Use of Mavoglurant in Reducing Cocaine Use or Preventing Relapse to Cocaine Use

Abstract

The present invention relates to the use of mavoglurant, or a pharmaceutically acceptable salt thereof, in reducing cocaine use by patients with cocaine use disorder; in preventing relapse to cocaine use by patients with cocaine use disorder; in promoting cocaine abstinence by patients with cocaine use disorder; and in treating depressive or anxiety symptoms associated with cocaine use disorder.

Description

[Technical field]

[0001] The present invention relates to the use of mGluR5 antagonists.

[0002] The present invention relates to the use of the mGluR5 antagonist named mavoglurant, or a pharma- ceutically acceptable salt thereof, in reducing cocaine use by patients with cocaine use disorder; preventing relapse to cocaine use by patients with cocaine use disorder; promoting abstinence from cocaine by patients with cocaine use disorder; treating depressive or anxiety symptoms associated with cocaine use disorder. In particular, the present invention relates to the use of mavoglurant, or a pharma- ceutically acceptable salt thereof, in reducing cocaine use / preventing relapse to cocaine use by patients with cocaine use disorder. [Background technology]

[0003] Cocaine use disorder is a complex mental disorder defined according to DSM-5 criteria (i.e., Diagnostic and Statistical Manual of Mental Disorders. 5th Edition, Washington, DC: American Psychiatric Association, 2013) that continues to grow into a significant global health problem with adverse medical, social and economic effects (D. Shorter et al., Expert Opin. Emerging Drugs, 20(1), 2015). Socioeconomic risks associated with cocaine use include increased crime and violence. Adverse medical effects caused by cocaine use include, but are not limited to, cardiovascular disorders (e.g., hypertension, stroke, heart attack, cardiac arrhythmia, cardiomyopathy), gastrointestinal disorders, respiratory disorders (e.g., bronchitis, chest pain), seizures, psychomotor agitation, sleep disorders and psychosis. Cocaine use also affects brain regions involved in cognition (e.g., memory, learning, attention). Further associated health risks include infectious diseases (e.g., Hepatitis B and C or HIV); in fact, any route of cocaine administration can lead to serious medical emergencies that may ultimately be fatal. In addition, patients with cocaine use disorder commonly exhibit comorbid psychiatric disorders.

[0004] The complete biological mechanisms of cocaine dependence are still not fully understood. Therefore, pharmacological treatments for cocaine use disorder focus on the different stages that a patient with cocaine use disorder may experience, thus targeting different aspects, such as: i) attenuating the rewarding effects of cocaine use (e.g., euphoric effects); ii) acting as a "substitution treatment" for cocaine; iii) reducing cocaine withdrawal symptoms (e.g., cocaine craving, anxiety, or depression). D. Shorter et al., Expert Opin. Emerging Drugs, 20(1), 2015. The most promising results have been obtained with desipramine and amantadine, which have been shown to reduce cocaine withdrawal symptoms. In particular, desipramine has been shown to reduce both cocaine use and cocaine craving, however, the reduction in craving occurs only slowly (i.e., over 7-14 days), which leads to high rates of cocaine relapse. Other pharmacological agents that have been tested include GABAergic agents (e.g., topiramate, tiagabine, baclofen, and vigabatrin), replacement agonists (e.g., modafinil, methylphenidate, methadone, buprenorphine), dopaminergic agents (e.g., bupropion, levodopa plus carbidopa, risperidone, olanzapine, aripiprazole, dextroamphetamine), D3 receptor ligands (e.g., CJB090), corticotropin releasing factor (CRF) receptor antagonists (e.g., CP154,526), ​​cannabinoid CB1 receptor antagonists, dual dopamine-serotonin releasing agents (e.g., PAL-287), noradrenergic inducers (e.g., doxazosin, disulfiram, nepicastat), and 5-HT 1AThese include receptor partial agonists (e.g., buspirone), μ opioid agonists (buprenorophine), desipramine and amantadine. However, despite many research efforts in this field, including over 100 clinical trials, no therapeutic medications are currently approved by regulatory agencies (Pharmacol Rev 68:533-562, July 2016; International Journal of Neuropsychopharmacology, 11, 425-438, 2008). In addition, clinical treatment for patients with cocaine use disorder is complicated by the high tendency of these patients to not complete treatment and to relapse.

[0005] Cocaine is one of the most addictive substances of abuse due to its immediate and powerful rewarding effects (e.g., euphoria and increased energy). Cocaine users often increase their doses in an attempt to enhance and prolong the rewarding effects of cocaine. Withdrawal from cocaine use is accompanied by adverse symptoms such as anxiety, depression, pain (e.g., headaches), and cocaine craving, among others. Often prompted by the severe discomfort caused by cocaine withdrawal, patients may revert to cocaine use in an attempt to alleviate the withdrawal symptoms. Finding a pharmacological therapy for the treatment of cocaine use disorder, and in particular, finding a medication that can help achieve or maintain abstinence from cocaine use, is a major challenge and a high medical need.

[0006] In preclinical models, other mGluR5 antagonists such as MPEP [i.e., 2-methyl-6-(2-phenylethynyl)pyridine] and MTEP [i.e., 3-[2-(2-methylthiazol-4-yl)ethynyl]pyridine] have been shown to reduce cocaine self-administration in mice (e.g., Chiamulera, C. et al., Nat. Neurosci. 2001, 4, 873-874) or rats (e.g., Kenny, PJ et al., Behav. Pharmacol. 14, S55; Martin-Fardon R., et al., J. Pharmacol Exp Ther 2009, 329(3):1084). However, neither MTEP nor MPEP have been further developed due to their shortcomings as therapeutic agents (Keck et al., 2013, Psychopharmacology, 229(2):253-65): MTEP, for example, exhibits potent cytochrome P450 1A2 inhibition and rapid metabolism (Smith et al. 2004, Bioorg Med Chem Lett 14:5481-5484), and MPEP, for example, exhibits off-target effects on NMDA receptors, monoamine oxidase, and norepinephrine transporters (Cosford et al., J. Med. Chem., 2003, 46(2), pp 204-206; O'Leary et al., 2000, Br J Pharmacol 131:1429-1437; Heidbreder et al., 2003, Synapse 50:269-276; Lea and Faden, 2006 CNS Drug Rev 12:149-166).

[0007] It has been found that masvoglurant may be an ideal candidate for the treatment of patients diagnosed with cocaine use disorder, as it possesses therapeutic benefits for said patient population, such as one or more of the following: i) mavoglurant promotes cocaine abstinence, e.g., by maintaining abstinence or by reducing the amount or frequency of cocaine use, e.g., compared to placebo, as assessed by urinalysis (e.g., by measuring urinary cocaine metabolites, such as benzoylecgonine) or by using self-reported cocaine use by standardized tools such as timeline followback self-report [Sobell, LC, Sobell, MB (1996) Timeline Followback User's Guide: A Calendar Method for Assessing Alcohol and Drug Use. Addiction Research Foundation, Toronto, Ontario, Canada; J. Anal. Toxicolo., 2002, 26:393-400]; ii) masvoglurant reduces relapse to cocaine use, e.g., compared to placebo, e.g., masvoglurant increases the time to relapse or patient relapse rate in a treatment program, e.g., a clinical trial; iii) Mavoglurant reduces (e.g., by eliminating or reducing the intensity, duration, or frequency of) one or more symptoms associated with cocaine use disorder selected from the following, e.g., compared to a placebo: a. Depressive symptoms, as assessed, for example, by the Beck Depression Inventory [Beck, AT et al., (1961) An inventory for measuring depression. Archives of General Psychiatry, 4, 561-571; Beck, AT et al., (1988) Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clinical Psychology Review, 8(1), 77-100]; and b. For example, the State-Trait Anxiety Inventory [Spielberger, CD (1989). State-Trait Anxiety Inventory: Bibliography (2 nd Anxiety symptoms as assessed by the [Spielberger, CD et al., (1983). Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press]. iv) mavoglurant increases patient retention in treatment, e.g., compared to placebo, e.g., mavoglurant increases patient retention in a treatment program, such as a clinical trial (e.g., as measured by patient attendance at scheduled clinic visits and / or time to drop out of a clinical protocol); v) Mavoglurant improves global functioning as assessed, for example, by the Clinical Global Impression Scale-Severity (CGI-S) and Improvement (CGI-I) (Psychiatry, 2007, 4(7):28-37). vi) mavoglurant has a favorable therapeutic profile, such as a favorable safety profile or metabolic profile, e.g., a favorable profile with respect to psychiatric adverse events, genotoxicity, or cardiovascular adverse events (e.g., blood pressure, heart rate, electrocardiogram parameters); for example, mavoglurant has a favorable therapeutic profile (e.g., fewer side effects, reduced toxicity, such as reduced off-target effects, or reduced genotoxicity) compared to one or more known therapeutic agents that have shown efficacy in treating cocaine use disorder; or vii) Mavoglurant has one or more of the therapeutic benefits i)-vi) as listed above and also reduces alcohol use, e.g., by reducing the amount or frequency of alcohol use, e.g., compared to a placebo, as assessed, e.g., by urinalysis (e.g., measuring alcohol metabolites such as ethyl glucuronide) or by using self-reported alcohol use by standardized tools such as timeline follow-back self-report (J. Anal. Toxicolo 2002, 26:393-400). Summary of the Invention [Means for solving the problem]

[0008] The present invention relates to -In reducing cocaine use by patients with cocaine use disorder; -In preventing relapse to cocaine use by individuals with cocaine use disorder; -In promoting cocaine abstinence in individuals with cocaine use disorder; - in the treatment of depression or anxiety symptoms associated with cocaine use disorder The present invention relates to the use of magoglurant, or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0009] [Figure 1] Cocaine (0.3 mg / kg / infusion, FR5) self-administration learning curves during Phase I. Data represent mean + SEM. N=12 / treatment group. [Diagram 2] Acute effects of masvoglurant on cocaine self-administration in two subcohorts of rats. Data are presented as mean + SEM. Asterisks (***: P<0.001) indicate significant differences compared to saline or vehicle treatment. N=12 / treatment group. [Diagram 3] Acquisition and extinction of cocaine self-administration responding in two subcohorts of rats (Phase II). Data represent mean + SEM. N = 14-15 / group. [Figure 4]Effect of masvoglurant (10 mg / kg, PO, 1 h pretreatment) on reinstatement of cocaine self-administration responding in rats. Data are presented as mean + SEM. Asterisks (***: P < 0.001) indicate significant differences. N = 14–15 / treatment group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The embodiments of the present invention are as follows.

[0011] Embodiment (a): 1a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in reducing cocaine use by a patient with cocaine use disorder.

[0012] 2a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in preventing relapse to cocaine use in a patient with a cocaine use disorder.

[0013] 3a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in facilitating cocaine abstinence by a patient with cocaine use disorder.

[0014] 4a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in the treatment of depressive or anxiety symptoms associated with cocaine use disorder.

[0015] 5a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a-4a, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting), or oral cocaine formulations; in particular associated with cocaine inhalation (i.e. smoking).

[0016] 6a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a-5a, wherein the cocaine use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0017] 7a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 6a, wherein the use is in combination with standardized psychological treatment, for example at individual or population level.

[0018] 8a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 7a, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0019] 9a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 8a, wherein the psychosocial or behavioral therapy is computer-assisted.

[0020] 10a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 9a, wherein the use is carried out in conjunction with methadone or buprenorphine treatment.

[0021] 11a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 10a, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent.

[0022] 12a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 11a, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0023] 13a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a-12a, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0024] 14a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 13a, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form.

[0025] 15a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1a to 14a, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0026] 16a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 15a, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal.

[0027] 17a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 15a or 16a, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration.

[0028] 18a. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0029] Embodiment (b): 1b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient for use in reducing cocaine use in a patient with cocaine use disorder.

[0030] 2b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient for use in preventing relapse to cocaine use in a patient with a cocaine use disorder.

[0031] 3b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use in promoting cocaine abstinence in a patient with cocaine use disorder.

[0032] 4b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient for use in the treatment of depressive or anxiety symptoms associated with cocaine use disorder.

[0033] 5b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b to 4b, wherein the cocaine use disorder is associated with cocaine inhalation (i.e., smoking), intravenous cocaine, cocaine snorting (i.e., snorting), or oral cocaine formulations; in particular with cocaine inhalation (i.e., smoking).

[0034] 6b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b-5b, wherein the cocaine use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0035] 7b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b to 6b, wherein the use is, for example, in combination with standardized psychological treatment at an individual or population level.

[0036] 8b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b to 7b, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0037] 9b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to embodiment 8b, wherein the psychosocial or behavioral therapy is computer-assisted.

[0038] 10b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b to 9b, wherein the use is in parallel with methadone or buprenorphine treatment.

[0039] 11b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to any one of embodiments 1b to 10b, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent.

[0040] 12b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to embodiment 11b, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0041] 13b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for use according to any one of embodiments 1b-12b, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0042] 14b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to any one of embodiments 1b to 13b in immediate release or modified release form.

[0043] 15b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to any one of embodiments 1b to 14b, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0044] 16b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to embodiment 15b, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal.

[0045] 17b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to embodiment 15b or 16b, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration.

[0046] 18b. A pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for use according to any of the preceding embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0047] Embodiment (c): 1c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use in reducing cocaine use in a patient with a cocaine use disorder.

[0048] 2c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use in preventing relapse to cocaine use in a patient with a cocaine use disorder.

[0049] 3c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use in promoting cocaine abstinence by a patient with cocaine use disorder.

[0050] 4c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use in the treatment of depressive or anxiety symptoms associated with cocaine use disorder.

[0051] 5c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 4c, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting), or oral cocaine formulations; in particular with cocaine inhalation (i.e. smoking).

[0052] 6c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c-5c, wherein the cocaine use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0053] 7c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 6c, wherein the use is, for example, in combination with standardized psychological treatment at individual or population level.

[0054] 8c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 7c, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0055] 9c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to embodiment 8c, wherein the psychosocial or behavioral therapy is computer-assisted.

[0056] 10c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 9c, wherein the use is carried out in parallel with methadone or buprenorphine treatment.

[0057] 11c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 10c, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0058] 12c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 11c, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0059] 13c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 12c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form.

[0060] 14c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any one of embodiments 1c to 13c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, e.g. 200 mg / bid.

[0061] 15c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to embodiment 14c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal.

[0062] 16c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to embodiment 14c or 15c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration.

[0063] 17c. A pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for use according to any of the preceding embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0064] Embodiment (d): 1d. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for reducing cocaine use in a patient with cocaine use disorder.

[0065] 2d. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for preventing relapse to cocaine use in a patient with a cocaine use disorder.

[0066] 3d. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for facilitating cocaine abstinence in a patient suffering from cocaine use disorder.

[0067] 4d. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of depression or anxiety symptoms associated with cocaine use disorder.

[0068] 5d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d-4d, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting), or oral cocaine preparations; in particular with cocaine inhalation (i.e. smoking).

[0069] 6d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d-5d, wherein the cocaine use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0070] 7d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 6d, wherein the use is in combination with standardized psychological treatment, for example at individual or population level.

[0071] 8d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 7d, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0072] 9d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to embodiment 8d, wherein the psychosocial or behavioral therapy is computer-assisted.

[0073] 10d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 9d, wherein the use is carried out in parallel with methadone or buprenorphine treatment.

[0074] 11d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 10d, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent.

[0075] 12d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to embodiment 11d, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0076] 13d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 12d, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0077] 14d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 13d, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form.

[0078] 15d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any one of embodiments 1d to 14d, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0079] 16d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to embodiment 15d, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal.

[0080] 17d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to embodiment 15d or 16d, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration.

[0081] 18d. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, according to any of the preceding embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0082] Embodiment (e): 1e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, for the manufacture of a medicament for reducing cocaine use in a patient with cocaine use disorder.

[0083] 2e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for the manufacture of a medicament for preventing relapse to cocaine use in a patient with a cocaine use disorder.

[0084] 3e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for the manufacture of a medicament for facilitating cocaine abstinence in a patient with cocaine use disorder.

[0085] 4e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient, for the manufacture of a medicament for the treatment of depression or anxiety symptoms associated with cocaine use disorder.

[0086] 5e. The use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 4e, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting), or oral cocaine formulations; in particular with cocaine inhalation (i.e. smoking).

[0087] 6e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e-5e, wherein the cocaine use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0088] 7e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient according to any one of embodiments 1e to 6e, wherein the use is, for example, in combination with standardized psychological treatment at individual or population level.

[0089] 8e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 7e, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0090] 9e. The use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to embodiment 8e, wherein the psychosocial or behavioral therapy is computer-assisted.

[0091] 10e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 9e, wherein the use is performed in parallel with methadone or buprenorphine treatment.

[0092] 11e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 10e, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent.

[0093] 12e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient according to embodiment 11e, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0094] 13e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient according to any one of embodiments 1e-12e, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0095] 14e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 13e, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form.

[0096] 15e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to any one of embodiments 1e to 14e, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0097] 16e. The use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to embodiment 15e, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal.

[0098] 17e. Use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient according to embodiment 15e or 16e, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration.

[0099] 18e. The use of a pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, according to any of the previous embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0100] Embodiment (f): 1f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient for the manufacture of a medicament for reducing cocaine use in a patient with a cocaine use disorder.

[0101] 2f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient for the manufacture of a medicament for the prevention of relapse to cocaine use in a patient with a cocaine use disorder.

[0102] 3f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient for the manufacture of a medicament for facilitating cocaine abstinence in a patient with cocaine use disorder.

[0103] 4f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient, for the manufacture of a medicament for the treatment of depression or anxiety symptoms associated with cocaine use disorder.

[0104] 5f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 4f, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting), or oral cocaine preparations; in particular with cocaine inhalation (i.e. smoking).

[0105] 6f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f-5f, wherein the cocaine use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0106] 7f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 6f, wherein the use is, for example, in combination with standardized psychological treatment at individual or population level.

[0107] 8f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 7f, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0108] 9f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to embodiment 8f, wherein the psychosocial or behavioral therapy is computer-assisted.

[0109] 10f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 9f, wherein the use is carried out in parallel with methadone or buprenorphine treatment.

[0110] 11f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 10f, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0111] 12f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 11f, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0112] 13f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1f to 12f, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form.

[0113] 14f. Use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to any one of embodiments 1c to 13c, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, e.g. 200 mg / bid.

[0114] 15f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to embodiment 14f, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal.

[0115] 16f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient according to embodiment 14f or 15f, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, with an interval of 12 hours between each administration.

[0116] 17f. The use of a pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient, according to any of the previous embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0117] Embodiment (g): 1g. A method for reducing cocaine use by a cocaine use disorder patient in need thereof, comprising administering to said cocaine use disorder patient an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof.

[0118] 2g. A method for preventing relapse to cocaine use in a patient with a cocaine use disorder in need thereof, comprising administering to said patient an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof.

[0119] 3g. A method of promoting cocaine abstinence by a cocaine use disorder patient in need thereof, comprising administering to said cocaine use disorder patient an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof.

[0120] 4g. A method for treating depression or anxiety symptoms associated with cocaine use disorder in a cocaine use disorder patient in need thereof, comprising administering to said cocaine use disorder patient an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof.

[0121] 5g. The method of any one of embodiments 1g-4g, wherein the cocaine use disorder is associated with cocaine inhalation (i.e., smoking), intravenous cocaine, cocaine snorting (i.e., snorting), or oral cocaine formulations; in particular with cocaine inhalation (i.e., smoking).

[0122] 6g. The method of any one of embodiments 1g-5g, wherein the cocaine use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0123] 7g. The method according to any one of embodiments 1g to 6g, wherein the administration of mavoglurant, or a pharma- ceutically acceptable salt thereof, is combined with standardized psychological treatment, for example at an individual or population level.

[0124] 8g. The method according to any one of embodiments 1g to 7g, wherein the administration of mavoglurant, or a pharma- ceutically acceptable salt thereof, is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0125] 9g. The method of embodiment 8g, wherein the psychosocial or behavioral therapy is computer-assisted.

[0126] 10g. The method according to any one of embodiments 1g to 9g, wherein the administration of mavoglurant, or a pharma- ceutically acceptable salt thereof, is performed in parallel with methadone or buprenorphine treatment.

[0127] 11g. The method according to any one of embodiments 1g to 10g, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent.

[0128] 12g. The method of embodiment 11g, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0129] 13g. The method of any one of embodiments 1g-12g, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0130] 14g. The method of any one of embodiments 1g-13g, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form.

[0131] 15g. The method according to any one of embodiments 1g to 14g, wherein masvoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0132] 16g. The method according to embodiment 15g, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered with a meal.

[0133] 17g. The method according to embodiment 15g or 16g, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in the morning and in the evening, 12 hours apart. 17g.

[0134] 18g. The method of any of the preceding embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0135] Embodiment (h): 1h. A method for reducing cocaine use in a patient with a cocaine use disorder in need thereof, comprising administering to said patient with a cocaine use disorder a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient.

[0136] 2h. A method for preventing relapse to cocaine use in a patient with a cocaine use disorder in need thereof, comprising administering to said patient with a cocaine use disorder a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient.

[0137] 3h. A method for promoting cocaine abstinence in a patient with a cocaine use disorder in need thereof, comprising administering to said patient with a cocaine use disorder a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient.

[0138] 4h. A method for treating depression or anxiety symptoms associated with cocaine use disorder in a cocaine use disorder patient in need thereof, comprising administering to said cocaine use disorder patient a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one pharma- ceutical acceptable excipient.

[0139] 5h. The method of any one of embodiments 1h-4h, wherein the cocaine use disorder is associated with cocaine inhalation (i.e., smoking), intravenous cocaine, cocaine snorting (i.e., snorting), or oral cocaine formulations; in particular with cocaine inhalation (i.e., smoking).

[0140] 6h. The method of any one of embodiments 1h-5h, wherein the cocaine use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0141] 7h. The method according to any one of embodiments 1h to 6h, wherein the administration of a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, is combined with standardized psychological treatment, e.g., at an individual or population level.

[0142] 8h. The method according to any one of embodiments 1h to 7h, wherein the administration of a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient, is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0143] 9h. The method of embodiment 8h, wherein the psychosocial or behavioral therapy is computer-assisted.

[0144] 10h. The method according to any one of embodiments 1h to 9h, wherein the administration of a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient is performed in parallel with methadone or buprenorphine treatment.

[0145] 11h. The method according to any one of embodiments 1h to 10h, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent.

[0146] 12h. The method of embodiment 11h, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0147] 13h. The method of any one of embodiments 1h-12h, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0148] 14h. The method of any one of embodiments 1h to 13h, wherein the pharmaceutical composition comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient is in immediate release or modified release form.

[0149] 15h. The method according to any one of embodiments 1h to 14h, wherein masvoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0150] 16h. The method according to embodiment 15h, wherein a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient is administered with a meal.

[0151] 17h. The method according to embodiment 15h or 16h, wherein a pharmaceutical composition comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient is administered in the morning and in the evening, with an interval of 12 hours.

[0152] 18h. The method according to any of the preceding embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0153] Embodiment (j): 1j. A method for reducing cocaine use in a patient with a cocaine use disorder in need thereof, comprising administering to said patient with a cocaine use disorder a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one additional pharma- ceutical active ingredient.

[0154] 2j. A method for preventing relapse to cocaine use in a patient with a cocaine use disorder in need thereof, comprising administering to said patient with a cocaine use disorder a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one additional pharma- ceutical active ingredient.

[0155] 3j. A method for promoting cocaine abstinence in a cocaine use disorder patient in need thereof, comprising administering to said cocaine use disorder patient a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one additional pharma- ceutical active ingredient.

[0156] 4j. A method for treating depression or anxiety symptoms associated with cocaine use disorder in a cocaine use disorder patient in need thereof, comprising administering to said cocaine use disorder patient a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one additional pharma- ceutical active ingredient.

[0157] 5j. The method of any one of embodiments 1j-4j, wherein the cocaine use disorder is associated with cocaine inhalation (i.e., smoking), intravenous cocaine, cocaine snorting (i.e., snorting), or oral cocaine formulations; in particular with cocaine inhalation (i.e., smoking).

[0158] 6j. The method of any one of embodiments 1j-5j, wherein the cocaine use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0159] 7j. The method according to any one of embodiments 1j to 6j, wherein the administration of a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is combined with standardized psychological treatment, e.g., at an individual or population level.

[0160] 8j. The method according to any one of embodiments 1j to 7j, wherein the administration of a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0161] 9j. The method of embodiment 8j, wherein the psychosocial or behavioral therapy is computer-assisted.

[0162] 10j. The method of any one of embodiments 1j-9j, wherein administration of a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutical acceptable salt thereof, and at least one further pharma- ceutical active ingredient is performed in parallel with methadone or buprenorphine treatment.

[0163] 11j. The method of embodiment 10j, wherein the further active agent is selected from a GABAergic agent (such as topiramate, baclofen or tiagabine) or a dopamine agent (such as bupropion, a combination of L-dopa and carbidopa).

[0164] 12j. The method of any one of embodiments 1j-11j, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0165] 13j. The method according to any one of embodiments 1j to 12j, wherein the pharmaceutical combination comprising mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is in immediate release or modified release form.

[0166] 14j. The method according to any one of embodiments 1j to 13j, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0167] 15j. The method according to embodiment 14j, wherein the pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is administered with a meal.

[0168] 16j. The method according to embodiment 14j or 15j, wherein a pharmaceutical combination comprising an effective amount of mavoglurant, or a pharma- ceutically acceptable salt thereof, and at least one further pharma- ceutical active ingredient is administered in the morning and evening, with an interval of 12 hours.

[0169] 17j. The method of any of the preceding embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0170] Further embodiments: Embodiment 1: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in reducing cocaine use in a patient with a cocaine use disorder.

[0171] Embodiment 2: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in preventing relapse to cocaine use in a patient with a cocaine use disorder.

[0172] Embodiment 3: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in facilitating cocaine abstinence in a patient with a cocaine use disorder.

[0173] Embodiment 4: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use in treating depressive or anxiety symptoms associated with cocaine use disorder.

[0174] Embodiment 5: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1-4, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting), or oral cocaine formulations; in particular associated with cocaine inhalation (i.e. smoking).

[0175] Embodiment 6: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1-5, wherein the cocaine use disorder is coexistent with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

[0176] Embodiment 7: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1 to 6, wherein the use is in combination with standardized psychological treatment, for example at individual or population level.

[0177] Embodiment 8: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1 to 7, wherein the use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0178] Embodiment 9: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to embodiment 8, wherein the psychosocial or behavioral therapy is computer-assisted.

[0179] Embodiment 10: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1 to 9, wherein the use is carried out in parallel with methadone or buprenorphine treatment.

[0180] Embodiment 11: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1 to 10, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent.

[0181] Embodiment 12: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1 to 11, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0182] Embodiment 13. Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1 to 12, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form.

[0183] Embodiment 14: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any one of embodiments 1 to 13, wherein the mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0184] Embodiment 15: Mavoglurant, or a pharma- ceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the cocaine use disorder is associated with recreational drinking.

[0185] Embodiment 16: Mavoglurant, or a pharma- ceutically acceptable salt thereof, in combination with a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), an agonist replacement agent (e.g., modafinil, methylphenidate, methadone, or buprenorphine), a dopaminergic agent (e.g., bupropion, a combination of levodopa and carbidopa, risperidone, olanzapine, aripiprazole, or dextroamphetamine), a D3 receptor ligand (e.g., CJB090), a corticotropin-releasing factor (CRF) receptor antagonist (e.g., CP154,526), ​​a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releaser (e.g., PAL-287), a noradrenergic inducer (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1ACombinations comprising at least one further active agent selected from the group consisting of a receptor partial agonist (e.g., buspirone), a μ opioid agonist (e.g., buprenorophine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharmaceutically acceptable salt thereof.

[0186] common terms The term "cocaine use disorder" or "CUD" as used herein is defined according to DSM-5 criteria (i.e., in accordance with the Diagnostic and Statistical Manual of Mental Disorders. 5th Edition, Washington, DC: American Psychiatric Association, 2013), the entire contents of which are incorporated herein by reference. As used herein, the term "cocaine use disorder" is defined as a problematic pattern of cocaine use leading to clinically significant impairment or distress occurring within a 12-month period, as manifested by at least two of the following: 1) Cocaine is often taken in larger amounts or for a longer period than intended. 2) Persistent craving for cocaine use or unsuccessful efforts to reduce or suppress it. 3) A large amount of time is spent in activities necessary to obtain cocaine, to use cocaine, or to recover from its effects. 4) Craving or strong desire or urge to use cocaine. 5) Recurrent cocaine use that interferes with fulfilling major role responsibilities at work, school, or home. 6) Continued cocaine use despite persistent or recurring social or interpersonal problems caused or exacerbated by the effects of cocaine. 7) Important social, occupational, or recreational activities are abandoned or diminished due to cocaine use. 8) Repeated cocaine use in physically dangerous situations. 9) Cocaine use continues despite knowledge of persistent or recurring physical or psychological problems likely caused or exacerbated by cocaine. 10) Tolerance as defined by any of the following: a) the need for significantly increased amounts of cocaine to achieve a state of intoxication or the desired effect; b) a significantly decreased effect with the same amount of cocaine used regularly. 11) Withdrawal, as manifested by any of the following: a) Cocaine-specific withdrawal syndrome: i) Cessation (or reduction) of cocaine use over time; ii) Dysphoric mood and two (or more) of the following physiological changes occurring within hours to days after cessation (or reduction) of cocaine use: fatigue; vivid and unpleasant dreams; insomnia or hypersomnia; increased appetite; psychomotor slowing or agitation. b) Cocaine is taken to reduce or avoid withdrawal symptoms.

[0187] "Cocaine use disorder" can be divided into three categories: mild (i.e., 2-3 symptoms as defined according to DSM-5 criteria), moderate (i.e., 4-5 symptoms as defined according to DSM-5 criteria), and severe (i.e., 6 or more symptoms as defined according to DSM-5 criteria). In one embodiment, "cocaine use disorder" as used herein refers to "mild cocaine use disorder", "moderate cocaine use disorder", and "severe cocaine use disorder". In a further embodiment, "cocaine use disorder" as used herein refers to "mild cocaine use disorder", "moderate cocaine use disorder", or "severe cocaine use disorder".

[0188] The term "cocaine use disorder patient" refers to a patient diagnosed with CUD as defined herein. In one embodiment, the term "cocaine use disorder patient" refers to a patient diagnosed with CUD who is abstaining from cocaine, for example, for at least one day, for example, three or more days. The term "cocaine use disorder patient abstaining from cocaine" refers to a patient diagnosed with CUD who is abstaining from cocaine for a period of time, for example, for at least one day. The term "cocaine use disorder associated with recreational drinking" refers to a patient who has been diagnosed with cocaine use disorder and who is an alcohol abuser (i.e., a heavy drinker). As explained at http: / / drugabuse.com / library / alcohol-abuse / , an alcohol abuser may not drink alcohol all the time, for example, only once a week, but when they do drink, they may drink heavily, which causes problems, such as developing alcoholism. For purposes of clarity, as used herein, an alcohol abuser is not an individual with an alcohol use disorder (i.e., does not meet criteria for an alcohol use disorder as defined according to DSM-5 criteria). The term "heavy drinker" refers to an individual with a pattern of heavy alcohol use. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the Substance Abuse and Mental Health Services Administration (SAMHSA) defines "heavy alcohol use" as recreational drinking on 5 or more days in the past month. The NIAAA defines recreational drinking as a pattern of drinking that leads to a blood alcohol concentration (BAC) value of 0.08 g / dL. This typically occurs after 4 alcoholic drinks for women and 5 alcoholic drinks for men in approximately 2 hours.The Substance Abuse and Mental Health Services Administration (SAMHSA) defines "recreational drinking" as 5 or more alcoholic drinks for men or 4 or more alcoholic drinks for women on the same occasion (i.e., at the same time or within a few hours of each other) on at least one day in the past month. The term "alcohol", as used herein with reference to, for example, a "drink", an "alcoholic drink", or "alcoholic drink", refers to ethyl alcohol (i.e., ethanol). The terms "alcoholic drink", "drink", or "alcoholic drink", as used herein, are understood in the context of a "standard drink", such as a distilled spirit or blend intended for human consumption, where a "standard drink" is equal to 12 grams ethanol.

[0189] The term "cocaine" as used herein refers to cocaine itself (free base benzoylmethylecgonine), its salts such as cocaine hydrochloride, or cocaine preparations such as coca leaves, coca paste, and cocaine alkaloids (such as crack), where cocaine is the active ingredient in all forms of the substance. The term "cocaine craving" as used herein refers to a conscious desire or urge to consume cocaine.

[0190] The term "cocaine use," as used herein, refers to cocaine consumption.

[0191] The terms "reducing cocaine use" or "reducing cocaine use" as used herein refer to a reduction in the amount or frequency of cocaine use as assessed, for example, by urinalysis (e.g., by measuring urinary cocaine metabolites, such as benzoylecgonine) or by using self-reported cocaine use by standardized tools such as the Timeline FollowBack Self-Report (Sobell LC, Sobell MB, 1996, Timeline FollowBack user's guide: A calendar method for assessing alcohol and drug use. Addiction Research Foundation, Toronto, Ontario, Canada; J. Anal. Toxicolo., 2002, 26:393-400).

[0192] The term "cocaine abstinence" or "abstinent from cocaine," as used herein, refers to not taking cocaine. The term "facilitating cocaine abstinence" or "facilitating cocaine abstinence," as used herein, refers to helping maintain abstinence from cocaine use, especially after at least one day of not taking cocaine, e.g., helping to maintain abstinence from cocaine use for a period of at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months or more, especially at least 1 week or more, e.g., 2 weeks.

[0193] The term "cocaine use relapse" or "cocaine consumption relapse", as used herein, refers to cocaine intake (i.e., taking cocaine) after a period of cocaine abstinence, e.g., after at least one day or more, e.g., 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months or more of cocaine abstinence.

[0194] The term "preventing cocaine use relapse" or "preventing cocaine consumption relapse" as used herein refers to the prevention of cocaine intake by a CUD patient after the patient has stopped taking cocaine, particularly after one or more days of not taking cocaine. In some embodiments, the term encompasses permanent cessation of cocaine intake. In other embodiments, the term encompasses a delay in resumption of cocaine intake as compared to the time to resumption by a subject not administered a compound of the invention. The delay in relapse may be, for example, several days (e.g., 2, 3, 4, 5, 6, 7 days), several weeks (e.g., 1, 2, 3 weeks), several months (e.g., 1, 2, 3, 4, 5, 6 months), or longer.

[0195] The term "psychosocial or behavioral therapy" as used herein includes, but is not limited to, cognitive behavioral therapy (e.g., as described in Arch. Gen. Psychiatry 1999;56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009;23(1):168-174), contingency management-based therapy (e.g., as described in Psychol Addict Behav 2009;23(1):168-174; J. Consul. Clin. Psychol. 2005;73(2):354-59; or Case Reports in Psychiatry, Vol. 2012, Article ID 731638), community reinforcement approach-based therapy (e.g., Drug Alcohol Dependence Therapy, Vol. 2012, Article ID 731638), and therapies based on the psychiatric treatment (e.g., Drug Alcohol Dependence Therapy, Vol. 2012, Article ID 731638). 2004;74:1-13), motivational interviewing-based therapies (e.g. as described in J. Consul. Clin. Psychol. 2001;69(5):858-62), motivational enhancement-based therapies (e.g. as described in Drug Alcohol Depend 2007,91:97-101) or meditation-based therapies, such as transcendental meditation-based therapies (e.g. as described in Addiction 2004;99(7):862-874 or J. Consul. Clin. Psychol. 2000;68(3):515-52); in particular contingency management-based therapies.

[0196] The terms "standardized psychological treatment" or "standardized psychological support" as used herein refer to standard counseling sessions, e.g., once a week, particularly counseling focused on cocaine consumption.

[0197] The term "computer-assisted" in the phrase "psychosocial or behavioral therapy is computer-assisted" as used herein refers to psychosocial or behavioral therapy that includes the use of electronic tools, such as online tools, smartphones, wireless devices, or health applications. In one embodiment, the term "computer-assisted" in the phrase "psychosocial or behavioral therapy is computer-assisted" as used herein should be understood as "computer-implemented" (i.e., the psychosocial or behavioral therapy is computer-implemented).

[0198] The term "administered with a meal" refers to any food with caloric content, e.g., solid or liquid. A dosage of mavoglurant, or a pharma- ceutically acceptable salt thereof, may be administered to a subject, e.g., 30 minutes before a meal to, e.g., 1 hour after a meal. In particular, administration of mavoglurant, or a pharma- ceutically acceptable salt thereof, occurs immediately after a meal to up to about 30 minutes after a meal.

[0199] The term "genetic variation" refers to a change in a gene sequence compared to a reference sequence (e.g., a commonly found and / or wild type sequence). A genetic variation can be a recombination event or a mutation, such as a substitution / deletion / insertion event, such as a point mutation and a splice site mutation. In one embodiment, the genetic variation is a genetic variation of mGluR5.

[0200] The terms "treat," "treating," "treatment," or "therapy," as used herein, mean to achieve a beneficial or desired result, e.g., a clinical result. A beneficial or desired result can include, but is not limited to, the alleviation of one or more symptoms, such as anxiety or depression symptoms associated with cocaine use disorder, by a patient with cocaine use disorder, as defined herein, particularly a patient with cocaine use disorder abstinent from cocaine, as defined herein. One aspect of treatment, for example, is that the treatment should have minimal adverse effects on the patient, e.g., the drug used should have a high safety level, e.g., without causing side effects of previously known treatment regimens. The term "alleviation," as used herein, e.g., with respect to symptoms of a condition, refers to reducing at least one of the frequency and breadth of the symptoms of the condition in the patient.

[0201] The term "concurrent" as used herein refers to both simultaneous and sequential administration, for example, with respect to "concurrent with methadone or buprenorphine treatment."

[0202] As used herein, the term "subject" refers to a mammalian organism, preferably a human being, male or female.

[0203] As used herein, the term "patient" refers to a subject suffering from a disease and who may benefit from treatment.

[0204] As used herein, a subject is "in need of" a treatment if such subject (patient) would benefit biologically, medically, or in terms of quality of life from the treatment.

[0205] The term "pharmaceutical composition" is defined herein to refer to a mixture or solution containing at least one active ingredient or therapeutic agent that is administered to a subject to treat a particular condition (i.e., a disease, disorder or condition or at least one of its clinical symptoms) that affects the subject.

[0206] As used herein, the term "pharmaceutically acceptable excipient" includes any solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as would be known to one of skill in the art (see, e.g., Remington's Pharmaceutical Sciences, 22). nd (See Ed. Mack Printing Company, 2013, pp. 1049-1070.) Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0207] The terms "drug", "active substance", "active ingredient", "pharmaceutical active ingredient", "active agent" or "therapeutic agent" should be understood to mean a compound in free form or in the form of a pharmaceutically acceptable salt, particularly a compound of the type specified herein. In particular, reference to mavoglurant, or a pharmaceutically acceptable salt thereof, in combination with a further active agent as used herein (e.g., in any of the above embodiments (a)-(j) or in any of the claims below) includes a GABAergic agent (e.g., topiramate, tiagabine, baclofen or vigabatrin), an agonist replacement agent (e.g., modafinil, methylphenidate, methadone or buprenorphine), a dopamine-based agent (e.g., bupropion, levodopa plus carbidopa combination, risperidone, olanzapine, aripiprazole, or dextroamphetamine), D3 receptor ligands (e.g., CJB090), corticotropin releasing factor (CRF) receptor antagonists (e.g., CP154,526), ​​cannabinoid CB1 receptor antagonists, dual dopamine-serotonin releasing agents (e.g., PAL-287), noradrenergic inducers (e.g., doxazosin, disulfiram, or nepicastat), 5-HT 1AIt refers to masvoglurant in combination with at least one further active agent selected from a receptor partial agonist (e.g., buspirone), a μ opioid agonist (e.g., buprenorophine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharmaceutically acceptable salt thereof.

[0208] The term "immediate release form" refers to a pharmaceutical composition designed to release an active agent immediately after administration in vivo.

[0209] The term "modified release form" refers to a pharmaceutical composition that does not release an active agent immediately, but rather provides a sustained, delayed, continuous, gradual, extended or pulsed release, thus characteristically altering drug plasma levels compared to immediate release forms. The term "modified release form" includes controlled release forms, sustained release forms, extended release forms, and long acting forms; particularly forms described as sustained release forms.

[0210] The term "combination" or "pharmaceutical combination" refers to either a mixed combination in one unit dosage form (e.g., capsule, tablet, caplet, or granule), a non-mixed combination, or a kit-of-parts for combination administration, wherein a compound of the present invention and one or more combination partners (e.g., another drug as specified herein, also referred to as a "pharmaceutical active ingredient," "therapeutic agent," or "co-drug") may be administered independently simultaneously or separately within time intervals, particularly those time intervals that allow the combination partners to exhibit a cooperative effect, e.g., a synergistic effect. The terms "co-administration" or "co-administration," and the like, as used herein, are meant to encompass administration of selected combination partners to a single subject (e.g., patient) in need thereof, and are intended to include therapeutic regimens in which the agents are not necessarily administered by the same route of administration or are not administered simultaneously. The term "mixed combination" means that the active ingredients, e.g., a compound of the present invention, and one or more combination partners are both administered simultaneously to a patient in the form of a single entity or dosage. The term "non-multidrug combination" means that the active ingredients, e.g., a compound of the present invention and one or more combination partners, are either both administered simultaneously to a patient as separate entities or administered sequentially without any particular time limit, where such administration provides therapeutically effective levels of the two compounds in the patient's body.

[0211] The compounds of the present invention may be administered separately by the same or different routes of administration, or together in the same pharmaceutical composition as the other agent. In the combination therapy of the present invention, the compounds of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention and the other therapeutic agent may be combined into a combination therapy: (i) before release of the combination product to the physician (e.g., in the case of a kit containing the compounds of the present invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; (iii) within the patient's own body, for example, during sequential administration of the compounds of the present invention and the other therapeutic agent.

[0212] As used herein, the terms "a," "an," "the," and similar terms used in connection with the present invention (particularly in connection with the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0213] Any examples provided herein, or the use of illustrative language (e.g., "such as"), are intended merely to better clarify the invention, and do not pose limitations on the scope of the invention as originally claimed.

[0214] As used herein, the compound of the present invention, also known as Compound (I), as used herein above and hereinafter, has the formula: [ka] The mGluR5 antagonist (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester, also referred to as (-)-(3aR,4S,7aR)-4-hydroxy-4-[2-(3-methylphenyl)ethynyl]perhydroindole-1-carboxylic acid methyl ester, also known as mavoglurant, can be prepared, for example, as described in WO 2003 / 047581, for example in Example 1, or as described in WO 2010 / 018154. WO 2003 / 047581 (incorporated herein by reference) also describes its in vitro biological data, as per page 7. As used herein, "mavoglurant" refers to the free form, and any reference to "a pharma- ceutically acceptable salt thereof" refers to a pharma- ceutically acceptable acid addition salt thereof. Thus, as used herein, the term "mavoglurant, or a salt thereof, e.g., a pharma- ceutically acceptable salt thereof," as used in the context of the present invention (particularly in the context of any of the above or following embodiments and claims), should be construed to encompass both the free form and a pharma- ceutically acceptable salt thereof, unless otherwise indicated herein.

[0215] In one embodiment, compound (I) is also intended to represent an isotopically labeled form. Isotopically labeled compounds have the structure depicted in the formula above, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, i.e., the formula: [ka] [In the formula, each R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 are independently selected from H or deuterium; provided that at least one deuterium is present in the compound. In other embodiments, multiple deuterium atoms are present in the compound.

[0216] In addition, certain isotopes, especially deuterium (i.e. 2 Incorporation of H or D) may provide certain therapeutic advantages resulting from increased metabolic stability, for example increased in vivo half-life or reduced dosage requirements or improved therapeutic index or tolerability. It is understood that deuterium in this context is considered a substituent of the compounds of the present invention. The concentration of deuterium may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a designated isotope. When a substituent in a compound of the present invention is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0217] Other examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen other than deuterium, isotopes of carbon, nitrogen, oxygen, and fluorine, e.g., 3 H, 11 C. 13 C.14 C. 15 N, 18 F. Thus, the present invention relates to, for example, 3 H and 14 Radioisotopes such as C, or 2 H and 13 It should be understood that the present invention includes compounds incorporating one or more of any of the aforementioned isotopes, including those in which a non-radioactive isotope such as C is present. Such isotopically labeled compounds may be used for metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. In particular, PET or SPECT studies include 18 F or labeled compounds may be particularly desirable. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to the described preparations of the compounds of the invention, by substituting the appropriate isotopically labeled reagent for the non-labeled reagent previously used.

[0218] As used herein, the term "free form" or "free forms" refers to a compound in a non-salt form, such as the base free form or the acid free form of the respective compound, e.g., a compound specified herein (e.g., mavoglurant or a further pharma- ceutical active ingredient, e.g., as defined herein).

[0219] As used herein, the term "salt", "salts" or "salt form" refers to an acid addition salt or a base addition salt of the respective compound, for example, a compound specified herein (e.g., mavoglurant or a further medicament active ingredient, e.g., as defined herein). "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound, which are typically not biologically or otherwise undesirable. A compound as specified herein (e.g., mavoglurant or a further medicament active ingredient, e.g., as defined herein) may be capable of forming acid salts and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. The compounds of the present invention are capable of forming acid addition salts, and therefore, as used herein, the term pharmaceutically acceptable salts of mavoglurant means pharmaceutically acceptable acid addition salts of mavoglurant.

[0220] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0221] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0222] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0223] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0224] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of Groups I to XII of the Periodic Table, in certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts.

[0225] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Some organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0226] Pharmaceutically acceptable salts can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of the compound with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base form of the compound with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where feasible. Further lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 22 nd edition, Mack Publishing Company (2013); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, 2011, 2 nd For more information, please refer to the IEEE International Conference on Statistical English (ISI) .

[0227] The compounds specified herein (e.g., mavoglurant or further medicament active ingredients, e.g., as defined herein) can be administered by conventional routes, in particular orally, such as in the form of tablets, capsules, caplets or granules, which can be prepared according to pharmaceutical techniques as known in the art (see, e.g., "Remington Essentials of Pharmaceutics, 2013, 1 st Edition, edited by Linda Felton, Pharmaceutical Press 2012, ISBN 978 0 85711 105 0; in particular Chapter 30), where pharmaceutical excipients are, for example, those described in “Handbook of Pharmaceutical Excipients, 2012, 7 th Edition, edited by Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton, ISBN 978 0 85711 027 5. In particular, WO 2014 / 199316 describes formulations comprising mavoglurant, in particular modified release formulations thereof, and more particularly the Examples, Detailed Description and Claims therein are incorporated herein by reference.

[0228] The pharmaceutical composition or combination of the present invention may be in a unit dosage form (e.g., tablet, capsule, caplet or granule) containing 1 mg to 300 mg, in particular 50 mg to 200 mg, for example 50 mg to 100 mg, more particularly 200 mg, of mavoglurant (based on the amount of mavoglurant in free form, if a salt thereof is used, this amount will be adapted accordingly; in particular mavoglurant is in free form). For the above-mentioned uses / treatment methods, the appropriate dosage may vary depending on various factors, such as age, weight, sex, route of administration or salt used. For example, for a patient weighing 50 to 70 kg, the indicated daily dosage is, for example, 200 mg / bid (based on the amount of mavoglurant in free form, if a salt thereof is used, this amount will be adapted accordingly).

[0229] Abbreviation BE=benzoylecgonine EtG = ethyl glucuronide CM = Contingency Management DSM 5=Diagnostic and Statistical Manual of Mental Disorders,5th Ed CUD = Cocaine Use Disorder PK = pharmacokinetics TLFB=Timeline Follow Back mg = milligrams bid=bid=twice a day (2 times) mmHg = millimeter of mercury msec=milliseconds HIV = Human Immunodeficiency Virus ELISA = Enzyme-Linked Immunosorbent Assay ECG = electrocardiogram QT = time between the beginning of the Q wave and the end of the T wave T wave = positive deflection after each QRS complex ST wave = the time between the start of the S wave and the end of the T wave QRS = time between the start of the Q wave and the end of the T wave QTcF = Fridericia QT correction formula SoA=standard of care SSRI = selective serotonin reuptake inhibitors C-SSRS = Columbia Suicide Severity Rating Scale hCG = human chorionic gonadotropin AST = aspartate aminotransferase ALT = alanine aminotransferase ULN = upper limit of normal GGT = gamma-glutamyl transpeptidase AV block = atrioventricular block UDS=urine drug screen MDMA = 3,4-methylenedioxy-methamphetamine MDEA = 3,4-methylenedioxy-N-ethylamphetamine MDA = 3,4-methylenedioxy-amphetamine EXAMPLES

[0230] The following examples are provided to illustrate the present invention without limiting its scope. The term "mavoglurant" as used in connection with these examples refers to the free form.

[0231] Example 1: Determining the Effects of Mavoglurant on Cocaine Dependence and Cocaine Reinstatement Using an Intravenous Self-Administration Model in Sprague-Dawley Rats animal Adult male Sprague-Dawley rats (300-325 g on arrival) from Harlan Laboratory (Indiana, USA) were used. Upon arrival, rats were assigned a unique identification number (appended to the tail). Animals were housed singly in suspended filter-top polycarbonate rat cages and allowed to acclimate for a maximum of 7 days. All rats were examined, handled, and weighed to ensure adequate health and fitness prior to the start of the study. A 12-h / 12-h light / dark cycle was maintained throughout the course of the study. Room temperature was maintained at 21-23°C, with relative humidity at 30-70%. Water was available ad libitum for the duration of the study.

[0232] Test Compounds Cocaine hydrochloride (Sigma-Aldrich, USA) (1.05 mg / ml, which corresponds to 0.3 mg / kg / infusion at 350 g body weight and 0.1 ml / infusion rate) was dissolved in saline (0.9% NaCl). The preparation was a clear solution.

[0233] Mavoglurant (free form) was formulated in 0.5% methylcellulose (MC) at 1, 3 and 10 mg / kg and administered orally in a dose volume of 1 ml / kg 60 minutes prior to testing.

[0234] Device Intravenous drug self-administration was performed in sound-attenuated operant chambers (Med Associates, VT) equipped with a ventilator. Each chamber contained two levers located on one wall of the chamber. Only one of the two levers was active (located on the left side). Pressing the active lever resulted in delivery of a reinforcer (food or cocaine). The other lever was "inactive," i.e., no reinforcement was delivered when pressed. Stimulus lights were located above each lever, but only the stimulus light above the active lever was on during the time-out period (defined below). A room light (providing illumination) was located on the opposite wall. For food training (see details below), a pellet container for delivery of pellet food (Bio-Serv's Dustless Precision Pellets #F0165, 45 mg) was placed between the two levers. Drug solutions were delivered from an infusion pump mounted above each chamber via Tygon tubing connected to a single channel fluid swivel, which was mounted on a balance arm above the operant chamber. The output of the fluid swivel was attached to the external end of the intravenous catheter.

[0235] method Phase I: Acute effects of mavoglurant on cocaine self-administration in rats Dietary training and surgery Prior to intravenous catheterization surgery, rats were trained to press an active lever to obtain food. Food training began after the rats were food-restricted to approximately 85% of their free-feeding body weight. After acquisition of the lever-press response to obtain food, rats were implanted with an internal jugular catheter (Access Technologies, USA). The catheter was flushed daily with 0.2 ml heparin-enrofloxacin solution to prevent clogging and ensure smooth drug infusion. The flush solution was made up in 50 ml volumes and contained 1500 U heparin and 320 mg enrofloxacin (Baytril®). The solution was stored in a 4°C refrigerator in sterile vials. Rats were allowed to eat ad libitum for 2 days before surgery and throughout their recovery.

[0236] The test used methohexital sodium (Brevital®, Henry Schein Animal Health, USA) to confirm proper infusion from the implanted catheter. Brevital is a short-acting barbiturate that produces obvious signs of sedation within seconds of infusion from the catheter. Brevital testing (0.2 ml of a 1% solution) was performed after both acquisition sessions and after the compound test session in Phase I. Animals that did not show immediate signs of sedation were removed from the study.

[0237] Acquisition of cocaine self-administration responses One week after surgery, singly housed rats were food restricted and maintained at approximately 85% of their free-feeding age-matched control weights throughout the study. Rats were then allowed to self-administer cocaine by pressing the active lever on a fixed ratio (FR) schedule of reinforcement. In this study, an FR5 schedule was used, i.e., one cocaine dose was given for every 5 lever presses. The dose of cocaine was 0.3 mg / kg / injection (this equates to 0.105 mg per rat (350 g) per injection (0.1 ml solution)). Each cocaine injection lasted 1.0 s. Cocaine delivery was followed by a 20 s time-out period during which no drug was delivered if the active lever was pressed. During the time-out, the stimulus light above the active lever was on. After 15 days of training, all rats showed a high and stable number of lever presses for cocaine. Each training or test session lasted 1 h.

[0238] Pharmacological treatment with mavoglurant After a stable cocaine self-administration baseline was established (daily drug infusions varying less than 20% over three consecutive days; a minimum of six drug infusions per session), pharmacological testing began. Pharmacological testing occurred twice weekly (usually Wednesdays and Fridays) while maintaining baseline cocaine training on the other days. N=12 medium Mavoglurant 1mg / kg Mavoglurant 3mg / kg Mavoglurant 10mg / kg

[0239] Phase II: Effects of mavoglurant on cue-induced reinstatement of self-administration responding Dietary training and surgery The methods of feeding training, catheter procedure, flushing and injection confirmation were the same as in Phase I.

[0240] Learning Cocaine self-administration training in this stage was conducted in a separate cohort of rats (N=32). The training method was the same as in Phase I, except that a cue (light flash + tone) was presented simultaneously during cocaine infusion and the cue light remained on for a 20-s time-out period. As in Phase I, rats underwent 15 days of acquisition training.

[0241] Extinction and cue-induced reinstatement After stable rates of cocaine self-administration were achieved, rats underwent a 9-day extinction procedure, which was similar to acquisition training, except that pressing the active lever resulted in an infusion of saline instead of cocaine. No cues were presented after pressing the active lever during the extinction session. All rats reached extinction criterion (≤5 infusions, i.e., <30 active lever responses in a 1-h session) by the 9th (and final) day of extinction training.

[0242] During the reinstatement session, which took place the day after the final extinction session, rats were presented with a cue (flash + tone) at the beginning of the session and their lever-pressing responses were recorded. During this reinstatement session, there were no cocaine infusions and subjects received only saline on a FR5 schedule. The study used an independent-group design, i.e., approximately half of the rats (N = 15 after infusion confirmation) received the optimal dose of mavoglurant before the reinstatement session and approximately half (N = 14 after infusion confirmation) received vehicle. Based on the results of Phase I, the optimal dose of mavoglurant to be used in Phase II was 10 mg / kg.

[0243] result Phase I: Acute effects of masvoglurant on cocaine self-administration Acquiring Cocaine Dependence Acquisition of cocaine self-administration responses during Phase I is shown in Figure 1. The study included 12 rats per group after confirmation of adequate infusion of Brevital. Cocaine self-administration steadily increased during the first week of training and stabilized during the second week of training. A two-way ANOVA confirmed learning (training day effect: F[14,330] = 6.199; P < 0.001). There was also a significant group × day interaction (F[1,330] = 4.850, P < 0.05), however post hoc comparisons did not show significant differences between groups on each training day, thus confirming equivalence of self-administration performance between groups (subcohorts).

[0244] Acute Effects of Mavoglurant on Cocaine Self-Administration For subcohort Ib, one-way ANOVA with repeated measures confirmed a significant effect of mavoglurant [treatment effect: F(3,33)=6.358; P<0.01]. Post hoc comparisons further confirmed that mavoglurant tended to reduce responding on the active lever at 3 mg / kg (p<0.10) and significantly reduced responding at 10 mg / kg (p<0.001).

[0245] Phase II: Effects of mavoglurant on cue-induced reinstatement of self-administration Acquisition and extinction of cocaine dependence Acquisition of cocaine self-administration responses is shown in Figure 3. These two groups (subcohorts) included 14 and 15 rats after confirmation of adequate infusion of Brevital. As in Phase I, cocaine self-administration steadily increased during the first week of training and stabilized during the second week of training. Two-way ANOVA confirmed a significant effect of training days (F[14,405] = 3.463; P < 0.001) and no differences between subcohorts (F[1,405] = 1.538, ns), indicating comparable learning performance between groups.

[0246] During the extinction phase, there was a progressive and significant decrease in responding on the active lever, which was confirmed by a two-way ANOVA (effect of days: F[8,243] = 41.635; P < 0.001). There was also a significant main effect of subcohort (F[1,243] = 5.306, P < 0.05), however post hoc comparisons indicated comparable performance between groups in each extinction session. All rats reached extinction criterion by training day 9.

[0247] Cue-induced reinstatement of self-administration responding The effects of vehicle and mavoglurant (10 mg / kg, PO, 1 h before testing) on ​​cue-induced reinstatement of self-administration responding are shown in Figure 4. Two-way ANOVA confirmed a significant effect of session (extinction vs. reinstatement, F[1,54] = 12,690; P < 0.001), a significant effect of treatment (vehicle vs. mavoglurant, F[1,54] = 8.194; P < 0.01), and a significant treatment × session interaction (F[1,54] = 12,805; P < 0.001). Post hoc analysis showed that the session effect was only attributable to the vehicle treatment, i.e., the cue induced significant reinstatement of active lever pressing (P < 0.001), but cue-induced reinstatement was suppressed in mavoglurant-treated rats.

[0248] Conclusion: This study examined the efficacy of mavoglurant in a rat model of cocaine self-administration and reinstatement of cocaine taking (i.e., cue-induced reinstatement).Mavoglurant (10 mg / kg, PO, 1 h before testing) significantly reduced cocaine self-administration in rats.

[0249] Furthermore, after extinction of self-administration responding, mavoglurant (10 mg / kg, PO, 1 h before testing) completely prevented cue-induced reinstatement of self-administration responding.

[0250] In conclusion, this study demonstrated that masvoglurant was effective in a rat cocaine self-administration model as well as in a relapse model.

[0251] Example 2: Placebo-controlled trials in patients with CUD

[0252] [Table 1]

[0253] [Table 2]

[0254] Study design This is a randomized, subject- and investigator-blinded, parallel-group, placebo-controlled study in patients with CUD. The study will consist of a screening period of approximately 21 days, followed by a 7-day baseline; a 98-day outpatient treatment period (14 days of an uptitration dose regimen, followed by an 84-day maintenance dose), and finally an end-of-study visit assessment approximately 14 days after the last study drug administration. The total duration of each patient in the study will be up to approximately 20 weeks. The study design is summarized in Scheme 1.

[0255] [Table 3]

[0256] Study Visits: (Days 1-112) Study visits will be conducted twice weekly in an outpatient setting. During these visits, urine samples will be collected for drug screening (cocaine BE and other drug metabolites) along with safety / efficacy assessments.

[0257] Screening (Days -28 to -8): Includes safety and other clinical tests to determine initial patient eligibility. Patients who meet the eligibility criteria at screening will be admitted to the baseline evaluation.

[0258] Baseline (Days -7 to -1): Includes patient self-assessment on a variety of scales and questionnaires in addition to safety assessments. During baseline, a self-reported history of cocaine use (TLFB) and two urine samples will be collected on two different days, with the second sample being collected 3 days prior to randomization to demonstrate abstinence from cocaine use.

[0259] Treatment (Days 1-98): After baseline, on Day 1, eligible patients will be randomized in a 1:1 ratio to receive either magoglurant (free form) or placebo. Group A - Mavoglurant (free form): Uptitration regimen for the first 2 weeks: 50 mg bid on days 1-7, 100 mg bid on days 8-14, followed by 200 mg bid for 84 days

[0260] The dose selected for adjuvant study (200 mg bid / modified release formulation) was chosen based on safety, tolerability, and pharmacokinetic data from completed mavoglurant studies. Group B: Matched placebo

[0261] Study Medication: Taken twice daily (bid) in the morning and evening (approximately 12 hours apart) with meals. For all morning outpatient visits involving any study evaluations or PK / urine sample collection, study medication will be self-administered by patients at the study site and supervised by study personnel. A standard breakfast will be provided at the study site on that day, and patients will eat it between taking their medication.

[0262] During the treatment period, patients will also undergo assessments with various scales and questionnaires, as well as safety assessments and pharmacokinetic sampling pre-dose and 2±1 hours post-dose according to the SoA.

[0263] Urine samples (Days 1-113): Samples will be collected twice weekly at the study facility with 48 hours between tests, e.g., Tuesday and Friday or Monday and Thursday or Tuesday morning and Thursday evening. Sample collection will be supervised by staff and quantitatively assessed for the presence of cocaine and alcohol metabolites [benzoylecgonine (BE) and ethyl glucuronide (EtG)]. Urine samples will be collected over the course of the study: 28 samples from patients who remain in treatment for 14 weeks (4 samples at weeks 1-2 of uptitration); 24 samples at weeks 3-14 (maintenance dose); 4 samples at weeks 15-16 (follow-up) and finally a final sample at the end-of-study visit. If a patient is unable to attend the clinic on the scheduled testing date or refuses to provide a sample, the sample will be considered positive unless a reason for absence is accepted (e.g., illness, other personal reasons). In the case of missing or refused samples, samples will be collected the next day whenever possible.

[0264] Clinical support to ensure medication and protocol adherence: Contingency Management (CM) and Psychosocial Support: In addition to study treatment, all patients will receive weekly contingency management (CM) therapy focused on patient adherence to the protocol and continued participation. In addition, patients will also receive standardized psychological support at least once a week.

[0265] · Medication Compliance: On PK collection days and all other days involving urine sampling assessments, patients will be present at the study site at the time of study drug administration for the morning dose. On these days, self-administration of study medication will be supervised by investigators and compliance will be ensured by oral checks after swallowing medication. To monitor medication adherence, patients will be given an individual medication diary (booklet) to record study medication administration. Medication compliance will be monitored at least weekly by the investigator and / or investigators using tablet counts. Dosage adherence will be confirmed by comparing the patient's self-reported data in the medication diary with the total number of tablets in the returned bottle or blister (depending on packaging). Adherence will be calculated as the total number of tablets taken divided by the total number of tablets planned to be taken during the treatment phase. Patients will also be contacted during outpatient periods to confirm compliance if the investigator feels appropriate.

[0266] Group The study will enroll patients ages 18 to 65 with a diagnosis of CUD who use cocaine snorting (intranasally).

[0267] CUD patient The Investigator will ensure that all subjects considered for the study meet the following eligibility criteria. No additional criteria will be applied by the Investigator. Subject selection must be established by reviewing all eligibility criteria at screening and baseline. Relevant records of eligibility criteria (e.g. checklists) will be kept at the study site along with source documents.

[0268] Any deviation from the inclusion criteria will result in the subject being excluded from study enrollment.

[0269] Inclusion criteria 1. Understand the study procedures and provide written informed consent prior to the conduct of any evaluations. 2. Male and female subjects, aged 18 to 65 years, diagnosed with cocaine use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Ed. (DSM-5). 3. The person must have been using cocaine intranasally. 4. Recent cocaine use confirmed by a positive urine screen for one or more benzoylecgonines (BEs) 5. Must be seeking treatment for cocaine dependence and wish to reduce or stop cocaine use according to goals assessed at baseline. 6. Baseline self-reported TLFB and two * Subjects must have abstained from cocaine use for at least 3 days prior to the first dose (Day 1) as assessed by a urine specimen. * The difference in BE levels between the two baseline samples must decrease 7. Must be in good health as determined by medical history and physical examination at the time of screening. 8. At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) must be within acceptable ranges as determined by the investigator to account for the pulse rate increasing effects of cocaine for a subject to be eligible. Investigators may use the following ranges as a guide: Systolic blood pressure: 90-150mmHg Diastolic blood pressure: 50-90mmHg Three readings are acceptable. At least one of the three readings must be within the acceptable range. 9. Patients must be able to: -Able to communicate verbally with the investigator and understand written instructions -Be able to verbalize your intention to complete all test procedures Verbally communicate that you will be available for each scheduled visit and that there are no other previously scheduled events or activities that would materially interfere with your study participation

[0270] Exclusion criteria 1. History of hypersensitivity to any of the study treatments or excipients or to drugs of a similar chemical class. 2. Currently have a diagnosis of a substance use disorder (per DSM-5) involving alcohol, cannabis, or other stimulants other than cocaine. 3. Meet current or lifetime DSM 5 criteria for schizophrenia or any psychotic disorder, or an organic mental disorder. Note: Subjects diagnosed with other psychiatric disorders may be enrolled, provided that concurrent treatment of a comorbid psychiatric condition does not prevent completion of the study or place the patient at increased risk through participation in the study. 4. Currently receiving treatment for a substance use disorder (e.g., disulfiram, acamprosate, methylphenidate, modafinil, topiramate, immediate-release dexamphetamine, or baclofen). 5. Requires treatment with any psychoactive medication, including any anticonvulsant (excluding medications used to treat short-term insomnia) Notes: SSRIs are permitted if they have been in an adequate stable dose for at least one month prior to initiation. 6. Use of other investigational drugs within 5 half-lives or 30 days of screening or enrollment, whichever is longer; or longer if required by local institution regulations. 7. Pregnant or lactating (lactating) women, pregnancy is defined as the state of a woman from conception through the end of pregnancy, confirmed by a positive hCG laboratory test 8. Women of childbearing potential, effective contraception during administration of the study drug and for 30 days after the final dose * is defined as any female with physiological capacity to become pregnant, unless otherwise specified. * Effective contraceptive methods include: Total abstinence (when this is consistent with the subject's preferred normal lifestyle). Note: Periodic abstinence (e.g., calendar, ovulation, symptom-thermographic, postovulatory methods) and withdrawal are not recognized methods of contraception. Female sterilization (surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks prior to receiving study treatment. Note: Ovariectomy alone is only allowed if the woman's reproductive status has been confirmed by follow-up hormone evaluation. Male sterilization (at least 6 months prior to screening). For female study subjects, the vasectomized male partner must be the subject's only partner. Barrier contraception: condoms or occlusive caps (diaphragms or cervical / vaginal vault caps) with spermicidal foams / gels / films / creams / vaginal suppositories; placement of an intrauterine device (IUD) or Intrauterine contraceptive system (IUS) Hormonal contraceptives that are injected, implanted, or administered orally or transdermally cannot be considered effective methods of contraception when taken with the study medication. Women are considered postmenopausal and non-fertile if they have been naturally (spontaneously) amenorrhea for 12 months and have an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) 9. History of porphyria 10. History or presence of treated or untreated malignancy of any organ system (other than localized cutaneous basal cell carcinoma or intraepithelial cervical carcinoma) within the past 5 years, with or without evidence of local recurrence or metastasis 11. Has any disease, condition, or history of medication that, in the opinion of the Investigator or designee, may compromise the results of the study or pose additional hazards to the administration of the investigational drug to the subject or may prevent successful completion of the study. 12. Any surgical or medical condition that may significantly alter drug absorption, distribution, metabolism, or excretion or that may put the subject at risk if participating in the study. The Investigator will determine this at screening, taking into account the subject's medical history and / or clinical or laboratory evidence of the following: Screening laboratory values ​​(including AST, ALT, total bilirubin, or creatinine) that, in the opinion of the investigator, are considered clinically unacceptable for the CUD population: ALT and serum bilirubin should not exceed 2×ULN GGT, AST and alkaline phosphatase should not exceed 5xULN If the safety laboratory values ​​assessed at screening are outside the ranges specified above, the assessment may be repeated once prior to randomization. If the repeated values ​​are still outside the specified ranges, the subject will be removed from the study. 13. Current and / or previous treatment with concomitant medications that are strong or moderate CYP3A4 inducers / inhibitors (e.g., clarithromycin, ketoconazole, ritonavir, etc.). 14. Concomitant use of medications known to prolong the QT interval unless they can be permanently discontinued during the study. 15. History or current diagnosis of ECG abnormalities at screening or baseline that indicate a significant safety risk to study participation, including: Concomitant clinically significant cardiac arrhythmias, such as sustained ventricular tachycardia and clinically significant second- or third-degree AV block without a pacemaker -Personal history of familial long QT syndrome or known family history of torsades de pointes QTcF>450msec (male); QTcF>460msec (female) Note: Sinus tachycardia, left axis deviation, and nonspecific ST or T wave changes are not excluded. 16. Known history or presence of cardiovascular or cerebrovascular disease such as angina, myocardial infarction, stroke, transient ischemic attack, peripheral vascular disease. 17. History of immunodeficiency disease, including positive HIV (ELISA and Western blot) test results. 18. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). 19. Score "Yes" on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS if this ideation has occurred in the past 6 months, or score "Yes" on any item in the Suicidal Behavior section except "Non-Suicidal Self-Injurious Behavior" (item also included in the Suicidal Behavior section) if this behavior has occurred in the past 2 years. 20. The patient is unable to: You do not foresee significant problems with arranging transportation to the study site or the time available to travel, and you plan to move within the next few months to a location that will make continued participation in the study impractical. · Involved in any unresolved legal matters that may jeopardize the continuation or completion of the trial

[0271] Statistical models and analytical methods Primary variable: Percentage of days of cocaine use during treatment (days 1-98).

[0272] The proportion of days of cocaine use was calculated for each patient by dividing the number of days on which cocaine was used by the duration of treatment, i.e., 98 days for completers and the number of days between Day 1 and the last dose if study treatment was discontinued early. This is considered a continuous variable. Cocaine consumption was recorded daily using the TLFB throughout the study (Yes / No).

[0273] A Bayesian analysis is performed on the percentage of days of cocaine use. It is assumed to be a continuous outcome with normally distributed errors. A linear model is fitted with treatment factors and past cocaine consumption as covariates. Non-informative priors are used for all parameters. Past cocaine consumption is the percentage of days of cocaine use in the 3 months prior to the screening visit assessed using the TLFB. The model determines the posterior probability that the difference in percentage of days of cocaine use between mavoglurant and placebo is <0 and the posterior probability that it is <-10%. Based on the literature in this disease, a difference in days of 10% is considered the minimal clinically meaningful effect, and a difference of 20% is a highly promising effect. The study will show a positive indication of efficacy if the following two criteria are met: 1. There is at least a 90% probability that the difference in the proportion of days of cocaine use between mavoglurant and placebo is <0 2. There is at least a 50% probability that the difference in the proportion of days of cocaine use between mavoglurant and placebo will be <-10%

[0274] Sensitivity analyses will be performed using other models, such as negative binomial regression, when the distribution of data is not normal.In addition, consumption profiles over time will be compared between treatment groups through the analysis of time series data (weekly use) using mixed models for repeated measures.

[0275] Secondary variables: will include UDS-negative rate over the treatment period and will be analyzed in the same manner as the primary variable. Safety and PK are secondary endpoints of this study. The present invention includes the following embodiments. [Claim 1] 13. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of reducing cocaine use in a patient with cocaine use disorder. [Claim 2] 1. Use of mavoglurant, or a pharma- ceutical acceptable salt thereof, for the manufacture of a therapeutic medicament for preventing relapse to cocaine use in a patient with cocaine use disorder. [Claim 3] 1. Use of mavoglurant, or a pharma- ceutical acceptable salt thereof, for the manufacture of a therapeutic medicament for promoting cocaine abstinence in a patient with cocaine use disorder. [Claim 4] 1. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of depressive or anxiety symptoms associated with cocaine use disorder. [Claim 5] 5. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to any one of claims 1 to 4, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting) or oral cocaine preparations; in particular with cocaine inhalation (i.e. smoking). [Claim 6] 6. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic pharmaceutical according to any one of claims 1 to 5, wherein the cocaine use disorder is comorbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or recreational eating disorder. [Claim 7] Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to any one of claims 1 to 6, wherein said use is, for example, in combination with standardized psychological treatment at individual or population level. [Claim 8] Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to any one of claims 1 to 7, wherein said use is in combination with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management. [Claim 9] 9. The use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to claim 8, wherein the psychosocial therapy or the behavioral therapy is computer-assisted. [Claim 10] 10. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to any one of claims 1 to 9, wherein said use is carried out in parallel with methadone or buprenorphine treatment. [Claim 11] 11. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to any one of claims 1 to 10, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in combination with a further active agent. [Claim 12] 12. The use of mavoglurant, or a pharma- ceutical acceptable salt thereof, for the manufacture of a therapeutic pharmaceutical according to any one of claims 1 to 11, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder. [Claim 13] 13. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to any one of claims 1 to 12, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in immediate release or modified release form. [Claim 14] 14. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to any one of claims 1 to 13, wherein mavoglurant, or a pharma- ceutically acceptable salt thereof, is administered in an amount of 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid. [Claim 15] 15. Use of mavoglurant, or a pharma- ceutically acceptable salt thereof, for the manufacture of a therapeutic medicinal product according to any one of claims 1 to 14, wherein the cocaine use disorder is associated with recreational drinking. [Claim 16] Mavoglurant, or a pharma- ceutically acceptable salt thereof, in combination with a GABAergic agent (e.g., topiramate, tiagabine, baclofen, or vigabatrin), an agonist replacement drug (e.g., modafinil, methylphenidate, methadone, or buprenorphine), a dopaminergic agent (e.g., bupropion, a combination of levodopa and carbidopa, risperidone, olanzapine, aripiprazole, or dextroamphetamine), a D3 receptor ligand (e.g., CJB090), a corticotropin-releasing factor (CRF) receptor antagonist (e.g., CP154,526), ​​a cannabinoid CB1 receptor antagonist, a dual dopamine-serotonin releasing agent (e.g., PAL-287), a noradrenergic inducer (e.g., doxazosin, disulfiram, or nepicastat), a 5-HT 1A Combinations comprising at least one further active agent selected from the group consisting of a receptor partial agonist (e.g., buspirone), a μ opioid agonist (e.g., buprenorophine), a NET inhibitor (e.g., desipramine), and an NMDA receptor antagonist (e.g., amantadine); or a pharmaceutically acceptable salt thereof.

Claims

1. 1. A pharmaceutical composition comprising mavoglurant for use in the treatment of reducing cocaine use in a patient with cocaine use disorder, said mavoglurant being administered in an amount of 200 mg / b.i.d.

2. 1. A pharmaceutical composition comprising mavoglurant for use in the treatment of facilitating cocaine abstinence in a patient suffering from cocaine use disorder, said mavoglurant being administered in an amount of 200 mg / b.i.d.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting) or oral cocaine preparations; in particular associated with cocaine inhalation (i.e. smoking).

4. 4. The pharmaceutical composition of any one of claims 1 to 3, wherein the cocaine use disorder is co-morbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or binge eating disorder.

5. A pharmaceutical composition according to any one of claims 1 to 4, in combination with a standardised psychological treatment, for example at an individual or population level.

6. A pharmaceutical composition according to any one of claims 1 to 5, in combination with a psychosocial or behavioural therapy or a combination thereof, in particular a therapy based on contingency management.

7. The pharmaceutical composition of claim 6 , wherein the psychosocial therapy or the behavioral therapy is computer-assisted.

8. The pharmaceutical composition according to any one of claims 1 to 7, which is administered in conjunction with methadone or buprenorphine treatment.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein magglurant is administered in combination with a further active agent.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein magglurant is administered in immediate release or modified release form.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the cocaine use disorder is associated with recreational drinking.

13. 1. A pharmaceutical composition comprising a pharma- ceutical acceptable salt of mavoglurant for use in the treatment of reducing cocaine use in a patient with cocaine use disorder, said mavoglurant being administered in an amount of 200 mg / b.i.d.

14. 1. A pharmaceutical composition comprising a pharma- ceutical acceptable salt of mavoglurant for use in the treatment of facilitating cocaine abstinence in a patient with cocaine use disorder, said mavoglurant being administered in an amount of 200 mg / b.i.d.

15. 15. A pharmaceutical composition according to claim 13 or 14, wherein the cocaine use disorder is associated with cocaine inhalation (i.e. smoking), intravenous cocaine, cocaine snorting (i.e. snorting) or oral cocaine preparations; in particular associated with cocaine inhalation (i.e. smoking).

16. 16. The pharmaceutical composition of any one of claims 13 to 15, wherein the cocaine use disorder is co-morbid with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder or binge eating disorder.

17. A pharmaceutical composition according to any one of claims 13 to 16, in combination with a standardised psychological treatment, for example at an individual or population level.

18. A pharmaceutical composition according to any one of claims 13 to 17, in combination with a psychosocial or behavioural therapy or a combination thereof, in particular a therapy based on contingency management.

19. 20. The pharmaceutical composition of claim 18, wherein the psychosocial therapy or the behavioral therapy is computer-assisted.

20. The pharmaceutical composition according to any one of claims 13 to 19, which is administered in conjunction with methadone or buprenorphine treatment.

21. The pharmaceutical composition according to any one of claims 13 to 20, wherein the pharma- ceutically acceptable salt of mavoglurant is administered in combination with a further active agent.

22. 22. The pharmaceutical composition of any one of claims 13 to 21, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

23. The pharmaceutical composition according to any one of claims 13 to 22, wherein the pharma- ceutically acceptable salt of mavoglurant is administered in immediate release or modified release form.

24. The pharmaceutical composition of any one of claims 13 to 23, wherein the cocaine use disorder is associated with recreational drinking.

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