Study quality.

Of the 29 reviews, 10 were appraised as ‘core’ reviews and the remaining were considered ‘supplementary’. Findings are summarized in Table 2, including systematic reviews and meta-analyses assessed, number of randomized controlled trials in each, and our statement of evidence. A complete list of pharmacological interventions included in the reviews for this paper, stratified by drug type and number of trials, are listed in S3 Appendix. A complete summary of population characteristics and key findings of each review can be found in S1 Table.

Contingency management.

Contingency Management (CM) involves participants receiving something of value such as a gift card, voucher or chance to win a prize as a reward for the achievement of a specific and measurable desired behaviour, most commonly a negative urine drug test for stimulants when implemented for the treatment of stimulant use disorder [20, 43]. Six trials have been included in this review assessing CM’s efficacy in the treatment of stimulant use disorder and have found consistently positive results. De Crescenzo et al. was evaluated as core evidence, with the remaining five reviews evaluated as supplementary evidence. Pooled data demonstrates significant benefit across studies. CM has been evaluated both independently and in combination with psychotherapy and pharmacotherapy.

1. a. Contingency management alone. De Crescenzo et al. included 50 RCTs evaluating 12 psychosocial interventions for the treatment of stimulant use disorder, including 15 RCTs that compared CM alone to treatment as usual (TAU). A significant benefit was found for the outcomes of abstinence at 12 weeks (Odds Ratio [OR] 2.29, 95% Confidence Interval [CI] 1.62, 3.24), abstinence at the end of treatment (OR 2.22, 95% CI 1.59, 3.10), dropout at 12 weeks (OR 1.39, 95% CI 1.09, 1.78), and dropout at the end of treatment (OR 1.41, 95% CI 1.10, 1.82), but the effect was not sustained at longest follow up (OR 1.10, 95% CI 0.83, 1.46) [15].

Schumacher and colleagues assessed the efficacy of CM in comparison to day treatment programs in Alabama for the management of stimulant use disorder. Their meta-analysis of four successive RCTs demonstrated a significant benefit of contingency managed housing interventions, specifically abstinence-contingent housing and/or employment, among people who use crack cocaine and are homeless. In the primary outcome of abstinence at two months, the contingency management only group had a higher prevalence of cocaine negative urine drug test (prevalence: 0.71, standard error [SE]: 0.029) versus no treatment (prevalence: 0.46, SE: 0.036), or day treatment only (prevalence: 0.50, SE: 0.023). Of note, the addition of day treatment programs to CM (prevalence: 0.75, SE: 0.019) showed no added benefit compared to CM alone [16].

1. b. Contingency management versus cognitive behavioural therapy. When compared to Cognitive Behavioural Therapy (CBT), CM was found to have more immediate, but possibly shorter-term benefit [17, 18]. De Crescenzo et al. found CM alone as well as CM in combination with CBT to be superior to CBT alone in the outcome of abstinence at the end of treatment (OR 1.88, 95% CI 1.52, 2.85, and 2.08, 95% CI 1.28, 3.33, respectively). Of note CM compared to CBT at 12 weeks of treatment, and at longest follow up were not reported [15]. Farronato et al. found that CM alone resulted in reduced cocaine use during active treatment in all eight trials included in the study. Additive effects of CM and CBT were found in two of the five trials included [17]. CBT demonstrated less reliable benefit with no positive effect during active treatment, but showed delayed positive results in three out of five trials.

Similar results have been demonstrated for methamphetamine use disorder. Lee et al. included 12 RCTs of which four trials compared CM to CBT and three trials compared CM to usual care. Significant benefit was found for CM across studies for the outcomes of treatment retention, methamphetamine- or amphetamine- negative urine samples, and continuous periods of abstinence [18].

1. c. Contingency management in combination with community reinforcement approach. De Crescenzo et al. found the combination of CM with CRA to be the only intervention that increased the rate of abstinence at the end of treatment (OR 2.84, 95% CI 1.24, 6.51), at 12 week follow up (OR 7.60, 95% CI 2.03, 28.37) and at longest follow up (OR 3.08, 95% CI 1.33, 7.17). They found this combination to be more effective than CBT (OR 2.44, 95% CI 1.02, 5.88), non-contingent rewards (OR 3.31, 95% CI 1.32, 8.28), and 12-step programme plus non-contingent rewards (OR 4.07, 95% CI 1.13, 14.69). CM with CRA also demonstrated significant benefit in the outcome of participant dropout when compared to TAU both at 12 weeks (OR 3.92, P < 0.001) and at the end of treatment (OR 3.63, P < 0.001) [15]. Schierenberg and colleagues evaluated CM in conjunction with standard treatment options for cocaine dependence, including CBT, pharmacotherapy and community reinforcement programs (CRA) [19]. The review included 16 studies and found that the addition of CM to CRA resulted in significant increase in cocaine abstinence and treatment retention. Roozen et al. included 11 RCTs and compared CM to CRA. The review found the addition of abstinence-contingent incentives (CM) to CRA to be superior to CRA alone in the treatment of cocaine dependence [20].

Of note, CRA was never explicitly evaluated in these reviews as it was only included as a comparison group. As a result, we are unable to assess its effectiveness alone based on current evidence.

1. d. Contingency management in combination with pharmacotherapy. Schierenberg et al. examined the effect of combining CM with pharmacotherapy for treatment of cocaine use disorder. CM had an additive effect when combined with pharmacological interventions, with a number needed to treat (NNT) between three and eight [19]. In a systematic review and meta-analysis by Castells et al. (2009) focusing on comorbid opioid and cocaine use disorder, the addition of contingency management for cocaine use to opioid agonist therapy was found to improve sustained cocaine abstinence [RR 3.11, 95% CI 1.80, 5.35] [44]

In summary, CM has been shown to have a significant benefit in treatment of both cocaine and stimulant use, and there may be an additive effect of CM when combined with both pharmacotherapy and other non-pharmacological interventions.

Cognitive behavioural therapy.

CBT involves psychotherapy aimed at modifying a patient’s thoughts and behaviours in order to reduce stimulant use. Its effectiveness in treating other substance use disorders has been well documented, however evidence is limited for its efficacy in treatment of stimulant use disorder [21]. The review by De Crescenzo et al. included seven RCTs comparing CBT to TAU. A significant benefit was found in the outcomes of dropout at 12 weeks (OR 1.42, 95% CI 1.05, 1.93), and dropout at the end of treatment (OR 1.47, 95% CI 1.08, 2.00). However, no significant benefit was identified for abstinence at 12 weeks, at the end of treatment, or at longest follow up [15].

A systematic review by Harada et al. evaluating the effectiveness of CBT for amphetamine-type stimulant use disorder included two RCTs and was unable to determine the effectiveness of CBT due to poor quality data [21]. There are limited available systematic reviews and meta-analyses focusing on CBT for the treatment of stimulant use disorder.

Acupuncture.

Acupuncture has been explored for its use in a wide range of substance use disorders [45]. Mills et al. examined its use in treating cocaine dependence in a systematic review of nine RCTs including 1747 participants. Biochemical confirmation of abstinence was analyzed from seven studies and no significant benefit was found for acupuncture compared to controls. (OR: 0.76, 95% Confidence Interval [CI]: 0.45, 1.27). However results were weakened by large loss to follow up [22].

Gates and colleagues conducted a systematic review and meta-analyses of seven studies comparing auricular acupuncture to sham acupuncture or no acupuncture among 1,433 participants who used cocaine or crack cocaine. No difference was found between sham acupuncture and auricular acupuncture with respect to biochemically validated cocaine use in either short-term (n = 3, Relative Risk [RR]: 1.01, 95% CI: 0.94, 1.08) or long-term (n = 1 RR: 0.98, 95% CI: 0.89, 1.09) follow up. Furthermore, no difference in self-reported cocaine use was found between acupuncture and no acupuncture groups in short term (n = 2, RR: 1.09, 95% CI: 0.71, 1.69) or long term (n = 2, RR: 1.04, 95% CI: 0.76, 1.43) assessment [23]. Results of the meta-analysis are limited by poor methodological quality of primary studies and small sample sizes.

Overall, results from several studies have shown no benefit in the use of acupuncture for treatment of stimulant use disorder.

Antidepressants.

Cocaine use increases availability of dopamine, serotonin and noradrenaline acutely, however results in down-regulation of these monoamine systems with chronic use. As a result, extensive investigation has been done into the use of antidepressants for treatment of stimulant use disorder [24]. A Cochrane review by Pani and colleagues included 37 randomized controlled trials covering a range of antidepressants, most commonly desipramine, fluoxetine and bupropion, and did not demonstrate benefit for cocaine dependence. Although there were positive results reported for mood-related outcomes consistent with the primary effects of antidepressants, these did not appear to affect outcomes directly related to cocaine abuse and dependence, including dropout (RR: 1.03, 95% CI: 0.93, 1.14) and abstinence from cocaine use (RR: 1.22, 95% CI: 0.99, 1.51 [24].

The recent systematic review and meta-analysis of pharmacotherapy for cocaine use disorder by Chan et al. found no effect of antidepressants on rates of abstinence in a meta-analysis of ten RCTs [n = 1226, RR 1.27 CI 0.99, 1.63], or retention in treatment (33 RCTs, n = 2918, RR 0.95 CI 0.87, 1.03). Low quality evidence did support antidepressants in the outcomes of lapse (2 RCTs, n = 116, RR 0.79, CI 0.62, 1.00) and relapse (RR 0.74, 95%CI 0.57, 0.96) [25].

Torrens et al. stratified results by the presence of comorbid depression as well as by selective serotonin reuptake inhibitor (SSRI) versus non-SSRI medication among participants with cocaine dependence. Findings did not support the use of antidepressants in either group. In those without comorbid depression (14 RCTs), a statistically significant difference was noted with respect to reduction in cocaine use between SSRI (OR: 0.5, 95% CI: 0.22, 1.13) and non-SSRI (OR: 1.85, 95% CI: 1.06, 3.22) antidepressant medications, with results favouring the use of non-SSRI medications. In those with comorbid depression (five RCTs), meta-analysis showed no significant reduction in cocaine use for SSRI (OR: 0.54, 95% CI: 0.74, 7.30) or non-SSRI (OR: 2.32, 95% CI: 0.74, 7.30) antidepressants [26]. However, this study was categorized as a supplementary review due to limited sample size and low quality of individual RCTs.

A systematic review and meta-analysis by Chan et al. focusing on pharmacotherapy for methamphetamine or amphetamine use disorder found predominantly negative results for the use of antidepressants. No difference was identified for the outcome of abstinence, (4 RCTs, n = 590) or retention in treatment (6 RCTs, n = 831). For the outcome of reduction in use, authors reported mixed results; only one RCT (n = 60) demonstrated reduction in use when treated with mirtazapine, as measured by urinalysis [27].

In summary, review of antidepressant medication for the treatment of stimulant use disorder has shown no significant benefit, although superiority of non-SSRI over SSRI antidepressant medications was noted in supplementary evidence.

Disulfiram.

Disulfiram is FDA-approved for treatment of alcohol use disorder, but has also been explored for the treatment of other substance use disorders. This is because disulfiram has been posited to act not only to inhibit aldehyde dehydrogenase, but as a broader enzyme inhibitor, including dopamine-beta-hydroxylase. Increased dopamine levels in meso-limbic circuits with the use of disulfiram may counter the depletion that is caused by chronic cocaine use [28]. A Cochrane review by Pani and colleagues examined seven studies with 492 participants for the use of disulfiram in the treatment of cocaine dependence and found mixed results. When compared to placebo, one out of four studies reported positive results for cocaine use, as measured by number of weeks of abstinence (weighted mean difference [WMD]: 4.50, 95% CI: 2.93, 6.07). No significant results were found for dropout (n = 2, RR: 0.82, 95% CI: 0.66, 1.03). When compared to naltrexone, no significant difference was noted in dropout rate (n = 3, RR: 0.67, 95% CI: 0.45, 1.01), although one study reported statistically significant reduction in cocaine use as measured by urine sample (WMD: -23.50, 95% CI: -26.58, -20.42). Finally, when comparing disulfiram versus no pharmacological treatment, one study found a statistically significant increase in weeks of consecutive abstinence (WMD: 2.10, 95% CI: 0.69, 3.51), and one study found a statistically significant increase in number of subjects to achieve three consecutive weeks of abstinence (RR: 1.88, 95% CI: 1.09, 3.23) [28].

In summary, these studies found low quality evidence to support the use of disulfiram for treating cocaine dependence though conclusions are limited by the small sample size of randomized controlled trials to date.

Dopamine agonists.

It has been hypothesized that dopamine agonists such as levodopa, cabergoline and pramipexole may reduce cravings, risk for relapse and withdrawal symptoms by increasing dopaminergic transmission in the mesolimbic pathway [29]. However, we found that the literature does not support the use of dopamine agonists for the treatment of stimulant use disorder. A Cochrane review by Minozzi et al. included 24 studies and 2147 participants, comparing dopamine agonists versus placebo in treatment of cocaine use disorder. No improvement was found in any of the outcomes studied, including dropout (RR: 1.04, 95% CI: 0.94, 1.14), abstinence (RR: 1.12, 95% CI: 0.85, 1.47), severity of dependence, and adverse events (RR: 1.27, 95% CI: 0.66, 2.44) [29].

Antipsychotics.

In contrast to dopamine agonists, antipsychotic medications block dopamine receptors and have been hypothesized to be effective by counterbalancing the increased dopamine neurotransmitter release from stimulant use [30]. The effects of atypical antipsychotics on the serotonergic system have also been proposed as an alternative mechanism of action for the treatment of stimulant use disorder [30]. A 2016 Cochrane review by Indave and colleagues included 14 studies and 719 participants with cocaine dependence. Antipsychotic medications were compared to placebo (11 studies) or to a different antipsychotic medication (three studies). The only primary outcome for which a significant difference was reported was reduction in study dropout compared to placebo in eight studies, with moderate quality of evidence (RR: 0.75, 95% CI: 0.57, 0.97). For all other primary outcomes including number of participants using cocaine during treatment, continuous abstinence, side effects, and cravings, no significant differences were reported, with low quality of evidence. Major biases reported were attrition bias in 40% of studies, and selection bias resulting from low quality reporting [30].

Chan et al. found predominantly negative results for the use of antipsychotics in the treatment of cocaine use disorder, with no difference reported in the outcome of abstinence (1 systematic review of 3 RCTs, n = 139, RR 1.30 95%CI 0.73, 2.32), reduction in use, lapse, or relapse. The aforementioned systematic review by Indave et al. was also included in the review by Chan et al. and reported positive results for retention in treatment [25].

Alvarez and colleagues conducted a meta-analysis of 12 randomized, double-blind placebo controlled clinical trials with 681 patients focusing on the use antipsychotics for cocaine use disorder, which was included as supplementary evidence. Results included 48% loss to follow up, no significant reduction in cocaine use (WMD: 0.01, 95% CI: -.12, 0.13), and no improvement in treatment retention (RR: 0.91, 95% CI: 0.82, 1.02) [31].

The use of antipsychotics for treatment of methamphetamine or amphetamine use disorder was evaluated in the systematic review and meta-analysis by Chan et al. No difference was reported for the use of aripiprazole for the outcomes of abstinence (1 RCT, n = 90), reduction in use (2 RCTs, n = 143), or retention in treatment (1 RCT, n = 53) [27].

Kishi et al. examined both cocaine and amphetamine use disorder, and found no difference between antipsychotic- and placebo- treated participants. The review was included as supplementary evidence. Outcomes reported included days of cocaine or amphetamine abstinence, addiction severity, craving, and mood related parameters [32].

In summary, antipsychotics had no superiority over placebo in treating stimulant use disorder but may result in greater study retention.

Anticonvulsants.

It is hypothesized that anticonvulsants may contribute to the treatment of stimulant use disorder by potentiating GABA inhibitory neurotransmission, thereby preventing the rise in dopamine that is caused by cocaine use. Conflicting evidence for the effectiveness of anticonvulsants for the treatment of stimulant use disorder has been reported in the literature [46–48]. Minozzi and colleagues conducted a Cochrane review of 20 studies including 2068 participants comparing anticonvulsants versus placebo for the treatment of cocaine dependence. There was no significant benefit demonstrated in any of the primary or secondary outcome measures, including dropout (17 studies, RR: 0.95, 95% CI: 0.86, 1.05), cocaine use (9 studies, RR: 0.92, 95% CI: 0.84, 1.02), and side effects as measured by the number of participants reporting at least one side effect (8 studies, RR: 1.39, 95% CI: 1.01, 1.9) [33].

Chan et al. found no effect of anticonvulsants in the treatment of cocaine use disorder. No difference was found for the outcomes of abstinence, reduction in use, retention in treatment, and withdrawal [25].

Alvarez and colleagues demonstrated insufficient evidence to support the use of anticonvulsant drugs in treatment of cocaine dependence. In this review of 15 RCTs including 1,236 participants, two outcome measures were assessed, with neither outcome demonstrating a significant improvement between the treatment and control groups: retention in treatment (15 studies, RR: 0.99, 95% CI: 0.90, 1.11), and cocaine use (13 studies, RR: 0.95, 95% CI: 0.85, 1.06) [34].

Chan et al. also assessed the use of anticonvulsants for the treatment of methamphetamine or amphetamine use disorder. No difference was reported for the outcomes of abstinence (1 RCT, n = 88) or retention in treatment (2 RCTs, n = 228) [27].

These studies are limited by a small number of trials for each anticonvulsant type and further clinical research in this area is warranted.

Topiramate.

Singh et al. included five peer-reviewed randomized controlled trials evaluating the use of topiramate in participants with cocaine dependence or cocaine use disorder in a systematic review and meta-analysis. No significant difference was reported for retention in treatment between topiramate-treated and control groups. Two out of five studies found improvement in continuous abstinence (RR: 2.43, 95% CI: 1.31, 4.53) and one study found a significant reduction in craving [35].

Chan et al. also reported positive results for topiramate in the outcome of cocaine abstinence. Results from two RCTs reported increased continuous abstinence for three or more weeks (RR 2.56, 95% CI 1.39, 4.73) [25].

Chan et al. also reported a reduction in use with topiramate for the treatment of amphetamine or methamphetamine use disorder (2 RCTs, n = 228) [27]. Although anticonvulsants for the treatment of stimulant use disorder have not shown it to be effective, data is limited on individual medications in this drug class such as topiramate, and more study in this area may be of benefit.

Psychostimulants.

It is hypothesized that psychostimulant treatment for stimulant use disorder may be effective by substituting a slow acting drug with a similar mechanism of action, thereby reducing withdrawal symptoms and cravings [36]. Eight reviews and meta-analyses assessing the use of psychostimulants for treatment of stimulant use disorder have been included in this review: four were appraised as core [25, 27, 36, 49], and four have been included as supplementary evidence[37–40]. Reviews focused on a single medication have been included as sub-categories.

The 2016 Cochrane review by Castells et al. included 26 studies with 2366 participants, examining nine drugs. Psychostimulants improved sustained cocaine abstinence (RR: 1.36, 95% CI: 1.05, 1.77) and NNT = 14, particularly for bupropion and dexamphetamine, but did not reduce use among participants actively using cocaine (standardized mean difference [SMD]: 0.16, 95% CI: -0.02, 0.33). Of note this review included all medications with some psychostimulant effect or those metabolised to a psychostimulant, including bupropion. There was moderate quality of evidence that psychostimulants did not improve treatment retention. There was no significant difference in adverse events between psychostimulants and placebo. In participants who used both opioids and stimulants and treated with methadone, sustained cocaine and heroin abstinence increased with psychostimulant treatment compared to placebo [36]. Attrition bias was a major limitation to these trials and further investigation into psychostimulant substitution treatment is encouraged.

The systematic review and meta-analysis by Chan et al. assessed the efficacy of psychostimulants for treatment of cocaine use disorder. Positive results for the outcome of abstinence were reported from the systematic review by Castells et al. No difference was reported for the outcomes of any cocaine use or retention in treatment [25].

A Cochrane review of 11 studies including 791 participants was conducted by Perez-Mana et al. examining the use of psychostimulants in the treatment of amphetamine use disorder. There was no significant improvement in sustained abstinence as measured by negative urinalysis over three consecutive weeks (RR: 1.12, 95% CI: 0.84, 1.49), or retention in treatment (RR: 1.01, 95% CI: 0.9, 1.14). The medication was well tolerated and adverse events were rare [49]. Data focusing specifically on amphetamine dependence is limited, and further investigation including larger and longer trials are needed to establish the utility of psychostimulants in this area.

Chan et al. found limited evidence for the use of psychostimulants for methamphetamine or amphetamine use disorder. No difference was reported for the outcomes of abstinence (1 SR, 2 RCTs, OR 0.86, 95%CI 0.46, 1.61) or retention in treatment (1 SR, 11 RCTs, OR 1.11, 95% CI 0.86, 1.44). Mixed results were reported for the outcome of reduction in use, with 8 RCTs reporting no difference, two RCTs with a positive effect of methylphenidate, and two RCTs with no effect [27].

A recent systematic review and meta-analyses by Bhatt et al. included 17 studies with 1387 participants, assessing psychostimulants for treatment of methamphetamine dependence. It was included in this review as supplementary evidence due to small sample size. The main outcome measure was sustained abstinence, for which no effect was reported (OR: 0.97, 95% CI: 0.65, 1.45). However only five studies were included in this subgroup analysis. Authors found no effect on treatment retention, but a small subgroup analysis suggested improvement with longer duration of psychostimulant treatment [37].

Perez-mana and colleagues conducted a systematic review in 2011 assessing indirect dopamine agonists (IDA) in treating psychostimulant dependence, including both cocaine and methamphetamine. Although this review included interventions with a broad range of mechanisms of action, positive results were found primarily in those studies assessing psychostimulant medication for cocaine dependence. IDAs considered to have psychostimulant effect included bupropion, dexamphetamine, mazindol, methamphetamine, methylphenidate, and modafinil. The analysis included 29 studies with 2,467 participants. Primary outcome measures assessed were stimulant abstinence and retention in treatment. Subgroup analysis of IDAs with psychostimulant effect showed minor but statistically significant positive results in the outcome of abstinence (14 studies, SMD: 0.22, 95% CI: 0.05–0.40), but no improvement in treatment retention (20 studies, RR: 1.00, 95% CI: 0.92, 1.09) [38]. Similar results were reported by Castells et al. for bupropion, dexamphetamine, disulfiram and mazindol as adjunct therapy to opioid agonist therapy in dual opioid-cocaine use disorder, with an increase in sustained cocaine abstinence (RR 1.44, 95% CI 1.05, 1.98) [36].

Modafinil.

A 2017 systematic review and meta-analysis of 11 RCTs by Sangroula et al. assessed the efficacy of modafinil for cocaine dependence. The primary outcome of treatment retention was not significantly different between the treatment and placebo groups, but significant positive results were found for the secondary outcomes of number of cocaine non-use days (SMD: -1.294, 95% CI: –2.572, 0.017) and proportion of negative urine samples (SMD: -0.633, 95% CI: –1.248, 0.018). No significant differences were found with respect to safety and adverse events [39].

Methylphenidate.

A review of the literature published by Dursteler et al. in 2015 concluded that methylphenidate treatment of up to 90 mg per day for cocaine-dependent participants is safe, however did not significantly reduce cocaine use. These results were generalizable to adults with or without ADHD and with or without concurrent opioid agonist treatment [40]. However, in the Chan et al. review of treatment of amphetamine and methamphetamine use disorder, two RCTs found a positive effect of methylphenidate on reduction in use, one trial reporting 6.5% versus 2.8% mean proportion amphetamine-negative urine samples in an intent-to-treat analysis (adjusted odds of positive urine sample 0.46, 95% CI 0.26, 0.81, p = 0.008), and another reporting 23% versus 16% amphetamine-negative urines (n = 54, p 0.047) [27].

In summary, review of the evidence of psychostimulant treatment of cocaine as well as amphetamine and methamphetamine dependence has shown some promising results, although further investigation is required for more definitive clinical evidence.

Opioid agonist.

Opioid agonist therapy (OAT), including buprenorphine-naloxone and methadone, are first and second line treatments for opioid use disorder [50]. A systematic review and meta-analysis by Castells and colleagues published in 2009 assessed the effectiveness of opioid agonists in the treatment of concurrent opioid and stimulant use disorder. Results included 37 studies, with 3,029 participants who used both cocaine and heroin. Higher doses of OAT had no effect on cocaine abstinence compared to lower doses. When compared to buprenorphine, methadone demonstrated greater improvement in cocaine abstinence (RR: 1.63, 95% CI: 1.20, 2.22). Adjunctive treatment options including indirect dopamine agonist therapy and CM were found to significantly improve cocaine abstinence [41]. Of note, no studies compared OAT to placebo, and it is difficult to decipher the direct effect of OAT on cocaine use from the benefit of parallel reduction in heroin use, in the context of dual heroin-cocaine dependence.

N-acetylcysteine.

N-acetylcysteine (NAC) is used primarily to treat acetaminophen overdose, and as a mucolytic [42]. It has also been hypothesized to be of use in treating cocaine use disorder by restoring glutamate transporter-1 (GLT-1), by clearing excess glutamate from the extrasynaptic space, thus restoring glutamatergic homeostasis that is impaired with chronic stimulant use [42, 51]. A recent systematic review by Nocito Echevarria et al. summarized the current data from six human trials and 16 animal studies on the use of NAC for cocaine use disorder. Preliminary results of this review reported significant reduction in craving, “cocaine-cue viewing-time” and “cocaine-related spending” in four clinical trials. Side effects were reported as mild and did not vary significantly between doses [42]. Results were included in this review as supplementary evidence due to limited human data and qualitative methodology.