73]). Smoking cessation was not significantly associated with cigarette type for either cocaine- or methamphetamine-dependent participants.

Conclusions

The present results suggest that mentholated cigarettes play a role in cocaine, but not methamphetamine, dependence.     

Reliability of use, abuse, and dependence of four types of inhalants in adolescents and young adults

Inhalants, as a class of drugs, consists of heterogeneous substances that increase the probability of many serious illnesses and death. Research on inhalant abuse has lagged behind other drugs partly because of the need for a diagnostic instrument of different types of inhalants. This study was conducted to obtain reliability estimates for the new Substance Abuse Module DSM-IV inhalants diagnoses for four types of inhalants: aerosols, gases, nitrites, and solvents as well as different diagnostic configurations of inhalant-related criteria. Participants were 162 community sample adolescents or young adults (mean age=20.3 years, S.D.=2.4). Two-thirds of the sample was male and 83.3% was Caucasian. Kappas and intraclass correlation coefficients were computed to estimate test-retest reliabilities. Results suggested (a) abuse was more common than dependence (34.6% versus 12.3%), (b) reliabilities of abuse criteria and diagnosis were good to excellent across subtypes, and (c) reliabilities of dependence criteria and diagnoses were poor to good across subtypes. Alternative configurations of DSM-IV criteria that were consistent with previous research on adolescents provided excellent reliabilities across subtypes of inhalants. Moreover, 11.1% of participants experienced inhalants withdrawal.     

Cocaine abuse versus cocaine dependence: Cocaine self-administration and pharmacodynamic response in the human laboratory

Cocaine has high abuse liability but only a subset of individuals who experiment with it develop dependence. The DSM-IV (APA. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-R. American Psychiatric Association, Washington, DC, 2000) provides criteria for diagnosing cocaine abuse and cocaine dependence as distinct disorders- the latter characterized by additional symptoms related to loss of control over drug use. In this study, two groups of cocaine users (n = 8/group), matched on demographic factors and length of cocaine use history and meeting criteria for either cocaine abuse (CocAb) or cocaine dependence (CocDep), were compared on (1) measures related to impulsivity and sensation seeking, (2) response to experimenter-administered cocaine (0, 12.5, 25 and 50 mg/70 kg, i.v.), and (3) cocaine self-administration using a Relapse Choice and a Progressive Ratio Procedure (0, 12.5 and 25 mg/70 kg, i.v.). Groups did not differ on impulsivity or sensation seeking scores. After experimenter-administered cocaine, the CocAb group reported feeling more suspicious and observers rated them significantly higher on unpleasant effects (e.g., irritability, difficulty concentrating). In contrast, the CocDep group reported significantly greater desire for cocaine, which was sustained over the course of the study, and gave higher street value estimates for cocaine (p < 0.05). While cocaine self-administration was dose-related and generally comparable across the two procedures, the CocDep users chose to take significantly more cocaine than the CocAb users. These data suggest that, while regular long-term users of cocaine with cocaine abuse or dependence diagnoses cannot be distinguished by trait measures related to impulsivity, they do exhibit significant differences with regard to cocaine-directed behavior and response to cocaine administration.     

Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence

Background

Alcohol use, abuse and dependence remain a pressing public health problem. Based on its mechanism of action, varenicline seemed to be a likely candidate for treating alcohol dependence.

Methods

Alcohol dependent subjects (n = 40) were enrolled in a 13-week double-blind placebo controlled clinical trial. Subject visits were once per week. At each visit, subjects were tested for breath alcohol levels, provided self-report data on alcohol and nicotine use, and on mood and craving. In addition, subjects received once a week medical management (MM).

Results

There was no difference between varenicline and placebo treated groups on any of the drinking outcomes. Compared to placebo-treated subjects, varenicline treated subjects had decreased rates of alcohol craving and cigarette smoking, as well as greater mood improvements during the later part of the study (weeks 6–13). In addition, among subjects who were cigarette smokers, those treated with varenicline were significantly less likely to report heavy drinking during the trial.

Conclusions

Although varenicline was not significantly more effective than placebo at reducing drinking during the trial, its effects on alcohol craving and mood suggest that future investigation of the mechanism of action of varenicline, as well as additional clinical studies may be warranted. In particular, the findings regarding the influence of smoking status on heavy drinking among varenicline-treated subjects should be investigated in future studies.     

Methamphetamine treatment: trends and predictors of retention and completion in a large state treatment system (1992-2002)

This report describes trends in treatment admissions for methamphetamine/amphetamine (MA) abuse from 1992 to 2002 in California and assesses predictors of treatment retention and completion. Results show such admissions increasing fivefold and representing a growing proportion of overall treatment admissions. Patients admitted for MA abuse were increasingly diverse in race/ethnicity, older in age, and more frequently under legal supervision status over time. There was a decrease in injection drug use. Several user characteristics played consistent roles as risk factors for noncompletion and shorter treatment retention for both residential and outpatient admissions: having lower than a high school education, being younger at treatment admission, having a disability, having greater severity of MA use, and using injection drugs. Consistently, those with legal supervision status at admission had higher completion rates and longer retention than those reporting no legal status. Overall, findings suggested that clients with greater socioeconomic disadvantage and more severe problems may require greater efforts (e.g., services) to be retained in treatment.     

A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler

Rationale: Nicotine replacement therapy (NRT) in varying forms is becoming widely used. Clinicians, therapists and regulatory authorities are interested in the abuse liability and dependence potential of the different forms. Objectives: To compare the abuse liability and dependence potential of nicotine gum, transdermal patch, spray and inhaler. Methods: 504 male and female smokers seeking help with stopping smoking were randomly allocated to the four products. Measures were taken at the designated quit date, then 1 week, 4 weeks, 12 weeks and 15 weeks later. Smokers were advised to use the product for up to 12 weeks. Those still using the product at the 12-week visit were advised to cease use by week 14. Measures included: pleasantness and satisfaction ratings at weeks 1 and 4 (used as a marker of abuse liability); ratings of feeling dependent on NRT at weeks 1, 4, 12 and 15 (used as a marker of subjective dependence); mood and physical symptoms ratings at weeks 12 and 15 (the change being used to assess physical dependence on NRT), continued usage of NRT at week 15 (used as an marker of behavioural dependence). Results: Average ratings of pleasantness were low. The nicotine patch was rated as less unpleasant to use than all other products. There were no significant differences between the products in terms of satisfaction or subjective dependence except at week 15 when no patch users rated themselves as dependent. Continued use of NRT at week 15 was related to rate of delivery of nicotine from the products – 2% for patch, 7% for gum and inhaler, 10% for spray (P<0.05 for linear association). Among those abstinent for 15 weeks, the figures were: 8%, 25% and 37%, respectively. Stopping NRT use between weeks 12 and 15 was not accompanied by withdrawal discomfort or increased frequency of urges to smoke although subjects stopping inhaler use experienced a mild increase in strength of urges to smoke. We conclude that abuse liability from all four NRT products was low. Subjective dependence was moderate and did not differ across products. Behavioural dependence was modest and was positively related to rate of nicotine delivery. Physicians can reassure their patients that most are able to come off NRT as recommended without discomfort. Received: 9 February 1999 / Final version: 4 January 2000     

Effects of a high-dose treatment of methamphetamine on caudate dopamine and anorexia in rats

Dose-effect curves of d-methamphetamine (MA) on intake of sweetened condensed milk by rats were obtained before and after twice a day treatment for four days with either saline (control) or a high (50 mg/kg) dose of MA previously shown to decrease the dopamine levels of the caudate. The animals that were more sensitive to MA's anorexic effects during the before-treatment determination were found to be more sensitive to the lethal effects of the high-dose treatment. This treatment produced a six month decrease in brain dopamine but no change in the anorexic effect on milk intake or in the stereotypic behavior elicited by the drug. Subsequently, the daily administration of 2.5 mg/kg of MA, 15 min before presentation of the milk, to both control and treatment groups produced tolerance to the drug's anorexic effect. After 4 to 5 weeks of repeated administration of this dose there was a significant difference between the control group's intake of milk and treatment group's intake as well as body weight. These differences indicate an effect of the treatment upon the formation of tolerance to the anorexic effects of MA.     

Effectiveness of pretreatment interim support group attendance in facilitating treatment enrollment among methamphetamine abusers

Decreasing state and federal budgets have led to shortages in public health funding for treatment programs to aid long-term users in recovery from methamphetamine abuse. These shortages have led to client "waiting lists" for government-subsidized treatment. Many of these "waiting list" individuals fail to show up for treatment when it is scheduled. The current study investigates the efficacy of "interim support groups" as a means of encouraging methamphetamine abusers to begin treatment programs (defined as attendance on the first day of treatment). A logistic regression revealed that interim group attendance predicted whether a methamphetamine abuser would show up for treatment. These results are discussed in terms of both the value of interim groups in facilitating treatment adherence and the role pretreatment support groups can play in facilitating a methamphetamine abuser's determination to engage in treatment.     

Assessment of cocaine and other drug dependence in the general population: "gated" versus "ungated" approaches

BACKGROUND: There is a need for large-scale epidemiological surveys to be (a) faithful to diagnostic specifications and (b) constrain time and participant burden associated with each section of a possibly lengthy interview. OBJECTIVE: To examine whether one "gating" approach devised for recent large-scale international psychiatric surveys results in a reduced number of identified cases of drug dependence and/or biases in estimated associations with background characteristics. DESIGN AND SETTING: Data from a recently released cross-sectional, nationally representative household survey, the United States National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) were analysed. PARTICIPANTS: Forty-three thousand ninety-three English speaking adults aged 18 years and over. MAIN OUTCOME MEASURES: Dependence upon cocaine and other illegal drug dependence, defined in two ways: "ungated" and "gated". "Ungated" dependence included all persons meeting criteria for DSM-IV dependence, without regard for DSM-IV drug abuse clinical features. "Gated" dependence required at least one feature of DSM-IV drug abuse. RESULTS: There was no statistically robust decrement in the estimated prevalence of cocaine or other drug dependence using a "gated" assessment. Patterns of association of cocaine dependence with background characteristics were not appreciably different when the gated and ungated approaches were applied. CONCLUSIONS: In panoramic mental health surveys, the inefficiency of an ungated approach must be balanced against the anticipated number of cases of dependence without associated social role impairments or harm. In this study, the reduction in the number of identified cocaine dependence cases appeared to be so small that even in a sample of over 40,000 participants, attenuation in population prevalence would prove difficult to detect.     

Symptoms and sleep patterns during inpatient treatment of methamphetamine withdrawal: a comparison of mirtazapine and modafinil with treatment as usual

The safety and tolerability of modafinil (400 mg/day, n = 14) and mirtazapine (60 mg/day, n = 13) in inpatient methamphetamine withdrawal treatment were compared to a historical comparison group receiving treatment as usual (pericyazine, 2.5–10 mg/day, n = 22). Modafinil and mirtazapine were well tolerated, producing minimal positive subjective effects and no discontinuation effects in this open-label study. Side effects were mild and transient. Aches and pains were most commonly reported by participants receiving mirtazapine, whereas headache was reported by modafinil-treated participants. Modafinil-treated participants had a milder withdrawal syndrome as measured by the Amphetamine Cessation Symptom Assessment and less sleep disturbance in comparison to mirtazapine. Pericyazine was associated with a more severe withdrawal syndrome in comparison to mirtazapine and modafinil. Both modafinil and mirtazapine were safe and well tolerated in methamphetamine withdrawal treatment. However, these early findings of efficacy in symptom amelioration should be replicated in an adequately powered, randomized, placebo-controlled double-blind design.