#96954: Methamphetamine Use Disorder

"Meth mouth" is widespread among certain populations of methamphetamine users, particularly those incarcerated for methamphetamine-related offenses [47]. "Meth mouth" (dental deterioration) is a constellation of signs and symptoms associated with chronic use of methamphetamine and is caused by methamphetamine-induced vasoconstriction and reduced salivary flow, methamphetamine-induced vomiting, jaw clenching, the high intake of sugary beverages often seen with methamphetamine users, and abandonment of oral hygiene. This condition is characterized by widespread tooth decay and tooth loss, advanced tooth wear and fracture, and oral soft tissue inflammation and breakdown [47].

The American Dental Association recommends that practitioners be particularly aware of the following signs, which may indicate that dental deterioration is linked to methamphetamine use [51]:

Prolonged use of methamphetamine is associated with changes to the brain and CNS through several general mechanisms, including depletion of presynaptic monoamine reserves, down-regulation of neurotransmitter transporters and receptors, and neurotoxicity through reactive metabolic byproducts of dopamine and serotonin. Neurotoxicity can occur from as little as several days of methamphetamine exposure and may persist for months and even years [39]. Even a sub-neurotoxic reduction of dopamine activity can produce the lingering motivational difficulties often encountered by patients in early to intermediate recovery [39]. Another mechanism of methamphetamine-induced neurotoxicity is the substantial and prolonged release of the excitatory neurotransmitter glutamate triggered by acute ingestion [3].

During the first several weeks of abstinence, methamphetamine abusers have been found to display functional and structural changes to key brain regions that are associated with attention deficits, impaired visual pattern recognition, and impaired decision-making speed and accuracy [52,53]. Abnormalities consistent with frontal lobe vascular damage are related to the amount and duration of methamphetamine use and may underlie the dysfunction in craving and compulsive behavior seen in methamphetamine addicts [54]. Substantial impairment in attention/psychomotor speed, verbal learning and memory, and fluency-based measures of executive systems functioning have been reported [55]. Metabolic brain abnormalities in the limbic and paralimbic regions observed in methamphetamine addicts may underlie the affective dysregulation often experienced in early recovery [56].

Cognitive performance in methamphetamine-dependent patients may actually worsen during the first three months of abstinence. Researchers found that abstinent patients with a recent lapse scored worse on neuropsychological testing than patients with ongoing methamphetamine use, indicating that abstinent patients may encounter difficulties in treatment when attention, understanding, and memory are needed [57].

Functional and structural deficits associated with methamphetamine use have been observed 6 to 12 months into continuous abstinence. The authors of one study found significant impairment in reaction time, working memory, and mental concentration [58]. This symptom constellation mimics subclinical Parkinson disease, another neurologic condition characterized by substantial dopamine transporter loss. Neuronal damage associated with metabolic abnormalities in frontal lobe regions was also found, which may explain the persistence of violence, paranoia, and personality changes well into intermediate-term abstinence [59]. Ongoing dysfunction in executive control of verbal encoding and retrieval consistent with neurologic damage to the prefrontal cortex has been observed [60]. Significant correlations between aggression severity, extent of serotonin transporter density reduction, and duration of methamphetamine use have been observed [61]. Moreover, the reduction in serotonin transporter density persisted well into abstinence, suggesting the decrease remains long after methamphetamine use stops. This finding is consistent with several other studies that have linked decreased serotonin function with increased aggression and violence [62,63,64,65].

Many studies have examined the impact of chronic methamphetamine use on the persistence of dopamine transporter density reduction beyond one year of abstinence. Severity of methamphetamine use, dopamine transporter reduction, and residual psychiatric symptoms (e.g., paranoia, anxiety, irritability and depressed mood, auditory hallucinations, disordered thinking) were found to be highly correlated, but no association between dopamine transporter density and duration of methamphetamine abstinence was observed [66]. In another study, degraded dopamine transporter activity was correlated with deficits in motor and memory performance, and duration of methamphetamine use was highly correlated with the severity of the effects [67]. No significant improvement beyond one year of abstinence was found. Together, these studies suggest that persisting dopamine transporter depletion underlies the pathophysiology of the ongoing psychiatric and neuropsychological disturbances in methamphetamine users with intermediate-length abstinence [66]. Significantly diminished activation in brain pathways has also been observed and was associated with reduced decision-making speed and impaired decision-making strategies, with the magnitude of activation deficit predictive of methamphetamine abuse duration. Long-term changes in dopamine transporter density were implicated in these findings [68].

Despite abundant evidence of durable changes in brain structure and function as a result of chronic methamphetamine abuse, several studies have documented improved functioning with abstinence from methamphetamine. Using proton magnetic resonance spectroscopy (MRS), researchers noted neuronal recovery with extended abstinence from methamphetamine and observed partial anterior cingulated cortex normalization that positively correlated with duration of methamphetamine abstinence [69]. The authors of another study, which also used proton MRS, also observed anterior cingulated cortex normalization with sustained methamphetamine abstinence (one to five years) [70]. Others found significant increases in striatum and putamen dopamine transporter density, with the degree of putamen increase inversely correlated with the amount and duration of methamphetamine use [67]. Another study demonstrated that metabolic activity in the thalamus improved between early and protracted abstinence and was correlated with improved motor skill and verbal memory [71].

The absence of longitudinal studies on methamphetamine users makes drawing a causal relationship between methamphetamine use and depression, paranoia, and reduced dopamine transporter density difficult. In the absence of such data, it remains unknown if users selectively chose methamphetamine to counter baseline anergia, depression, or impaired cognition if a vulnerability to psychoses predated the methamphetamine use or if these symptoms/neuronal changes arose as a consequence of the methamphetamine use itself.

Methamphetamine is potentially neurotoxic to the developing fetus, and the lifestyle of methamphetamine-addicted mothers, who typically engage in poor prenatal care (e.g., neglect proper nutrient intake or consume cigarettes, alcohol, or cannabis), is a contributory factor. Infants born to methamphetamine-addicted mothers may exhibit methamphetamine withdrawal upon birth, with one study finding 49% of 134 methamphetamine-exposed infants exhibiting withdrawal symptoms [72]. Neonates exposed to methamphetamine tend to exhibit lower birth weight, decreased head circumference, and overall decreased growth, as well as subsequent increased aggressive behavior, impaired social adjustment, deficits in the acquisition of mathematics and language skills, and poor visual recognition memory relative to non-methamphetamine-exposed infants [4,72]. These infants also display reduced hippocampal and striatal nuclei volume associated with long-term emotional and behavioral dysfunction [4]. Abnormalities in brain microstructure that persist into childhood and adolescence have been observed in children with prenatal exposure to methamphetamine [73]. Methamphetamine-exposed children often exhibit deficits in brain development, including significantly smaller subcortical brain volume corresponding with significantly worse scores on measures of visual motor integration, attention, verbal memory, and long-term spatial memory compared with healthy infants [58]. However, a study using magnetic resonance spectroscopy and magnetic resonance imaging found no evidence of neuronal damage or loss in selected brain regions [74].

The Matrix Model was first conceptualized and developed during the 1980s in response to the overwhelming need for cocaine treatment programs, following evidence that the traditional private sector 28-day inpatient treatment programs for alcohol- and opioid-dependent patients were ineffective for patients with stimulant dependence [91,92]. This model integrates several empirically validated interventions into a single treatment model, with pragmatics given priority and programs based on theory and ideology being avoided [90,92]. The goals of the Matrix Model include stopping drug use, transmitting knowledge of issues critical to addiction and relapse to the patient, educating family members impacted by addiction and recovery, familiarizing patients with 12-step programs, and implementing drug and alcohol testing [88,93].

Elements of the Matrix Model include [90]:

These elements are incorporated into several treatment protocols, including individual sessions, early recovery groups, relapse prevention groups, family education sessions, 12-step meetings, social support groups, relapse analysis, and urine tests [88].

A convenience sample of 114 patients out of an original population of 500 patients receiving the Matrix Model was analyzed for follow-up two to five years after treatment initiation [46]. A combination of self-report and urine screen revealed that in the 30 days preceding the follow-up interview, 82.5% reported no methamphetamine use, 11.4% reported some use, and 6.1% reported daily use. This is compared with 13.2% no use, 38.6% some use, and 47.4% daily use in the 30 days prior to treatment intake. Other drug use also decreased from intake to follow-up, and full-time employment increased from 26% at baseline to 62% at follow-up. Interestingly, the frequency of depression, headache, and hallucinations were statistically unchanged from baseline to follow-up. Although these results indicate decreased methamphetamine and other substance use and increased psychosocial function associated with Matrix Model-based treatment, 77% of the sample was lost to follow-up, and there was evidence that the subjects in the sample utilized treatment services significantly more than the pooled population of patients, hampering the generalizability of this data.

In a multisite study across eight different communities, 978 methamphetamine-dependent outpatients were randomized to either the Matrix Model or conventional outpatient treatment [94]. Conventional treatment was considered the best available option in the eight communities in which the study took place. Significant variation existed in the conventional outpatient conditions. Although subjects receiving the Matrix Model exhibited significantly better treatment retention, program completion, treatment engagement, more methamphetamine-free urine samples, and longer periods of abstinence during treatment than conventional treatment recipients, these differences did not persist into the post-treatment follow-up period. No differences were noted in methamphetamine-free urine after six months (69% of total urine samples methamphetamine-free in both groups). The authors state that although the Matrix model resulted in a more rapid reduction in methamphetamine use and increased treatment utilization, comparing the Matrix Model to eight different types of comparison treatment conditions increased within-group variance and obscured differences among the groups.

CBT is one of the most studied psychosocial approaches in the treatment of substance abuse disorders in general and non-methamphetamine stimulant abuse in particular. This approach integrates behavioral theory, cognitive social learning theory, and cognitive therapy. The rationale for CBT is the finding that craving for methamphetamine is triggered by exposure to conditioned cues and that the strength of cue response is a factor in relapse. CBT is delivered by a clinical psychologist or other licensed mental health professional in either an inpatient or outpatient setting. Most treatment programs for substance abuse in the United States, and even 12-step programs such as Alcoholics Anonymous (AA), incorporate elements of CBT [90].

A 2005 study suggests that CBT can improve the psychological well-being of outpatient methamphetamine users [95]. Specifically, a four-week, one hour per week CBT intervention was delivered to 507 outpatients (87.2% amphetamine-dependent), consisting of well-defined cognitive, behavioral, and motivational interviewing methods focused on five core areas [95]:

According to self-report, 33% of participants completed the treatment protocol and remained abstinent. Treatment completers experienced significant improvement from baseline on measures of somatic symptoms, anxiety, social dysfunction, and depression, as well as significant improvement in amphetamine refusal self-efficacy, all of which remained significant following intention-to-treat analysis. The authors noted that patients with more severe dependence and general health concerns displayed the greatest improvements. Self-reported drug use reduction or abstinence was not verified with drug screening, and the high attrition rate hampers conclusions on efficacy.

The effectiveness of brief CBT in transmitting the skills and confidence to minimize relapse was also evaluated [96]. In a sample of newly incarcerated inmates residing in a residential detoxification facility, 30 methamphetamine users were randomized to receive five sessions of CBT that emphasized skill acquisition in managing interpersonal and intrapersonal situations related to drug use, and 37 were randomized to a control treatment group consisting of no CBT. Subjects receiving CBT exhibited greater confidence in resisting using situations than control subjects; however, actual changes in drug use were not evaluated.

A group of researchers conducted a randomized controlled trial to evaluate the efficacy of brief CBT for regular methamphetamine use among methadone-maintained women [97]. Eligible women received either brief CBT (treatment group) or drug education (control group). Five questionnaires assessed the efficacy of brief CBT at weeks 0, 4, and 12. Urinalysis verified self-reported methamphetamine use at week 0. Urinalyses were also used for participants who reported methamphetamine abstinence at weeks 4 and 12. Of 120 total participants, 16 were lost to follow-up. Compared with the control group, the treatment group showed significant reductions in frequency of methamphetamine use, severity of methamphetamine dependence, and number of days of methamphetamine use at weeks 4 and 12. Significant improvements in readiness to change, psychological well-being, and social functioning were observed in the brief CBT group at weeks 4 and 12. Nineteen urine specimens (31.66%) in the brief CBT group were negative for methamphetamine use at post-treatment and follow-up; no change was observed in the control group [97].

Developed and first evaluated in 2005 to address the dual concern of methamphetamine abuse and HIV-risk behavior, GCBT integrates the core features of CBT with an emphasis on behavioral and cultural aspects that are relevant to gay and bisexual men. Topics are gay-referent, and discussion of relapse triggers includes gay cultural events and environments. Group sessions cover topics such as sexual risk reduction, sexual behavior on and off of methamphetamine, and recognition of characteristics of sexual partners and significant others who do and do not use methamphetamine [90].

Researchers randomized 162 methamphetamine-dependent gay and bisexual men (52.2% of whom were HIV positive) to 16 weeks of CBT, CM, CBT plus CM, or GCBT to determine efficacy in reducing drug use and sexual risk behavior [90]. Immediately post-treatment, GCBT group participants exhibited a significant reduction in unprotected receptive anal intercourse, and participants in the CM and CBT plus CM groups showed the greatest mean duration of methamphetamine-negative urine and the greatest total methamphetamine-negative urine samples. At one-year follow-up, all four groups displayed significant reductions in unprotected receptive anal intercourse relative to baseline, and there were no significant between-groups differences for methamphetamine use, with all groups reporting significant reductions from baseline levels. Interestingly, employment and legal problems increased from baseline to end of treatment and follow-up. The data suggest that the culturally sensitive GCBT leads to the most rapid reduction in sexual risk behavior, while treatments containing CM result in the most rapid reduction in methamphetamine use, although reductions in sexual risk behavior and drug use were eventually achieved with all treatment approaches studied.

Application of CBT in lesbian, gay, bisexual, transgender, and intersex (LGBTI) communities has consistently shown positive results. CBT either alone or combined with contingency management reduced methamphetamine use, cravings, or relapse during treatment in this population [98].

CM is based on the behavioral theory that both desired and undesired behavior increase when they are reinforced. CM manipulates reinforcers to shape behavior in the desired direction. This type of therapy is used in outpatient settings and is provided by conventional chemical dependency treatment personnel. Patients are rewarded for submitting drug-free urine samples by receiving vouchers with progressively increasing value. The vouchers are ultimately exchanged for goods and services that promote a drug-free lifestyle, such as groceries, clothing, electronic equipment, or plane fare, but are not exchanged for cash [90,99]. Studies comparing the effectiveness of different reinforcement schedules in promoting abstinence from methamphetamine found that an escalating schedule, whereby the reinforcement vouchers are progressively greater for each successive negative drug test with a reset contingency that reduces voucher value with evidence of drug use, is most effective [100].

CM in the form of prize-based vouchers was added to usual care and compared with usual care only in a mixed sample of 415 cocaine- and methamphetamine-dependent outpatients [101]. Subjects randomized to CM exhibited significantly greater treatment retention, increased counseling session attendance, and more frequent alcohol and drug-free urine tests. These individuals were also more likely to achieve 4, 8, and 12 weeks of continuous abstinence than control subjects. Although the authors state that CM increased treatment retention and improved drug-free outcomes, it remains unknown if these short-term benefits persisted when reinforcement was withdrawn [101].

One study compared the efficacy of CM alone to CM plus strengths-based case management (CM/SBCM) in reducing methamphetamine use [102]. CM/SBCM was associated with attending more sessions for people who reported being in a couple. Participants who earned more rewards in the first part of the study were more likely to have more clean urinalysis in the second part of the study. Also, participants who were in a couple, without sexual abuse history, and less methamphetamine use at baseline tended to have more clean urinalysis in the CM/SBCM intervention [102].

Several factors appear to predict CM treatment outcome, including problem severity, race, HIV status, education, and income. CM therapy was least effective for participants who reported a long history of drug use or more methamphetamine use during baseline; it was most effective in White participants [103,104,105,106].

The efficacy of conventional residential treatment with methamphetamine-dependent patients was the focus of a 2004 study [107]. A sample of 199 methamphetamine abusers was admitted to an inpatient residential treatment setting for a mean stay of 86 days. Treatment consisted of group therapy, individual case management, and psychiatric assessment and referral in a semi-structured environment. The therapy was performed by trained chemical dependency counselors with knowledge of methamphetamine addiction. At 60 days following admission, significant reductions were observed on measures of anxiety (e.g., compulsions, obsessions, social phobia, generalized anxiety) and major depression. Approximately 25% of the sample was available for six-month follow-up, with significant reductions in methamphetamine use noted through self-report. Conclusions of efficacy are severely limited by subject attrition and subjective, nonverifiable outcome measures [107].

The efficacy of two residential treatment programs among 108 methamphetamine users was the focus of another study [108]. Patients from one center (amphetamine-type stimulant group) received conventional group therapy plus an additional 10 hours of group therapy focused on stimulant use. Patients from the other center received conventional group therapy only (treatment as usual). A drop-out rate of 40.7% was observed with no significant difference between the two groups. Patients remained significantly longer in treatment as usual compared to amphetamine-type stimulant treatment. In both treatment programs, craving and psychiatric symptoms significantly decreased while psychosocial resources, processing speed, and cognitive flexibility improved over time. Other cognitive measures yielded mixed results. History of injection drug use was a significant predictor for treatment drop-out [108].

Although many patients with methamphetamine addiction are coerced into treatment through criminal justice or child protection services pressure, little research has been completed about the outcome of such patients. The authors of one analysis evaluated the treatment outcomes of 350 outpatient methamphetamine abusers randomly selected from a large database of outpatient and residential treatment patients in Los Angeles County [109]. Approximately 50% of the sample reported legal coercion as the motivation to enter treatment. Coerced clients remained in treatment longer but did not significantly differ from noncoerced clients in abstinence rates at six-month follow-up (59% coerced versus 49% noncoerced). Although there were no significant differences between the groups in percentage of days of methamphetamine use or percentage of patients reporting complete abstinence at 24-month follow-up, the number of months in treatment was associated with a more positive outcome, suggesting a benefit of longer treatment programs for methamphetamine-dependent patients.

In 2017, the FDA permitted marketing of reSET, the first mobile medical application to help treat substance use disorders. The reSET device delivers CBT to patients to teach skills that aid in treatment of substance use disorders, to increase abstinence from substance abuse, and to increase retention in outpatient therapy programs [110]. The device has been shown to be effective in reducing methamphetamine use and craving during treatment [98].

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive FDA-approved medical procedure for treatment of depression in adults. Transcranial direct current stimulation (tDCS) uses a direct-current field delivered at varying intensities to electrodes placed on the scalp. rTMS acts as a neuro-stimulator; tDCS acts as a neuromodulator. Randomized clinical studies compared rTMS with sham stimulation or with treatment-as-usual among individuals with methamphetamine use disorder. Compared with healthy controls, individuals with methamphetamine use disorder displayed significant reductions in craving, executive functions, withdrawal symptoms, and/or mood status with rTMS [111,112,113,114]. rDCS also has been shown to significantly reduce methamphetamine craving and to increase executive functions compared to controls [115,116,117,118].

Many methamphetamine withdrawal symptoms (e.g., fatigue, anhedonia, depressed mood, hypersomnia) simulate a major depressive episode, providing the rationale for the use of the selective serotonin reuptake inhibitor (SSRI) sertraline in methamphetamine patients. However, the authors of a controlled trial found that outpatients receiving sertraline exhibited significantly worse outcomes in tested urine samples, group attendance, and ability to achieve three consecutive weeks of methamphetamine abstinence, with no reduction in depressive symptoms or cravings [99]. These findings suggest that sertraline should not be given to methamphetamine users complaining of depression or depressive-like symptoms. It is possible that depressive symptoms in early methamphetamine abstinence may be a syndrome distinct from primary, non-methamphetamine-induced depression. Additionally, a subsequent study found that a poor response to treatment with sertraline resulted in sustained craving and increased propensity to relapse during treatment among research participants dependent on methamphetamine [122].

Another trial using the SSRI paroxetine to treat methamphetamine dependence was reported by researchers who randomized 20 methamphetamine-dependent patients to either paroxetine 20 mg/day or placebo for eight weeks [123]. The substantial attrition rate (85%) prohibited any conclusions regarding efficacy to be drawn. However, the authors stated that the weight gain, sexual side effects, and sedation often induced by paroxetine and other SSRIs are opposite of the desired effects of methamphetamine, possibly heightening problems with patient acceptance and compliance with this class of medications.

A randomized, placebo-controlled trial of mirtazapine, an antidepressant with presynaptic alpha2-adrenergic antagonist, serotonin 5-HT1 agonist, serotonin 5-HT2 and 5-HT3 antagonist, and histamine H1 antagonist properties, was performed to assess its impact on amphetamine withdrawal [9]. Twenty amphetamine-dependent subjects detained in a short-term correctional facility received either mirtazapine (15–60 mg/day) or placebo for 14 days and were evaluated on days 3 and 14. Active treatment subjects exhibited significantly lower hyperarousal, anxiety, and total withdrawal scores compared with subjects receiving placebo, with no significant differences in depression between the groups. These results may indicate specificity for amphetamine withdrawal symptom reduction distinct from depression reduction with mirtazapine.

As noted, chronic methamphetamine use can result in neuroadaptation in presynaptic dopamine neurons, manifesting as dysphoria, drug craving, and cognitive impairment in early abstinence. This indicates the possible utility of the dopamine and norepinephrine reuptake blocker bupropion. In a randomized, single-blind, placebo-controlled trial, 26 non-treatment-seeking subjects meeting the criteria for methamphetamine abuse or dependence received either a placebo two times per day or 150 mg extended-release bupropion two times per day for six days in addition to IV methamphetamine or placebo [124]. Subjects were housed in a clinical research unit during the study. Compared with placebo, bupropion treatment was associated with reduced ratings of "drug effect," "high," and "desire to use," as well as reduced cue-elicited cravings. The sample was small, however, and the results require replication. A Cochrane Review that included 11 studies (791 participants) evaluated the safety and efficacy of psychostimulants (including bupropion) for amphetamine abuse or dependence. Results of the review found no significant differences between the drugs and placebo in their ability to reduce amphetamine use or craving or to increase sustained abstinence [125].

An approach consistent with the harm reduction model has been proposed and involves prescribing dextroamphetamine to patients addicted to methamphetamine [49]. The basis for this treatment is the success seen with agonist replacement therapy (methadone) treatment of heroin addiction and nicotine replacement therapy for smoking cessation. However, ideologic and regulatory obstacles exist in the United States to the implementation of such a treatment regimen.

Preliminary data from an investigation utilizing methylphenidate to treat withdrawal symptoms in non-ADHD, long-term prescription amphetamine abusers appears promising [126]. Specifically, severe and protracted depression following amphetamine cessation was resolved with ongoing methylphenidate treatment at long-term (two- to four-year) follow-up assessment.

The efficacy of extended-release dextroamphetamine (d-AMP) 60 mg/day as a replacement therapy for methamphetamine dependence was evaluated in a randomized, placebo-controlled trial [127]. Although d-AMP did not significantly reduce methamphetamine use, reductions in withdrawal and craving scores were observed among subjects receiving d-AMP. The authors state that further investigation of d-AMP using higher doses is warranted. Another randomized placebo-controlled trial evaluating extended-release d-AMP was performed in 2010 [128]. In this study, subjects were randomized to d-AMP up to 110 mg/day for a maximum of 12 weeks, which was gradually reduced over a 4-week period. Subjects receiving d-AMP remained in treatment significantly longer than those receiving placebo (86.3 days versus 48.6 days), showed a non-significant reduction in methamphetamine use, and had a lower extent of methamphetamine dependence at follow-up.

Modafinil

Modafinil is a drug indicated for use in patients with excessive daytime sleepiness secondary to narcolepsy and other conditions. Initially believed to work through CNS histamine activation, more recent research has identified the dopamine agonist properties of modafinil. The hypothesis that the dopamine agonist properties of modafinil may help normalize brain dopamine function in methamphetamine-dependent patients and improve abstinence rates in the process has been evaluated in several studies [129]. In a randomized, double-blind trial comparing modafinil (200 mg/day) with placebo, researchers found non-significant trends in reduced methamphetamine use among subjects who remained engaged in counseling, had no other substance dependencies, and who adhered with medication [130]. A randomized, double-blind study of modafinil 400 mg/day found no statistically significant effects on methamphetamine use or craving, treatment retention, or depressive symptoms [131]. A subgroup of patients with high-frequency methamphetamine use showed a non-significant trend toward reduced use. A study comparing the effect of modafinil 400 mg/day and mirtazapine 60 mg/day on methamphetamine withdrawal among inpatients found that subjects treated with modafinil demonstrated a milder withdrawal syndrome as measured by the Amphetamine Cessation Symptom Assessment and less sleep disturbance compared with mirtazapine [132]. A 2020 study was undertaken to determine the efficacy of mirtazapine for the treatment of methamphetamine use disorder and reduction in HIV risk behaviors [133]. Outcomes assessed were positive urine test results for methamphetamine over 12, 24, and 36 weeks (primary outcomes) and sexual risk behaviors (secondary outcomes). Of 241 individuals assessed, 120 were enrolled. Mirtazapine resulted in reductions in positive urine test results at 24 weeks and 36 weeks versus placebo; medication adherence was slightly lower (38.5%) in the mirtazapine group versus the placebo group (39.5%). Changes in sexual risk behaviors were not significantly different at 12 weeks, but individuals assigned to the mirtazapine group had fewer sexual partners and fewer episodes of high-risk sexual behavior [133].

Gamma-aminobutyric acid (GABA) neurons decrease dopamine transmission in the nucleus accumbens and ventral tegmental mesolimbic regions, possibly decreasing the reinforcing effects of methamphetamine and providing the basis for trials of GABA agonists with methamphetamine-abusing patients. Researchers reported the results of two GABA agonists, baclofen (20 mg three times per day) and gabapentin (800 mg three times per day), in a double-blind, randomized, placebo-controlled trial of 16 weeks duration [134]. A total of 88 methamphetamine-dependent outpatients were randomized to either baclofen, gabapentin, or placebo, and all subjects attended clinic three times a week for assessment, counseling, and urine drug testing. There were no statistically significant differences in completion of the 16-week trial, reduction in depressive symptoms, craving of methamphetamine, or reduction in methamphetamine-positive urine samples between the groups. However, when patients with high protocol adherence were compared, baclofen recipients exhibited greater numbers of methamphetamine-negative urine samples relative to gabapentin and placebo subjects, suggesting a small but positive effect of baclofen in reducing methamphetamine use. Greater attendance of psychosocial therapy groups was also associated with decreased methamphetamine use across all three groups, underscoring the importance of psychosocial therapy augmentation of pharmacotherapy for methamphetamine addiction. Observations of dysregulated brain GABA(A) function during and immediately following the active abuse of substances, including methamphetamine, provides the rationale for combining two agents with GABA action in the treatment of methamphetamine dependence. A randomized, double-blind study comparing flumazenil (a benzodiazepine antagonist) plus gabapentin with placebo found significant reductions in craving and decreased methamphetamine use among subjects receiving the study drugs relative to those receiving placebo [135].

The safety and efficacy of another GABA agonist, gamma vinyl-GABA (GVG), was evaluated in a nine-week, open-label, pilot study involving 10 methamphetamine-dependent, 17 methamphetamine- and cocaine-dependent, and 3 cocaine-dependent subjects [136]. Because GVG has not received FDA clearance in the United States due to concerns over concentric visual field defects associated with its use, the study was carried out in Mexico. A total of 18 subjects completed the trial. Of those 18, 16 subjects tested negative for methamphetamine and cocaine during the last six weeks, with a median of 42 days drug free for this group during the 63-day study period. Visual field defects were not observed during the study period. Although unblended and lacking a control group, these results are promising, especially in light of the absence of effective pharmacotherapy for methamphetamine addiction. However, more rigorous testing must be completed before any conclusions regarding efficacy and safety can be drawn.

The possible efficacy of the tricyclic antidepressant imipramine in improving treatment retention and drug use-related outcomes was tested in a randomized controlled trial of 32 methamphetamine-dependent outpatients [137]. Participants received either 10 mg/day or 150 mg/day imipramine for 180 days in addition to counseling, medical care, and psychiatric support. Although patients receiving the 150 mg dose remained in treatment longer, no differences in craving, depression, percentage of methamphetamine-positive urine, days since last methamphetamine use, or study visit attendance were noted between the groups. These results suggest that imipramine may be ineffective as a treatment for methamphetamine dependence. Results of a systematic review of 43 studies and 4,065 participants reporting on 23 individual pharmacotherapies found that neither tricyclic antidepressants nor SSRIs were effective in reducing methamphetamine use [138].

Mesolimbic dopamine pathways are believed to play a large role in the reinforcing properties of stimulant drugs, including methamphetamine, and serotonin (5-HT) may also contribute to the subjective effects of amphetamines. Based on the observation that dopamine-blocking agents attenuate the reinforcing properties of stimulant drugs in animal studies, the dopamine D2 blocker haloperidol and the D2 and 5-HT2 receptor antagonist risperidone were given to nonaddicted human subjects in a placebo-controlled trial to examine their possible efficacy in blocking the rewarding effects of methamphetamine [139]. Neither drug was found to block the euphoric effects of methamphetamine, suggesting that the pleasurable and rewarding properties of methamphetamine are not mediated through dopamine D2 or 5-HT2 activation. Lack of efficacy of dopaminergic medications has been attributed to a decrease in dopamine D2 receptor levels in the striatal subregions in people who chronically abuse methamphetamines [140,141].

Ondansetron is a 5-HT3 receptor antagonist and modulator of cortico-mesolimbic dopamine function. Results of a reduction in the rewarding effects of d-amphetamine in animal and human laboratory studies have prompted the investigation of ondansetron in the treatment of methamphetamine dependence. However, the results of a randomized, double-blind trial comparing ondansetron 0.25 mg, 1 mg, or 4 mg twice daily with placebo did not find an advantage in decreased methamphetamine use, withdrawal, craving, or clinical severity of methamphetamine dependence compared with placebo [142].

As discussed, the cortico-mesolimbic dopamine system is the primary reinforcing or reward pathway involved with methamphetamine use; however, other neurotransmitter systems modulate brain dopamine[143]. For example, mesolimbic dopamine neurons containμ-opioid receptors and the ventral tegmental area and the substantia nigra contain neurons in which dopamine and opioids coexist. These regions of the brain are known to play a role in adaptive behaviors related to methamphetamine addiction. It is hypothesized that opioid antagonist agents may reduce the subjective effects of methamphetamine and modulate the dopamine-opioid interaction.

The opioid receptor antagonist naltrexone, commonly used to treat alcohol and opiate dependence, has been demonstrated to reduce cravings and relapse in methamphetamine addicts in a small-scale Swedish study[143]. The participants in the treatment group reported significantly reduced craving levels and amphetamine use and had a greater number of amphetamine-negative urine samples (65.2%) compared to the placebo group (47.7%). The length of time until a relapse was longer in the treatment group (six weeks) compared to the control (three weeks). An earlier animal study found that naltrexone reduced drug-seeking behavior following administration of conditioned environmental cues in rats that had exhibited extinction behavior in response to a sudden switch from an amphetamine solution to saline solution; however, when primed with methamphetamine, naltrexone had no effect on cue induced drug-seeking[144]. These researchers also concluded that naltrexone may be helpful in preventing relapse. The results of a 2019 systematic review of the effects of naltrexone on methamphetamine use indicate that the drug did not significantly affect either abstinence rates or craving levels[145].

A recent Phase III clinical trial found that a combination of oral bupropion and injectable naltrexone was effective in the treatment of moderate-to-severe methamphetamine use disorder [146]. The combination was safe and successfully reduced cravings compared with placebo. Bupropion may alleviate the dysphoria associated with methamphetamine withdrawal by acting on the dopamine and norepinephrine systems, thereby reducing cravings and helping to prevent relapse. Naltrexone may reduce the reward effects and cravings by blocking opioid receptors [147,148]. Bupropion or naltrexone administered alone showed limited and inconsistent efficacy [118].

Several medications for treatment of methamphetamine use disorder are in different stages of clinical trials, including oxytocin, doxazocin, lobeline, disulfiram, acamprosate, atomoxetine, and entacapone [149].

Immunotherapy is being investigated for treatment of methamphetamine use disorder. Passive immunotherapy involves vaccination with a monoclonal antibody designed to bind to the drug in the bloodstream. Active immunotherapy involves vaccination with an immunogenic methamphetamine-containing conjugate that is able to stimulate specific antibodies that sequester the drug in the brain's periphery, thereby reducing methamphetamine use and relapse [150,151,152]. The antibody is in Phase II trials. Despite promising early preclinical results, no active methamphetamine vaccine has reached clinical trials [118].

Although the number of female methamphetamine users seeking treatment is nearly comparable in number to men, women often display special needs, including high frequencies of personal and social disadvantage, psychiatric illness, sexual risk behavior, and history of sexual and/or physical abuse [24,84,153]. It is imperative that these special needs be assessed and addressed by treatment providers. Failure to address physical and sexual abuse issues and associated psychiatric disorders, such as post-traumatic stress disorder, may contribute to resumption of chemical use [84]. Gender differences in the motivation to use methamphetamine have also been found, with women more likely to use methamphetamine for weight loss and energy enhancement and men more likely to use methamphetamine for increased work productivity and sexual enhancement [40].

Women who are pregnant or have small children necessitate a higher level of care than other patients, with attention to proper prenatal care. Treatment staff may need special training in managing their negative emotions toward the patient(s) while working with pregnant women who relapse to methamphetamine use. Women with small children may require sober living arrangements or day treatment that can accommodate their children [93].

In the United States, methamphetamine abuse by gay and bisexual men is endemic in urban settings, where its use is profoundly intertwined with sexual and social behavior. Rates of use in this population are 5 to 10 times that of the general population [154]. It has been hypothesized that methamphetamine's effects of stimulating energy, confidence, and libido may be particularly effective in counteracting depression or fatigue [155]. This, coupled with the drug's relative inexpensiveness, may make methamphetamine particularly attractive to gay and bisexual men and/or persons with HIV [155]. Methamphetamine use can also increase the frequency and duration of sexual encounters and result in the abandonment of safe sex practices [156]. Consequently, methamphetamine-dependent gay and bisexual men are at heightened risk of STIs, in particular HIV transmission [20]. The issues surrounding concurrent methamphetamine use and hypersexuality among gay and bisexual men does not lend itself to discussion in a mixed group setting with heterosexual men, which could increase the likelihood of poor treatment engagement and early dropout [93].

The Male Training Center for Family Planning and Reproductive Health asserts that men who have sex with men (MSM) in conjunction with illicit drug use (particularly methamphetamine use) should be screened more frequently for sexually transmitted infections, including gonorrhea and syphilis.

(https://rhntc.org/sites/default/files/resources/mtc_male_prevrhc_2014.pdf Last Accessed: June 9, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

The profound connection of methamphetamine use with HIV infection in gay and bisexual men in urban settings has been documented by researchers who found that 61% of a sample of 162 methamphetamine-dependent, treatment-seeking outpatients in Los Angeles were HIV-positive [157]. In another study, 77.6% of a sample of 143 outpatients in San Francisco were HIV-positive [158]. Although unprotected sex, particularly receptive anal intercourse, is highly correlated with HIV infection, other factors are also associated with infection, including prior treatment for methamphetamine dependence, history of STI, and negative health insurance status [157]. Among inmates in the California state correctional system, methamphetamine use was strongly associated with sex-related HIV risk, indicating the importance in addressing this risk with methamphetamine users enrolled in prison-based drug treatment programs [159].

Treatment of gay or bisexual methamphetamine users can be complicated by the presence of HIV infection. In these patients, the onset and severity of the medical, neurologic, and neurocognitive consequences of methamphetamine use can be accelerated. In addition, increased viral load and decreased compliance with antiretroviral therapy, possibly resulting in rebound of viral replication and the development of resistance to antiretroviral drugs, is common [160,161]. However, abstinent methamphetamine abusers who adhere to antiretroviral therapy can suppress HIV replication, underscoring the need to properly engage HIV-positive methamphetamine abusers in treatment [162]. Many methamphetamine abusers are also afflicted with hepatitis C virus, and the negative effects of hepatitis, HIV, and methamphetamine abuse on neurocognitive functioning are synergistic [163].

Methamphetamine use is particularly prevalent in rural areas, where the relative privacy allows the operation of manufacturing labs to go undetected [13,164]. The demographics and use trends are different, with equal numbers of male and female users and a higher number of injection drug users than urban counterparts [13]. Methamphetamine users in rural areas, especially areas designated as frontier regions (defined as six persons or less per square mile) are likely to experience great difficulty in accessing medical, psychiatric, or substance abuse services. Even self-help groups are likely to be nonexistent in these areas, and when they are available, the degree of anonymity in a 12-step group in a small town may be compromised. The nearest available small city often serves as the population center for the region. Social services in these cities may be overwhelmed by numbers of transient persons from the surrounding rural areas needing services in addition to the inhabitants of the city [20].

Substance abuse treatment approaches should be tailored to meet the needs of this rural population. One such approach, Structured Behavioral Outpatient Rural Therapy, is designed around the use of storytelling activities, a more culturally acceptable form of therapy than the traditional role-playing techniques [165]. Case management and behavioral contracting have also been identified as useful approaches to engage and maintain rural residents in therapy [164]. It is also important that healthcare professionals in rural settings receive the training necessary to effectively diagnose and treat methamphetamine-dependent patients. Kentucky and North Carolina have implemented a system by which specialists in substance abuse are available at welfare or social services offices [164]. Other possible approaches in the treatment of rural methamphetamine abuse include treatment of jail and prison inmates and the use of drug courts [164].

Twelve-step programs for stimulant and other drug abuse and dependence include Narcotics Anonymous (NA) and Crystal Meth Anonymous (CMA) and are modeled after AA, an abstinence-based support and self-improvement program that is based on the 12-step model of recovery. AA has helped hundreds of thousands of alcoholics achieve sobriety [170]. The 12-step model emphasizes acceptance of addiction as a chronic progressive disease that can be arrested through abstinence but not cured. Additional elements of the AA model include spiritual growth, personal responsibility, and helping other addicted persons. By inducing a shift in the consciousness of the addict, 12-step programs offer a holistic solution and are a resource for emotional support [170].

Part of the effectiveness of AA, NA, and CMA is rooted in their ability to provide a competing and alternative reinforcer to drug use. Involvement in a 12-step program can enhance the quality of social support and the social network of the member, a potentially highly reinforcing aspect that would be forfeited if drug use is resumed. Other reinforcing elements of 12-step involvement include recognition for increasingly durable periods of abstinence and frequent awareness of the consequences of drug and alcohol use through attendance of meetings [171]. Research shows that establishing a pattern of 12-step program attendance early in treatment predicts the level of ongoing involvement. Thus, healthcare providers should emphasize and facilitate early engagement in a 12-step program [172]. Twelve-step programs are not considered substitutes for treatment. Instead, they are organizations that provide ongoing support in maintenance of abstinence, personal growth, and character development.

Crystal Meth Anonymous (CMA)

Although a fairly new organization, CMA meetings can be found in over 114 metropolitan areas throughout the United States, Canada, New Zealand, and Australia. Only a few studies involving members of CMA have been published; not surprising considering it is a relatively new organization. One study primarily focused on the role of CMA on sexual behavior in a subpopulation of methamphetamine- and cocaine-abusing gay and bisexual men attempting to abstain from sex through 12-step program involvement [173]. The qualitative study noted that many methamphetamine users have difficulty with sex in recovery because sex is so intimately associated with methamphetamine use. Although the reductions in stimulant use were not explicitly measured, data gathered from this study indicate that CMA involvement led to dramatic reductions in the number of sexual partners (reduced from seven per month to one per month) and the frequency of unprotected anal intercourse (declined from 70% to 24%). The authors concluded that although the reductions in HIV risk behavior may not be entirely due to the teachings of CMA, the program appears to be a valuable forum to help methamphetamine- and cocaine-addicted persons work through issues, such as sex, that are intimately associated with their stimulant abuse [173]. For additional information, please visit the CMA website at https://www.crystalmeth.org.