Pharmacological Treatments for Cocaine Craving: What Is the Way Forward? A Systematic Review

Background: cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving efficacy of pharmacotherapies tested for cocaine use disorder, in the context of randomized-controlled clinical trials. Objectives: we assessed the databases of the U.S. National Library of Medicine, Google Scholar, and PsycINFO, without date restrictions up to August 2022, to identify relevant studies. Study eligibility criteria, participants, and interventions: we included double-blinded randomized-controlled trials investigating pharmacotherapies for cocaine craving and/or cocaine use disorder whose outcomes included cocaine craving. Study appraisal and synthesis methods: Two authors screened studies’ titles and abstracts for inclusion, and both read all the included studies. We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study set-ting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes. Results: Overall, we appraised 130 clinical trials, including 8137 participants. We further considered the drugs from the studies that scored equal to or greater than six points in the quality assessment. There was a correlation between craving and cocaine use outcomes (self-reports, timeline follow-back or urinary benzoylecgonine) in the vast majority of studies. In the short-term treatment, acute phenylalanine-tyrosine depletion, clonidine, fenfluramine, meta-chlorophenylpiperazine (m-CPP) and mecamylamine presented promising effects. In the long term, amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone presented promising anti-craving effects. Unfortunately, the highly tested medications were not successful in most of the trials, as follows: propranolol in the short term; amantadine, aripiprazole, bromocriptine, citicoline, ketamine, modafinil, olanzapine, topiramate in the long term. The remaining 52 medications had no positive anti-craving outcomes. Limitations: Our review was limited by high heterogeneity of craving assessments across the studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence and retention in treatment as the main outcomes, whereas craving was a secondary outcome and some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity. Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy. Conclusions: There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment, and amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone in the long-term treatment.


Introduction
Cocaine use disorder causes a host of medical, psychological, and social problems worldwide, including cardiovascular disease, infection, violence, and crime. The United Nations Office on Drugs and Crime [1] estimates that, in 2018, 19 million people used cocaine, a number that is expected to grow against the backdrop of the socioeconomic crisis caused by SARS-CoV-2 pandemic. Yet, despite decades of clinical research, thus far no pharmacological treatments for cocaine use disorder have been established. One of the most critical barriers to abstinence and relapse prevention is craving [2], a core symptom of cocaine use disorder, and one whose clinical relevance is underscored by its inclusion as a diagnostic criterion to diagnose stimulant use disorders in the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [3].
At the neurobiological level, prolonged cocaine use can cause brain circuitry modifications and progressively sensitize dopamine systems, leading to recurrent and intense urges-or craving-to use cocaine. Craving is defined as "a more intense, urgent abnormal desire characterized by longing, yearning and physiological need for drug" [4]. The shift from "wanting" to use a drug to "craving" it occurs due to a progressive salience attributed to drug-related stimuli, even when negative cognitions are attributed to drug use itself [5]. Craving can be elicited by cocaine cues-such as paraphernalia and places/situations related to cocaine use-by acute withdrawal, by cocaine, and by stress, which makes feasible to evaluate in a naturalistic way with an ecological momentary assessment or in laboratory studies with the induction of craving.
Distinct biological and psychological mechanisms are believed to contribute to various types of craving [6]. Some evidence indicates that specific types of craving may be particularly amenable to pharmacological interventions, such as the craving for compulsive use in early abstinence [7].
Although the precise pathophysiology of craving remains elusive, some of its neural substrates have been identified, including progressive alterations in limbic, striatal and cortical systems. The amygdala plays a critical role in learning the relationship between significant stimuli and the signals that anticipate them; the anterior cingulate connects to the amygdala and subserves mood regulation and emotional responsivity; the nucleus accumbens mediates the reinforcing properties of cocaine [6]; and the basal ganglia are believed to underlie compulsive component of addiction. Altogether, the shift of cognitive and emotional aspects of cocaine-related memory can lead to compulsive drug-seeking behavior [8].
Converging functional neuroimaging studies involving persons who use cocaine show cue-elicited increases activity in limbic regions, such as the amygdala and anterior cingulate, cerebellum, and prefrontal cortex, as well as decreased activity in subcortical regions, such as the basal ganglia [6,[8][9][10]. Another study with positron emission tomography (PET) [9] using personalized cues and autobiographical memories found a decreased activity in the prefrontal cortex, lending support to previous findings showing a disruption of prefrontal activity during craving [4].
Although multiple clinical trials have investigated pharmacological interventions for cocaine use disorder, thus far few of them have included craving as a treatment efficacy outcome. Given the clinical relevance of craving as a potential mediator of return to using cocaine, there is growing interest in studying stimulants, antidepressants, and anticonvulsants as anti-craving pharmacotherapies, as reviewed in recent metanalysis [11][12][13][14].
As craving is strongly associated with compulsive cocaine use [15,16] and is a significant predictor of relapse [2], it is an important treatment target for persons with cocaine use disorder. Hence, we have summarized and appraised findings from randomized trials investigating anti-craving medications for this clinical population. To our knowledge, this is the first systematic review to specifically synthesize and appraise the evidence for anti-craving effects of pharmacological interventions for cocaine use disorder.

Assessment of Methodological Quality
Two authors, D.L.S.L. and J.M.C.M. independently assessed the risks of bias in each study included, using the Study Quality Guide from the Cochrane Consumers and Communication Review Group [18].

Data Collection Process
Two authors, D.L.S.L. and J.M.C.M., read all the 130 included studies independently. D.L.S.L. tabulated the data, which J.M.C.M. evaluated. Disagreements between the two authors were resolved by discussion and consensus.

Data Items
We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study setting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes.

Participants
Combined, the studies included had 8137 participants; the smallest study had eight participants, whereas the largest had 358 participants. Men comprised the majority (75%) of the sample and 21 studies had only male participants. Conversely, only one study enrolled exclusively women. Seven studies did not report the participant's gender. The median age was 39 years.
While in 50% of the studies, participants were treatment-seeking, 40% of the studies did not describe participants' intention to engage in treatment. Approximately 27% of studies included participants who used cocaine through the smoked route; 2% of studies participants who used cocaine intravenously; and 58% of studies included participants who used cocaine through more than one route of administration. Information on the route of administration on the remaining 12% of studies was lacking.

Assessments
Ninety-three percent of the included studies used the Diagnostic and Statistical Manual of Mental Disorders criteria for cocaine abuse or dependence (20% DSM-III, 71% DSM-IV, 2% DSM-5). The other 7% included criteria from International Classification of Diseases (ICD-10) and unstructured self-report measures.
Craving was assessed by single or multi-factorial craving scales. Approximately 51% of the studies used a Visual Analog Scale (VAS), either alone or in combination with another semi-structured assessments. The most frequent semi-structured assessments were: The Addiction Severity Index (ASI) (39%); the Cocaine Craving Questionnaire (CCQ) (20%); the Brief Substance Craving Scale (BSCS) (20%); the Minnesota Cocaine Craving Scale (MCCS) (16%); and the Cocaine Selective Severity Assessment (CSSA) (12%). These measures are summarized in Table S1, in the Supplementary Materials Section.

Quality Assessment
The quality assessment was performed using the Study Quality Guide from the Cochrane Consumers and Communication Review Group [18], considering six domains of risk of bias: random sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessment; incomplete data outcome; and selective reporting.
We used a previously established scoring system, in which low risk is indicated by 2 points, unclear risk 1 point, and high risk 0 points, as shown in Table S2, in the Supplementary Materials Section. The scores of the studies included ranged from 2 to 12 points: 85% (111 studies) scored 6 or more (only one scored 12 points, and only one scored 2 points).

Interventions and Outcomes
Setting: 74%, 21% and 5% of the studies were conducted in the outpatient, inpatient, and hybrid settings, respectively.
Duration of intervention: The duration of the intervention ranged from single-dose/oneday intervention to 16 weeks. The most prevalent duration of intervention was 12 weeks (21% of studies). Most (92%) studies compared a pharmacological agent to placebo, and 8% of studies compared two or more active drugs, directly and indirectly.
Adjuvant interventions: Over 60% of trials (74) offered-in addition to the study intervention-treatment as usual, such as individual counseling, cognitive behavioral counseling, or 12-step based approaches.
Efficacy: The majority of trials-46% or 60 studies-found no significant improvement in craving measures by time or group intervention. In approximately 21% of trials, or 27 studies, the active drug intervention suppressed craving and differentiated from placebo.
A total of 84 studies evaluated both craving and cocaine use as outcomes, 76% of them (64) presented a direct correlation between craving and cocaine use after the treatment. The other studies (20) showed divergent results.
First, we separated the studies into two large groups according to the duration of intervention: Acute interventions when up to 7 days and Sub-Acute interventions for more than 7 days. Within each large group, pharmacotherapies were divided into pharmacological classes: antidepressants, antipsychotics, psychostimulants, and other drugs. Detailed data is depicted in Tables 1-5.     Oral sustained-release dexamphetamine 60 mg or placebo daily, in addition to co-prescribed methadone and diacetylmorphine (max 150 mg) for 12 weeks; NA VAS: significant changes in craving from baseline (Wald = 52·36; p < 0·001), but no significant group differences (Wald = 6·52; p = 0·011) Cocaine dependence (self-report); NA; C VAS: 100-mm lines ranging from "not at all" to "extremely" for "am craving cocaine," "desire to use cocaine," "would use cocaine," and "want to buy cocaine." S1: Oral methylphenidate 45 mg daily dose for 11 weeks; NAS2: Oral methylphenidate (15, 30, and 60 mg) followed by placebo for 1 week; NA . S1: found neither positive nor negative influences of methylphenidate on treatment outcome; S2: found neither positive nor negative influences of methylphenidate on treatment outcome .S1: 58% (   for "All I want to use now is cocaine" and for "Nothing would be better than using coke right now" (F= 2.37; p= 0.008). Examination of the data suggest that these findings were not due to systematic changes over time in craving for either group; rather the placebo group reported slightly higher scores reliably throughout the trial and for one week (Week 11) the atomoxetine group reported higher scores (creating the interaction) which declined the following week. No other differences on craving items were observed. 44% (22); Y S1: study 1; S2: study 2.     Cocaine dependence (DSM-IV); NA; C VAS (100 mm left to right "not at all" to "extremely")-("crave", "desire", "want cocaine", and "could refuse cocaine")          L-dopa/carbidopa 800/200 mg or 1600/400 mg or placebo daily for 9 weeks; supportive behavioral counseling S1: Craving: no differences between groups; S2: Craving: no differences between groups S1: 62% (45), YS2: 57% (70); Y  Cocaine dependence in methadone-maintained opioid-dependent (DSM-IIIR); S, I, IV; C Self-report cocaine craving Oral disulfiram 250 mg or placebo daily, was placed directly in the methadone for 12 weeks; weekly individual and group counseling There was a significant decrease in craving over time for the entire sample (Z 5 9.05; p, 0.01), but no significant decrease in craving by treatment group Table 5. Cont.   3.6. Acute Interventions 3.6.1. Antidepressants

Author
One study administering acute fenfluramine [22] found evidence of anti-craving effects 2-fold greater than placebo.

Psychostimulants
Acute administration of serotonergic (5HT) agonist meta-chlorophenylpiperazine (m-CCP) [39] led to a substantial reduction (20%) in craving. The 5HT agonist lorcaserin in a single dose showed mixed results; it had anti-craving effect only after placebo IV doses, but not after IV cocaine doses [58].

Other Drugs
The dopaminergic (DA) precursor depletion method (APTD) significantly reduced both cue-and cocaine-induced craving [112]. Two trials of noradrenergic (NA) agonists-one with clonidine [103] and one with guanfacine [99]-resulted in improvement in craving compared to placebo, while another study with guanfacine reported negative results [121]. Finally, the beta NA blocker propranolol, compared to placebo, significantly reduced craving in a single-dose study [134].

Antipsychotics
Aripiprazole led to a significant reduction in craving in one study [66], while another two studies [70,71] did not differentiate from placebo. Studies administering olanzapine [65,67,68,72], quetiapine [76] and risperidone [65,69,74] did not find evidence of craving suppression effects either. When compared to haloperidol, olanzapine demonstrated significantly better results in one trial [75], while another showed that haloperidol [73] was significantly better in reducing craving than olanzapine.

Other Drugs
Nicotinergic agonists (nicotine and varenicline) were investigated in two trials, and an antagonist (mecamylamine) in two studies: mecamylamine significantly reduced craving in one trial [85], while in another [131] only the placebo group showed significant reduction; transdermal nicotine significantly increased cue-induced craving in comparison to placebo in one trial [145] while varenicline [126] did not differ from the placebo. Biperiden, a muscarinic antagonist, reduced craving by 37.6%, compared to a 19% change from baseline produced by the placebo [96]. Bromocriptine led to a significant reduction in craving in one study [92], while another two [97,102] did not differentiate from the placebo. The DA precursors levodopa/carbidopa, administered for more than 5 weeks and combined with non-pharmacological therapies, were found to reduce craving in one [138] of two studies [120,138], in which it was administered for a longer period (12 weeks) and combined with cognitive behavioral therapy. The administration of amantadine was found to have anti-craving effects in one [140] of three [101,109,140] studies; as citicoline did in one [132] out of three studies [90,113,132]. Two [100,117] studies in three [100,117,146] comparing 7 days of allopregnanolone to the placebo showed a significant decrease in craving. Ketamine showed a significant craving reduction in one [93] of the three studies [93][94][95]. The PPAR (Peroxisome proliferator-activated receptor)-Gamma agonist Pioglitazone reduced cocaine craving by a factor of b = 0.24 when compared to a factor of b = 0.09 for participants receiving placebo [136].

Treatment Dropout
Attrition varied widely among clinical trials, ranging from 0 to 82%, with an average attrition of 40%. Twenty-seven trials did not report their dropout rate. Among the studies with outpatients, 32% showed more than half of the sample dropped out at the end of intervention, against 14% of the inpatient trials. Half of the studies with 5HT agents had an attrition rate greater than 50%. Notably, studies that included adjuvant nonpharmacological therapies had lower attrition rates.

Discussion
We sought to systematically review and appraise the evidence base on pharmacological interventions for cocaine craving, an important treatment target for cocaine use disorder. Altogether, we appraised 130 clinical trials examining a wide range of compounds, with several mechanisms of action. From the analysis of the current review, we observed correlation between craving and cocaine use outcomes (self-reports, timeline follow-back or urinary BE) in the vast majority of studies. Therefore, we can consider craving as an intermediate target for achieving abstinence.
Craving can be triggered by the drug itself, by cues related to drug use, by stress, and by withdrawal. It may occur in the period of immediate abstinence or in a longer period of abstinence. In the first process, there is an immediate activation of limbic system related to an anticipatory state and reward expectancy, and a disruption of medial prefrontal activity leading to compulsive drug-related behavior [4]. Despite having a low number of studies, clonidine, fenfluramine and m-CPP showed to be promising medications for acute anti-craving effects, based on the experimental studies (i.e., cue-induced, stress-induced) included in this review.
The craving that occurs after a longer period of abstinence, on the other hand, can be better explained by the incubation mechanism, in which even after drug use suspension and exposure to drug cues, there is a progressive increase in craving, remaining high within 3 months of abstinence, with a reduction after 6 months and is related to neuroadaptations and increased brain-derived neurotrophic factor (BDNF) levels [149]. The most promising drugs for such chronic purposes came from the longer randomized controlled trials included in this review. The class of psychostimulants had several options such as amphetamine, lisdexamfetamine, lorcaserin and methamphetamine for chronic cocaine craving. Our findings are in line with a review [150] of 9 clinical trials, of which 4 evaluated craving and one showed a significant anti-craving effect of dexamphetamine. Progesterone was shown to be effective for treating craving in two out of three studies, in cocaine-dependent men and women who used the drug for 7 consecutive days. The antidepressant mirtazapine also showed a significant reduction in craving in 1 of 2 studies with it. Carbamazepine, biperiden and pioglitazone also presented significant anti-craving effects in long term treatments, although each one was evaluated once.
There are currently no approved drugs for the treatment of cocaine use disorder, with psychosocial intervention still being the standard approach. Recommendations of United Nations Office on Drugs and Crime [151] state that stimulant medications, such as amphetamines, may have modest effects on withdrawal and craving suppression for patients with stimulant use disorder. These recommendations refer to stimulants as "replacement" or "substitution therapy" and highlight studies that found evidence of craving suppression following the administration of extended-release formulations of methamphetamine 30 mg/day and lisdexamphetamine 70 mg/day. Findings of this review endorse these recommendations, but not the recommendations of The European Monitoring Centre for Drugs and Drugs Addiction, which stated in a summary of systematic reviews [152] that antipsychotics are the most prominent anti-craving drugs, although this could not be established as effective treatment. Several studies have been conducted to evaluate the efficacy of pharmacotherapies regarding dual substance disorders: some reports indicated that buprenorphine decreases cocaine use [153][154][155] in opioid-dependent humans who were concurrently abusing cocaine; one in particular [155] evaluated craving and demonstrated a significant reduction in its rate. Recent studies examined the therapeutic potential of orexin receptor antagonists in rodent models of cocaine use disorder, in reducing cocaine seeking behavior [156,157], pointing to future directions in studies in clinical settings.
We found that most studies made direct comparisons of one individual compound to placebo, or indirect comparisons between more than one individual compound and placebo. None of the studies investigated the anti-craving effects of combined pharmacological interventions. This is in stark contrast with the complex, multi-system pathophysiology of craving, which may require a combination of pharmacotherapies with complementary mechanisms [2,4,5]. This is exemplified by a randomized, placebo-controlled trial investigating the combination of topiramate and sustained release amphetamine among 127 persons with cocaine dependence, which found significant anti-craving effects over 12 weeks [158]. A pre-clinical study [159] suggested that the combination of buprenorphine and naltrexone decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction. Hence, multi-function therapies maybe represent a more promising avenue of intervention.
Moreover, as craving is elicited by cues, stress, drug and withdrawal, studies must include, besides laboratory assessment, Ecological Momentary Assessment (EMA) due to the temporal association between exposure to drug cues, or subjective experiences, allowing for a more dynamic investigation of therapeutic effects of anti-craving treatments.

Limitations
To our knowledge, this is the first systematic review of pharmacotherapies targeting cocaine craving. Our review has notable strengths. First, published and widely accepted guidelines to conduct and report systematic reviews were used [17]. A highly sensitive search strategy was used across several electronic databases, which yielded multiple studies providing data on anti-craving efficacy of pharmacotherapies. Further, 2 independent reviewers performed all stages of the review, with good interrater reliability.
Previous reviews [11][12][13][14] reported challenges in systematically assessing anti-craving effects across multiple studies, primarily due to a high heterogeneity of craving measures. For instance, some studies used standardized scales whereas other studies used Visual Analogue Scales (VAS), or non-standardized questionnaires, some with unclear psychometrical properties. A study [16] comparing unidimensional and multidimensional craving scales suggested that the latter had higher predictive validity for relapse of cocaine use and for treatment dropout. Further, a review of craving measures [7] even suggests that researchers use different scales within the same study due to its complexity. Still, our review was limited by high heterogeneity of craving assessments across studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence retention as the main outcome in cocaine treatment, whereas craving was a secondary outcome; also, some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy. Nonetheless, the results of the review help bring clarity to the mixed findings on anti-craving pharmacotherapies reported in multiple clinical trials.

Conclusions
There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Given its clinical relevance, future studies aiming to develop pharmacotherapies for cocaine use disorder must consider craving as a therapeutic outcome, employing multimodal and standardized assessments-neurophysiological biomarkers, cue reactivity, ecological momentary assessment-to study this complex experience.
Despite most of the studies evaluate craving as a secondary outcome and having a low number of studies per medication in most of the cases, clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment. In addition, amphetamine, biperiden, carbamazepine, levodopa, lisdexamfetamine, lorcaserin, guanfacine, methamphetamine, mirtazapine, pioglitazone, progesterone, nefazodone exhibited anti-craving effects in long-term treatment. Future trials targeting craving as the main outcome should include these medications trying to replicate their preliminary positive results.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/brainsci12111546/s1, Table S1: Structured cocaine craving scales.; Table S2: Results of the quality/bias assessment using the Cochrane Collaboration tool for assessing risk of bias.