WO2025252686A1 - Compounds for the treatment of cannabis use disorder - Google Patents

Abstract

Peptide compounds of formula (I): AA¹-AA²-D-Ile-D-Tyr-AA³-D-Tyr-D-Ala-D-Tyr-D-Val-D-Ala-Gly-D-Ile-D-Leu-D-Lys-D-Arg-D-Trp-NH₂ wherein, AA¹ represents an amino acid selected from the group consisting of D-Tryptophan (D-Trp), D-1-naphthylalanine (D-1-Nal) and D-2-naphthylalanine (D-2-Nal); AA² represents an amino acid selected from the group consisting of D-Leucine (D-Leu), D-Norleucine (D-Nle) and D-Phenylalanine (D-Phe); and AA³ represents an amino acid selected from the group consisting of D-Methionine (D- Met) and D-Norleucine (D-Nle), or a pharmaceutically acceptable salt thereof, which are useful in the treatment and/or prevention of cannabis use disorder.

Description

TITLE: Compounds for the treatment of cannabis use disorder

FIELD OF THE INVENTION

The present invention relates to the fields of medicine and mental health and, particularly, to compounds and compositions useful as medicaments for the treatment of mental disorders, particularly addictions.

BACKGROUND ART

Cannabis preparations are the illicit drugs most widely used worldwide. Mental and behavioural disorders due to use of cannabinoids are diagnoses recognized in the United States Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM V) and the WHO International Classification of Diseases, Tenth Revision (ICD-10).

Cannabis use can cause physical dependence and addiction together with mental and behavioural disorders as Cannabis Use Disorder (CUD). CUD development is an underappreciated risk that affects about 10% of the 193 million cannabis users worldwide, characterized by the compulsive use of cannabis and/or cannabinoids despite negative consequences on various aspects of the user’s life, including cognitive, mental, and physical health, as well as work and relationships.

The USA National Survey on Drug Use and Health in 2020 revealed that, among people aged 12 or older, an estimated 5.1 % (ca. 14.2 million) had experienced CUD in the past 12 months. The percentage of young people who develop CUD after first trying cannabis is higher among adolescents (ages 12-17, 16%) than among young adults (ages 18-25).

Comorbidity of CUD and psychiatric problems has been reported as high as 77%. It is known that cannabis use is linked with higher levels of suicidal ideation, plan, and attempt, and alterations in cognitive performance. Neurocognitive impairment across the user’s lifespan is one of the long-term consequences of cannabis use.

Main targets for CUD treatment, both pharmacological and behavioural, are the cessation of the use and the reduction of the withdrawal symptoms. Due to the lack of effective pharmacological treatments, main options are behavioural therapies including cognitive behavioural therapy. Behavioural therapies, such as contingency management, are based in the provision of tangible rewards to patients for positive behaviours. Cognitive behavioural therapy helps to identify and modify damaging thinking and behaviour. One of the drawbacks of behavioural therapy is its low treatment compliance as it depends entirely on the motivation of the subject. Treatment compliance is further impaired by the comorbidity of CUD with several psychiatric problems. Tetrahydrocannabinol (THC) is known as the primary molecule responsible for the addictive properties of cannabis. THC and other cannabinoids have great therapeutic potential in cannabisbased medicines.

However, medical use of THC and other cannabinoids raises safety concerns for many physicians, as they are known to be associated with a variety of negative effects with major consequences, such as memory impairment and other psychoactive responses, that constitute important drawbacks for the use of cannabinoids as therapeutic agents.

WO2021064165A1 describes peptides, compositions and methods useful for reducing side effects of cannabinoid CBi receptors (CBiR) agonists. Examples 8 and 9 show the in vivo effect of the peptides on pain and on memory. Compounds described in WO2021064165A1 are orally active, proteolytically stable, and non-immunogenic short peptides which are disclosed to be candidates for combined administration with THC, taking advantage of its analgesic effects but avoiding its associated cognitive impairment.

For these reasons, there is a need to develop effective pharmacological treatments for cannabis use disorder, to minimize the risk of addiction and the threat to mental health. Further, there is a high medical interest in harnessing the beneficial effects of THC and other cannabinoids while avoiding the risks of developing cannabis use disorder.

SUMMARY OF THE INVENTION

The present invention provides compounds useful for the treatment and/or prevention of cannabis use disorder, in a subject in need thereof.

Surprisingly, the inventors have found that the compounds provided herein show an outstanding activity against cannabis use disorder by inhibiting addiction-like behaviour towards the consumption of cannabinoids.

The working example in the present document provides detailed experimental data demonstrating the effect of the peptide of SEQ ID NO: 1 as an inhibitor of addiction-like behaviour towards the consumption of cannabinoids by decreasing in vivo the persistence of response, the motivation for the drug, and/or the compulsive-like behaviour in a cannabinoid addict murine model.

Accordingly, the first aspect provided herein relates to a compound of formula (I) (SEQ ID NO: 2) AA¹-AA²-D-lle-D-Tyr-AA³-D-Tyr-D-Ala-D-Tyr-D-Val-D-Ala-Gly-D-lle-D-Leu-D-Lys-D-Arg-D-Trp-NH₂ (I) wherein,

AA¹ represents an amino acid selected from the group consisting of D-Tryptophan (D-Trp), D- 1 -naphthylalanine (D-1-Nal) and D-2-naphthylalanine (D-2-Nal);

AA² represents an amino acid selected from the group consisting of D-Leucine (D-Leu), D-Norleucine (D-Nle) and D-Phenylalanine (D-Phe); and

AA³ represents an amino acid selected from the group consisting of D-Methionine (D-Met) and D- Norleucine (D-Nle), or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cannabis use disorder in a subject.

The first aspect can alternatively be formulated as related to the compounds as defined above for use as an active pharmaceutical ingredient for treating, preventing or ameliorating cannabis use disorder, or symptoms, complications and/or sequelae thereof.

In particular, the treatment and/or prevention of cannabis use disorder comprises decreasing the persistence of response, the motivation for the drug and the compulsive-like behaviour in a subject in the need thereof.

Throughout the description and claims the word "comprise" and its variations are not intended to exclude other technical features, additives, components, or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein. The following examples and drawings are provided herein for illustrative purposes, and without intending to be limiting to the present invention.

DESCRIPTION OF DRAWINGS

FIG. 1 shows the schedule of the protocol of CUD using a mouse model of cannabinoid addictionlike behaviour based on WIN 55,212-2 self-administration. A shows the timeline where FR 1 and 2 refer to Fixed Ratio 1 and 2, and PR refers to Progressive Ratio. B shows the daily doses of vehicle or of the peptide of SEQ ID NO: 1 administered orally before operant sessions. C shows the animal categorization during operant conditioning and extinction periods.

FIG. 2 shows WIN 55,212-2 operant conditioning in male mice. A shows the number of infusions obtained by the animal groups. B shows the number of responses to the active nose-poke during the 10 s time-out period, measuring impulsivity as a behavioural phenotypic trait of vulnerability to addiction-like behaviour.

FIG. 3 shows responses in the three addiction-like criteria tests. A shows persistence of response as the number of responses to the active nose-poke during the 15 min drug-free period. B shows motivation as the maximum number of responses an animal is willing to obtain one drug infusion. C shows compulsivity as the number of shocks received in the 50 min shock test. D shows the percentage of mice categorized as addicted or non-addicted in each group.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Cannabinoid: The term “cannabinoid” or “cannabinoid-based medicine” is used herein to refer any compound, substance or mixtures thereof and any pharmaceutical product, related with the active constituents of cannabis, both natural or synthetic, e.g., 2-arachidonoylglycerol (2-AG), 2- arachidonylglyceryl ether (2-AGE, noladin ether), anandamide (N-5 arachidonoylethanolamine or AEA), N-arachidonoyl dopamine, palmitoylethanolamide (PEA); 11-hydroxy-A⁸-tetrahydrocannabi- nol, 11-hydroxy-A⁹-tetrahydrocannabinol, Cannabinol, A⁸-tetrahydrocannabinol, A⁹-tetrahydrocan nabinol (Dronabinol, THC or A⁹-THC), AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole), AM-678 (1-pentyl-3-(1-naphthoyl)indole), arachidonyl-2'-chloroethylamide (ACEA), CP 55,940 ([(-)-cis-3-[2- hydroxy-4-(1 ,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol]), HU- 210, JWH-018 (1-pentyl-3-(1-naphthoyl)indole), JWH-073, linoleyl ethanolamide, levonantradol (CP 50,556-1), Nabilone, Nabiximols, WIN 55,212-2, cannabigerol, cannabivarin, A⁹-tetrahydrocannabi varin, marinol, and mixtures thereof. The term “cannabinoid” includes both natural or synthetic compounds, e.g., compounds obtained by isolation from the natural plant, modification of the structure of a compound isolated from the plant, or a completely synthetic compound which mimics the structure or effects of the naturally occurring compounds.

Excipient: The terms "excipient" and "carrier" are used interchangeably and refer to an inert substance added to a e.g., pharmaceutical composition, to further facilitate administration of a compound of the present disclosure.

Subject: The terms "subject", "patient", "individual", "host" and variants thereof are used interchangeably herein and refer to any mammalian subject, particularly humans, but also including without limitation, humans, domestic animals (e.g., dogs, cats and the like), farm animals (e.g., cows, sheep, pigs, horses and the like), and laboratory animals (e.g., monkey, rats, mice, rabbits, guinea pigs and the like) for whom diagnosis, treatment, or therapy is desired. The compositions and methods described herein are applicable to both human therapy and veterinary applications.

Subject in need thereof: As used herein, "subject in need thereof includes subjects, such as mammalian subjects, that would benefit from the administration of the compounds provided herein.

Therapeutically effective amount: As used herein the term "therapeutically effective amount" is the amount of a compound/composition of the present disclosure that is enough to produce a desired therapeutic effect, pharmacological and/or physiological effect on a subject in need thereof.

Treatment: The terms "treat", "treatment", and "therapy" as used herein refer to, e.g., the reduction in severity of disease or condition disclosed herein; the amelioration or elimination of one or more symptoms, complications, or sequelae associated with a disease disclosed herein; the provision of beneficial effects to a subject with a condition/disease disclosed herein, without necessarily curing the disease or condition. The term also includes prophylaxis or prevention of a disease or condition or symptoms, complications, or sequelae thereof.

The term refers to a clinical or nutritional intervention to prevent the disease or condition; cure the disease or condition; delay onset of the disease or condition; delay onset of a symptom, complication or sequela; reduce the seriousness of the disease or condition; reduce the seriousness of a symptom, complication, or sequela; improve one or more symptoms; improve one or more complications; improve one or more sequelae; prevent one or more symptoms; prevent one or more complications; prevent one or more sequelae; delay one or more symptoms; delay one or more symptoms; delay one or more complications; delay one or more sequelae; ameliorate one or more symptoms; ameliorate one or more complications; ameliorate one or more sequelae; shorten the duration of one or more symptoms; shorten the duration of one or more complications; shorten the duration of one or more sequelae; reduce the frequency of one or more symptoms; reduce the frequency of one or more complications; reduce the frequency of one or more sequelae; reduce the severity of one or more symptoms; reduce the severity of one or more complications; reduce the severity of one or more sequelae; improve the quality of life; increase survival; prevent a recurrence of the disease or condition; delay a recurrence of the disease or condition; or any combination thereof, e.g., with respect to what is expected in the absence of the treatment with the compound/composition of the present disclosure.

Prevent: The terms "prevent," "preventing," "prophylaxis" and variants thereof as used herein, refer, e.g., to partially or completely delaying the onset of a disease, disorder and/or condition disclosed herein; partially or completely delaying the onset of one or more symptoms, features, or clinical manifestations, complications, or sequelae of a particular disease, disorder, and/or condition disclosed herein;

(i) partially or completely delaying the onset of one or more symptoms, features, or manifestations, complications, or sequelae of a particular disease, disorder, and/or condition disclosed herein;

(ii) partially or completely delaying progression from a particular disease, disorder and/or condition disclosed herein; and/or

(iii) decreasing the risk of developing pathology associated with the disease, disorder, and/or condition disclosed herein.

Symptom: As used herein, the term "symptom" refers to subjective or physical sign, indication, or evidence of disease or physical disturbance observed by the subject. In general, the term refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the patient and indicative of disease. Symptoms are felt or noticed by the individual experiencing the symptom but may not easily be noticed by others. In some aspects, a symptom can be a mild symptom, a moderate symptom, or a severe symptom. As used herein, the term "mild symptom" refers to a symptom that is not life threatening and does not require, e.g., intensive care treatment (e.g., at a hospital ICU). As used herein, the term "moderate symptom" refers to a symptom that requires monitoring because it may become life threatening and may require, e.g., hospitalization. As used herein, the term "severe symptom" refers to a symptom that is life threatening and requires, e.g., intensive care treatment (e.g., at a hospital ICU).

Complication: As used herein, the term "complication" refers to a pathological process or event occurring during a disease or condition that is not an essential part of the disease or condition; where it may result from the disease/condition or from independent causes. Accordingly, the term complication refers to medical/clinical problems that are observed in subjects diagnosed with a disease or condition disclosed herein, e.g., malaria. In some aspects, a complication can be temporary. In some aspects, a complication can be chronic or permanent.

Sequela: As used herein, the term "sequela" refers to a long-term, chronic, or permanent complication.

Pharmaceutically acceptable salt: As used herein, the term “pharmaceutically acceptable salt” refers to that the salt derived from the corresponding compound is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.

Uses of the compounds

All the methods and uses described herein can be formulated as a peptide compound provided herein for use in treating and/or preventing cannabis use disorder (CUD) and the other uses described herein. Alternatively, this can be formulated as the use of any of the compounds described herein for the manufacture of a pharmaceutical composition, a nutraceutical composition, a veterinary composition, a food product or a personal care product for the treatment, and/or prevention of CUD and the other uses disclosed herein. This can be also alternatively formulated as methods of treating and/or preventing CUD and the other uses described herein in a subject in need thereof comprising administering to the subject the herein described compounds.

The examples of the present invention provide evidence of the activity as a therapy of Cannabis use disorder of the compounds described herein. Thus, the present invention describes for the first time the positive effect of the compounds disclosed herein in the treatment, prevention and amelioration of cannabis use disorder, symptoms, complications and/or sequelae thereof.

In the present document, the term Cannabis Use Disorder or CUD as well as most of the symptoms, complications and sequela, are defined following the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), where cannabis abuse and dependence were combined from past editions in a single disorder named CUD. According to DSM-5, the term “cannabis use disorder” encompasses “cannabis addiction” as both are used to describe the wide range of the disorder, from a mild form to a severe state of chronically relapsing, compulsive pattern of drug taking.

According to DSM-5, CUD is defined as a problematic pattern of cannabis use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period:

1 . Cannabis is often taken in larger amounts or over a longer period than was intended.

2. There is a persistent desire or unsuccessful efforts to cut down or control cannabis use.

3. A great deal of time is spent in activities necessary to obtain cannabis, use cannabis, or recover from its effects.

4. Craving, or a strong desire or urge to use cannabis.

5. Recurrent cannabis use resulting in a failure to fulfil major role obligations at work, school, or home.

6. Continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis.

7. Important social, occupational, or recreational activities are given up or reduced because of cannabis use.

8. Recurrent cannabis use in situations in which it is physically hazardous.

9. Cannabis use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by cannabis.

10. Tolerance, as defined by either of the following: a. A need for markedly increased amounts of cannabis to achieve intoxication or desired effect. b. Markedly diminished effect with continued use of the same amount of cannabis.

11 . Withdrawal, as manifested by either of the following: a. The characteristic withdrawal syndrome for cannabis (refer to Criteria A and B of the criteria set for cannabis withdrawal). b. Cannabis (or a closely related substance) is taken to relieve or avoid withdrawal symptoms.

Severity is graded as either Mild, Moderate, or Severe, pending if 2 or 3, 4 or 5, or 6+ of the above criteria are present.

CUD also includes problems associated with use of substances derived from the cannabis plant and chemically similar synthetic compounds. For instance, the primary component with psychoactive effects, addiction and dependence potential in cannabis is the cannabinoid A⁹-tetrahydrocannabinol (A⁹-THC orTHC). Other synthetic cannabinoid compounds, e.g., K2, Spice, JWH-018, JWH-073, are designed to mimic cannabis effects. These compounds may cause more severe adverse effects than cannabis plant products, including more severe risk of developing CUD. Cannabinoids have diverse effects in the brain, prominent among which are actions on CB1 and CB2 cannabinoid receptors found throughout the central nervous system.

The most common medical uses for cannabis, cannabinoids and derived compounds are pain management, nausea and vomiting, appetite stimulation, muscle spasticity, epilepsy, anxiety and depression, sleep disorders, neurological disorders, post-traumatic stress disorder (PTSD), Tourette syndrome, Parkinson, Huntington, inflammatory bowel disease, Dravet syndrome, Lennox-Gastaut syndrome, sleep disorders, depression, anxiety, panic disorders, phobia, but the conditions approved for medicinal cannabis use vary in each country. Therapeutic administration of cannabis or derived compounds as cannabinoids is considered as a risk factor for the onset of CUD.

As said, the present invention relates to the compounds described herein, for use in the treatment, prevention and/or amelioration of CUD, symptoms, complications and/or sequelae thereof.

According to the art, persistence of response, motivation for the drug, and compulsive-like behaviour are three addiction-like criteria that summarize the addiction hallmarks according to the DSM-5 (see, Deroche-Gamonet V, et al. 2004; Piazza, P.V., et al. 2013; Domingo-Rodriguez L, et al. 2022). Persistence of response refers to perseveration in drug-seeking when the drug is not available. Motivation for the drug measures the amount of effort an individual aims to make to obtain the drug, and compulsivity-like behavior is the loss of control over drug taking, even if it is associated with negative consequences.

In a particular embodiment, the compounds provided herein are for the treatment of CUD, comprising decreasing the persistence of response, the motivation for the drug and the compulsive-like behaviour in a subject in the need thereof.

The invention also encompasses the compounds described herein for CUD treatment susceptible to amelioration by decreasing the persistence of response, the motivation for the drug and/or the compulsive-like behaviour in a subject in the need thereof, comprising administering a therapeutically effective amount of at least one compound described herein.

The invention also encompasses a method of treatment, prevention and/or amelioration of CUD, symptoms, complications and/or sequelae thereof comprising the administration of a therapeutically effective amount of the compounds provided herein. In a particular embodiment, the invention encompasses a method of treatment of cannabis use disorder comprising administering a therapeutically effective amount of the compounds provided herein. The invention also encompasses a method of treatment, prevention and/or amelioration of CUD, symptoms, complications and/or sequelae thereof by decreasing the persistence of response, the motivation for the drug and the compulsive-like behaviour in a patient in the need thereof, comprising administering a therapeutically effective amount of the compounds provided herein.

In some embodiments, the administration of the compounds provided herein results in at least one outcome (i.e., effect) selected, but not limited to, from the group consisting of:

- increased control over drug substance (i.e., cannabis and/or cannabinoids) use,

- reduced social impairment,

- safer use of the substance, and/or

- decreased pharmacological effects of addiction.

More particularly the outcome (i.e., effect) is selected, but not limited to, from the group consisting of:

- decrease of substance amount (i.e., cannabis and/or cannabinoids) consumed or over a shorter period than originally intended,

- improvement in the success in the efforts to decrease or discontinue use of the substance,

- decrease of the time spent by the individual for obtaining the substance, using the substance, or recovering from its effects,

- decreased desire or urge for the substance,

- improvement in the fulfillment of major role obligations at work, school, or home,

- increased abstention, e.g., due the persistent or recurrent social, interpersonal, physical or psychological problems caused or exacerbated by the effects of the substance,

- increase of social, occupational, or recreational activities or get back to them,

- decreased recurrent substance use e.g., in situations in which it is physically hazardous

- decreased tolerance to the substance, and/or

- increased withdrawal of the use of the substance.

In a particular embodiment, the administration of the compounds provided herein results in at least one outcome (i.e., effect) selected, but not limited to, from the group consisting of decreasing:

- persistence of response,

- motivation for the drug, and/or

- compulsive-like behaviour.

In one aspect, the present disclosure provides a method for increasing control over the use of cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for reducing social impairment in a subject due to cannabis and/or cannabinoids use, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for improving the safety of the use of cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for reducing pharmacological effects of addiction to cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for reducing the amount of cannabis and/or cannabinoids consumed or for reducing the time of consumption in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for improving in the success of decreasing or discontinuing the use of cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for reducing the time spent by a subject for obtaining, using, or recovering from the effects of cannabis and/or cannabinoids, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for decreasing the desire or urge for cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for improving in the fulfilment of major role obligations at work, school, or home impaired by the use of cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for increasing abstention of cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for increasing social, occupational, or recreational activities or get back to them in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for decreasing recurrent use of cannabis and/or cannabinoids in a subject e.g., in situations in which it is physically hazardous, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for decreasing tolerance to cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for increasing withdrawal of the use of cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for decreasing addiction to cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for decreasing persistence of response to cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for decreasing motivation for cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

In one aspect, the present disclosure provides a method for decreasing compulsive-like behaviour related to the use of cannabis and/or cannabinoids in a subject, comprising the administration of the compounds provided herein to a subject in need thereof.

The present disclosure provides methods to avoid complications such as comorbid mental problems or amelioration thereof, avoid or reduce hospitalization, reduce (shorten) ICU treatment time, delay the need for ICU treatment, avoid ICU admission (i.e., eliminate the need for ICU treatment), reduce patient mortality rate, increase patient survival rate, reduce patient’s chance of death, increase patient’s chance of survival, decrease patient’s risk of death, reduce the severity of at least one symptom, reduce the severity of at least one complication, reduce the severity of at least one sequela, reduce the duration of at least one symptom, reduce the duration of at least one complication, reduce the duration of at least one sequela, or any combination thereof in a subject, said methods comprising administering the compounds provided herein to a subject in need thereof.

As said, all the methods comprising the administration of the compounds provided herein to a subject in need thereof, can be alternatively formulated as the provision of the compounds for the indicated uses or the use of the compounds for the manufacture of a pharmaceutical composition and other compositions for such uses. As used herein, the subject is a mammal, in particular a human, at risk of developing, or already having, cannabis use disorder.

Particularly, the subject can be a recreational user of cannabis and/or cannabinoids or a patient being medicated with cannabis or a cannabinoid-based medicine.

In a particular embodiment, the compounds provided herein are used for the treatment or prevention of cannabis use disorder in a subject who is a recreational cannabis user.

In a particular embodiment, the compounds provided herein are used for the treatment or prevention of cannabis use disorder in a subject who is simultaneously, sequentially or separately treated with cannabis or a cannabinoid-based medicine.

Main treatment options for CUD are behavioural therapies, such as contingency management, based in the provision of tangible rewards to patients for positive behaviours, and cognitive behavioural therapy, which helps to identify and modify damaging thinking and behaviour. Thus, the peptide compounds provided herein can be administered together (concomitantly) with other treatments/strategies to treat or prevent CUD development or with other type of treatments.

In a particular embodiment, the subject is administered with a compound provided herein and with a phytocannabinoid, endocannabinoid and/or synthetic cannabinoids. In particular, the subject is administered with a compound provided herein and with cannabis and/or a cannabinoid selected from the group consisting of 2-arachidonoylglycerol (2-AG), 2-arachidonyl glyceryl ether (2-AGE, noladin ether), anandamide (N-5 arachidonoylethanolamine or AEA), N-arachidonoyl dopamine, palmitoylethanolamide (PEA); 11-hydroxy-A⁸-tetrahydrocannabinol, 11-hydroxy-A⁹- tetrahydrocannabinol, Cannabinol, A⁸-tetrahydrocannabinol, A⁹-tetrahydro cannabinol (Dronabinol, THC or A⁹-THC), AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole), AM-678 (1 -pentyl-3-(1 - naphthoyl)indole), arachidonyl-2'-chloroethylamide (ACEA), CP 55,940 ([(-)-cis-3-[2-hydroxy-4-(1 ,1- dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol]), HU-210, JWH-018 (1 -pentyl-3-(1 - naphthoyl)indole), JWH-073, linoleyl ethanolamide, levonantradol (CP 50,556-1), Nabilone, Nabiximols, WIN 55,212-2, cannabigerol, cannabivarin, A⁹-tetrahydrocannabivarin, marinol, and mixtures thereof. In particular, the cannabinoid is THC.

As understood by the skilled person in the present context, the compounds provided herein can be administered simultaneously, sequentially or separately with cannabis or a cannabinoid. Therefore, the compounds provided herein and cannabis and/or the cannabinoids can be administered as a combination, e.g. simultaneously as a single composition or e.g. sequentially as two separate compositions. Accordingly, the term "combination" of some embodiments herein relates to the various combinations of the compounds provided herein and cannabis and/or a cannabinoid, e.g., in a single pharmaceutical composition, in a combined mixture composed from separate pharmaceutical formulations/compositions of the single active compounds, such as a "tank-mix", and in a combined use of the single active ingredients when applied in a sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days or in simultaneous administration. A combination of the compounds provided herein and cannabis and/or the cannabinoid can be formulated for its simultaneous, separate or sequential administration. Particularly, if the administration is not simultaneous, the compounds are administered in a relatively close time proximity to each other, e.g. the compound provided herein is administered in the first place and cannabis and /or the cannabinoid is administered in second place. Furthermore, the compounds are administered in the same or different dosage form or by the same or different administration route, e.g. one compound can be administered intravenously and the other compound can be administered orally. The combination of the two compounds can e.g. be administered:

- as a combination that is being part of the same medicament formulation, the two compounds being then administered always simultaneously;

- as a combination of two units/compositions, each with one of the substances giving rise to the possibility of simultaneous, sequential or separate administration.

For instance, a compound provided herein is independently administered from cannabis and/or the cannabinoid (i.e. in two units) in simultaneous, separate or sequential administration.

In another suitable example, a compound provided herein is administered first and then cannabis and/or the cannabinoid is separately or sequentially administered. Alternatively, cannabis and/or the cannabinoid is administered first and then the compounds provided herein are separately or sequentially administered.

Dose

A therapeutically effective dose level of the compounds provided herein will depend on many factors. In addition, it is well-known within the skill of the art to start doses of the active composition at relatively low levels and increase the dosage until the desired effect is achieved. Efficacy of the methods provided herein can be determined using any appropriate method. For example, criteria for substance use disorder can be determined and evaluated with any one of several objectives, standard behavioural tests known in the art, which include behavioural surveys and clinical analysis by a physician, which are routinely used by all professional healthcare practitioners.

Clinicians, physicians, and other health care professionals can administer the compounds provided herein to a subject in need thereof according to a method provided herein. In general, more than one administration of the compound is performed at various intervals (e.g., once per week, twice per week, daily, monthly) or according to any other appropriate treatment regimen. The duration of treatment can be a single dose or periodic multiple doses for as long as administration of the compounds provided herein is tolerated by the subject.

In some embodiments, the compounds provided herein are administered in a single dose or repeated dose at specific time intervals, e.g., can be administered daily for a specific number of days or according to a specific dosing schedule. In an embodiment, the compounds provided herein are administered during from 10 days to 90 days. More particularly, they are administered during a period from 10 days to 60 days or from 15 to 45 days, more particularly during 30 days. In another embodiment, the compounds are administered while the subject continues the use of cannabis and/or cannabinoids, both therapeutically or recreationally.

In an embodiment, the compound is administered in a dose that can be in the range of 0.1 to 250 mg/daily, in particular of 1 .75 to 150 mg/daily. In a particular embodiment herein the dose is from 7 to 70 mg/daily.

Compounds

The compounds provided herein for use in the treatment and/or prevention of cannabis use disorder and the other uses and methods disclosed herein are those of formula (I) (SEQ ID NO: 2) AA¹-AA²-D-lle-D-Tyr-AA³-D-Tyr-D-Ala-D-Tyr-D-Val-D-Ala-Gly-D-lle-D-Leu-D-Lys-D-Arg-D-Trp-NH₂ (I) wherein,

AA¹ represents an amino acid selected from the group consisting of D-Tryptophan (D-Trp), D- 1 -naphthylalanine (D-1-Nal) and D-2-naphthylalanine (D-2-Nal);

AA² represents an amino acid selected from the group consisting of D-Leucine (D-Leu), D-Norleucine (D-Nle) and D-Phenylalanine (D-Phe); and

AA³ represents an amino acid selected from the group consisting of D-Methionine (D-Met) and D-Norleucine (D-Nle), or a pharmaceutically acceptable salt thereof.

In a particular embodiment, AA¹ represents D-Tryptophan (D-Trp).

In a particular embodiment, AA² represents D-Leucine (D-Leu).

In a particular embodiment, AA³ represents D-Methionine (D-Met).

In a particular embodiment herein the compound is (D-Trp-D-Leu-D-lle-D-Tyr-D-Met-D-Tyr-D-Ala-D- Tyr-D-Val-D-Ala-Gly-D-lle-D-Leu-D-Lys-D-Arg-D-Trp) (SEQ ID NO: 1) and its salts. In some embodiments, the invention relates to pharmaceutically acceptable salts of compounds of formula (I). As used herein the expression “pharmaceutically acceptable salt” designates any salt which, upon administration to the subject, is capable of providing (directly or indirectly) a compound as described herein. For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are, e.g., prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both. Generally, non-aqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred. Examples of acid addition salts include mineral acid addition salts such as, e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of alkali addition salts include inorganic salts such as, e.g., sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, e.g., ethylenediamine, ethanolamine, N,N- dialkylenethanolamine, triethanolamine and basic amino acid salts.

In some embodiments, the salt is hydrochloride, hydrobromide, sulfate, nitrate, phosphates, acetate, propionate, benzoate, maleate, hemimaleate, fumarate, lactate, tartrate, citrate, succinate, hemisuccinate, glycollate, gluconate, tosylate, mesylate, esylate, napsylate, isethionate, besylate, hexanoate, octanoate, decanoate, oleate, or stearate.

The synthesis and purification of the compounds provided herein can be carried out by conventional synthetic methods for peptides, e.g. by the methods disclosed in WO2021064165A1 , which is incorporated herein by reference in its entirety. An example of the methods of synthesis and purification is shown in EXAMPLE 2.

Products/compositions comprising the compounds

In some embodiments, the compounds described herein are in a pharmaceutical form, such as a capsule, a powder, a suspension, a tablet, or a solution.

The term “pharmaceutical form" is understood in its widest meaning, including any composition that comprises an active ingredient, in this case, a peptide compound described herein together with at least a pharmaceutically (also referred as nutraceutical or veterinary) acceptable excipient. The term "pharmaceutical form" is not limited to medicaments but includes e.g., pharmaceutical compositions, nutraceutical compositions or veterinary compositions. A pharmaceutical form can adopt different names depending on the product regulatory approval route and depending on the country.

A nutraceutical composition can also be named e.g., a food supplement or dietary supplement. A nutraceutical composition is understood as a preparation or product intended to supplement the diet, made from compounds usually used in foodstuffs, which provide nutrients or beneficial ingredients that are not usually ingested in the normal diet or may not be consumed in sufficient quantities. Nutraceutical compositions are usually sold “over the counter”, i.e., without prescription.

In an aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and pharmaceutically acceptable excipients or carriers.

In some embodiments, the composition described herein is formulated as pharmaceutical form in which the peptide compound described herein is the only active agent or is mixed with one or more other active agents and/or are mixed with pharmaceutically/nutraceutical/veterinary acceptable excipients. Particularly, the additional active agent or agents are cannabis and/or cannabinoids. Depending on the formulation, cannabis and/or the cannabinoid can be added alone or together with suitable carriers or ingredients.

The term "pharmaceutically/nutraceutical/veterinary acceptable" is art-recognized, and includes excipients, compounds, materials, compositions, carriers, vehicles and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., human or animal) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be “acceptable" in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, excipients, etc. can be found in standard pharmaceutical/nutraceutical/veterinary texts.

Thus, some embodiments of the invention relate to a pharmaceutical composition, a nutraceutical composition, and a veterinary composition comprising a compound of the invention described herein together with at least a pharmaceutically/nutraceutical/veterinary acceptable excipient as described above. Excipients are selected, without limitation, from the group comprising: fillers/diluents/bulking agents, binders, anti-adherents, disinteg rants, coatings, anti-caking agents, antioxidants, lubricants, sweeteners, flavors, colors, or surfactants.

In each case, the presentation of the composition will be adapted to the type of administration used. In a particular embodiment, the composition is formulated for administration in liquid form or in solid form. The composition can be thus formulated into solid, semisolid or liquid preparations, such as tablets, capsules, powders, granules, solutions, suppositories, gels or microspheres. In a particular embodiment, the compositions are formulated for oral administration. In other embodiments, the compositions can be in the form of an injectable e.g., subcutaneous, intravenous or intraperitoneal administration. In a particular embodiment, the composition is in solid form such as tablets, lozenges, sweets, chewable tablets, chewing gums, capsules, sachets, powders, granules, coated particles or coated tablets, pills, troches, g astro- resista nt tablets and capsules, dispersible strips and films. More particularly, the composition is in the form of a capsule, a powder, a tablet, a pill, lozenges, sachets, sticks, or granules. In a more particular embodiment, the composition is in the form of a pill, a tablet or a capsule.

In another embodiment, the composition is in liquid form such as oral solutions, drops, suspensions (e.g., oil), emulsions and syrups.

Oral tablets are often crushed to help make them easier to swallow. Consequently, in another embodiment, the composition is in the form of a syrup, granules, powders or tablets which can be dissolved in water. Particularly, the composition further comprises a flavoring agent.

In a particular embodiment herein, the composition is a capsule or an extended release subcutaneous depot formulation.

EXAMPLES

EXAMPLE 1 : Effect of the peptide of SEQ ID NO: 1 on the cannabinoid addiction-like behaviour of mice.

The inventors of the present invention performed a study of the effects of a treatment with the peptide of SEQ ID NO: 1 on the operant mouse model of cannabinoid addiction-like behaviour using WIN 55,212-2 self-administration.

1. Materials and equipment

1.1 Animals

Eight weeks old male C57BL/6J mice (n = 33) (Charles River, France) were housed individually with food and water available ad libitum in controlled laboratory conditions (21 °C ± 1 °C, 55% ± 10%). Mice were tested during the first hours of the dark phase of a reversed light/dark cycle (lights off at 8:00 a.m. and on at 8:00 p.m.). Body weight and food intake were monitored throughout the entire experiment. All animal procedures were approved by the local ethical committee (Comite Etic d’Experimentacio Animal-Parc de Recerca Biomedica de Barcelona, CEEA-PRBB, agreement N°9687) and conducted in strict conformity with the guidelines of the European Communities Council Directive (2010/63/EU) regulating animal experimentation, in the animal facility at Universitat Pompeu Fabra-Barcelona Biomedical Research Park (UPF-PRBB; Barcelona, Spain). All the experiments were performed under blind and randomized conditions. The male sex was chosen according to the previous literature that has validated the operant WIN 55,212-2 self-administration model only in males (see, Martin-Garcia E. et al. Neuropsychopharmacology. 2016;41 (9):2192-2205; Garcia-Blanco A. J. Clin. Invest. 2022;132(10):e156281 ; Cajiao-Manrique MDM et al. Front Pharmacol. 2023;14:1143365; Cajiao-Manrique MDM. et al., Front Psychiatry. 2023;14:1148993).

1 .2 Drugs

Peptide of SEQ ID NO: 1 was synthetized as disclosed in Example 2. For the self-administration, WIN 55,212-2 [(R)-(+)-WIN 55,212-2 mesylate salt (Sigma-Aldrich, U.S.A.), a synthetic cannabinoid which acts as a complete agonist of CB1 and CB2 receptors, was dissolved in one drop of Tween 80 (TWEEN 80, Sigma-Aldrich, U.S.A.) and then diluted in heparinized (1 %) sterile saline solution and made available at two different doses: 0.1 mg/kg for intraperitoneal (ip) injection 24 h before the first operant session and 12.5 pg/kg/infusion for the self-administered iv infusions. The preparation was covered from the light and stored at room temperature. After each self-administration session, 0.05 mL of sodic heparin (Hospira 5%, Hospira, Pfizer) was applied through the iv catheter to avoid coagulation and obstruction of the latter. Thiopental sodium (5 mg/mL, Braun Medical S.A.) was dissolved in distilled water and injected in a volume of 0.05 mL through the iv catheter to evaluate catheter patency.

1 .3 Operant self-administration apparatus

Experiments were performed in mouse operant chambers (model ENV-307A-CT, Med Associates Inc., Georgia, VT, U.S.A.) equipped with two nose-pokes, one randomly selected as the active hole and the other as the inactive hole. A house light was located on the chamber’s ceiling, and two stimuli lights (cues) were placed one inside the active hole and the other above it. Nose-poking on the active hole resulted in the delivery of one WIN 55,212-2 infusion (under the associated schedule) paired with the activation of the stimulus light located above the active hole, while nose-poking on the inactive hole had no consequences. The chambers were made of aluminum and acrylic and placed inside sound- and light-attenuated boxes equipped with fans providing ventilation and white noise. The chamber’s floor was a grid made with metal bars that could conduct electrical current when performing the shock test. WIN 55,212-2 (12.5 pL/kg/infusion) was delivered in a volume of 23.5 pL over 2 s via a syringe firmly attached to a micro infusion pump (PHM-100A, Med-Associates, Georgia, VT, U.S.A.) and connected with flexible polymer tubing (0.96 mm outer diameter, Portex Fine Bore Polythene Tubing, Portex Limited, Kent, England) to a single channel liquid swivel (375/25, Instech Laboratories, Plymouth Meeting, PA, U.S.A.) and the mouse iv catheter.

1 .4 Experimental design

Mice received a daily dose of vehicle orthe peptide of SEQ ID NO: 1 dissolved in phosphate-buffered saline solution with 2% DMSO. The peptide was administered by oral route (gavage) with disposable probes (Feeding needle, malleable metal, 20G, 1.9mm tip, 38mm, pkg=5, Agntho’s AB, Agavagen 52 181 55 Lidingb, Sweden). The rate of administration was 0.1 ml per 10g of body weight in 5 seconds, administered manually, approximately 0.02 ml per second. Afterward, mice were implanted with an intrajugular catheter to perform iv drug administrations. Subsequently, mice were trained to acquire an operant drug self-administration conditioning maintained by iv infusions of WIN 55,212-2 under a fixed-ratio (FR) 1 schedule of reinforcement during five sessions, followed by five sessions of a FR2 schedule of reinforcement. After the training, three addiction-like criteria resembling DSM-5 criteria for addiction, persistence to response, motivation, and compulsive-like behavior, two parameters related to craving, resistance to extinction and drug-seeking behavior, and two phenotypic traits considered factors of vulnerability to substance misuse, impulsivity and sensitivity to reward, were evaluated in each mouse. Mice received the peptide of SEQ ID NO: 1 by oral route (gavage), 45 min before self-administration sessions, once a day for 13 consecutive days (training period), and on one additional day after the extinction period on the evaluation of cue-induced reinstatement. Two increasing doses of the peptide of SEQ ID NO: 1 , 10 mg/kg and 20 mg/kg, were compared to the vehicle. See FIG. 1 for details.

FIG. 1 shows the schedule of the protocol of CUD based on WIN 55, 212-2 self-administration. A. Timeline. After recovery from surgery for iv catheter implantation, animals underwent operant conditioning maintained by WIN 55, 212-2 during 10 sessions, divided in 5 sessions of fixed ratio 1 (FR1) and 5 sessions of FR2. On session 11 , mice underwent a progressive ratio (PR) session to assess motivation for the synthetic cannabinoid WIN. On session 12 an additional session of FR2 is introduced prior to session 13, where the shock test is applied to measure compulsivity-like behavior. B. Mice received a daily dose of vehicle or the peptide of SEQ ID NO: 1 (dose of 10 or 20 mg/kg) orally administered during these 13 days 45 min before operant sessions. After this session, mice underwent 14 days of extinction sessions without treatment. C. Cue induced reinstatement was measured once without treatment (after 10 extinction sessions) and a second time after oral treatment administration (after 14 extinction sessions).

2. Methods

2.1 WIN 55,212-2 self-administration

2.1.1 Jugular vein catheterization

Mice (n = 33) were anesthetized by ip injection (0.2mL/10 g of body weight) of ketamine hydrochloride (75 mg/kg of body weight, Ketamidor, Richterpharma ag, Austria) and medetomidine hydrochloride (1 mg/kg of body weight, Domtor, Esteve, Spain) dissolved in 0.9% sterile physiological saline and then implanted with indwelling iv silastic catheters in the right jugular vein, as previously described (Martin-Garcia et al., 2009). Briefly, a 6 cm long silicone tubing (0.3 mm inner diameter, 0.6 mm outer diameter; Silastic, Dow Corning, Houdeng-Goegnies, Belgium) was adapted to a 22-gauge steel cannula (Semat, Herts, England) curved at a right angle and embedded in a dental cement disk (Dentalon Plus, Heraeus Kulzer, Germany) with a nylon mesh underneath. The catheter tubing was inserted 1.1 cm into the right jugular vein and attached with a suture. The remaining tubing was inserted subcutaneously (sc) to the cannula, exiting at the midscapular region. All incisions were sutured and coated with a local analgesic (Blastoestimulina, Almirall, Spain). Post-surgery procedure consisting of an ip injection of antibiotic (1 mg/kg of body weight, Gentamicine, Genta-Gobens, Laboratorios Normon, Spain), a sc injection of analgesic (mixture of glucose serum (GlucosaVet, B. Braun Vet Care, Spain) and meloxicam (2 mg/kg of body weight, Metacam, Boehringer Ingelheim, Rhein) and a sc injection of an anesthesia reversor, atipamezole hydrochloride (2.5 mg/kg of body weight, Revertor, Virbac, Spain), was applied all dissolved in 0.9% sterile physiological saline. Mice were allowed to recover for 3 days, with follow-up analgesics, prior to the initiation of the selfadministration sessions. The patency of iv catheters was assessed by a thiopental sodium test at the end of the self-administration experimental sequence. The mouse was removed from the experiment if prominent signs of anesthesia were not observed immediately after injection.

2.1.2 WIN 55,212-2 self-administration training

The operant model was applied accordingly to previous drug self-administration paradigms (see, Cajiao-Manrique MDM et al., 2023 14:1143365). To avoid the aversive effects of the drug’s first administration, mice received an ip injection of WIN 55,212-2 (0.1 mg/kg) only 24 h before the first self-administration session (see, Cajiao-Manrique MDM. et al. 2023 14:1143365). Subsequently, mice (n = 33) were trained to acquire an operant self-administration conditioning maintained by iv infusions of WIN 55,212-2. The schedule was a fixed ratio (FR) 1 schedule of reinforcement during 5 consecutive sessions, followed by a progression to FR2 for another 5 sessions. All sessions were performed at the same time and scheduled every day. Each daily self-administration session was started with a priming injection of WIN 55,212-2 (0.0125 mg/kg/infusion) automatically delivered iv through the catheter when the session was initiated (Mendizabal et al., 2006; Martin-Garcia et al., 2016; Flores et al., 2020), followed by two 55 min active periods separated by a 15 min drug-free period for a total duration of 125 min. The initiation of each session was signaled by turning on the house light only during the first 3 s. The cue lights, together with the noise of the infusion pump, acted as environmental cues signaling the drug infusion. A 10 s time-out period was fixed after each drug delivery, during which the cue light was off, and no reward was provided after responding to the active nose-poke. Responses to the active and inactive holes and all responses executed during the time-out were recorded. During the drug-free period, no reinforcer nor cue was delivered, signaled by the activation of the house light. The session was concluded after 50 reinforcers were delivered or after 125 min, whichever occurred first. The acquisition of the self-administration behavior was achieved when the three following conditions were met: 1) mice maintained 80% of stability in three consecutive training sessions, meaning that the variance during these 3 days was 20% or less, 2) at least 75% responding on the active hole, and 3) a minimum of five reinforcers per session. After each session, mice were brought back to their home cages.

2.1 .3 Three addiction criteria

The development of addictive-like behaviour was evaluated at the end of the training sessions based on three addiction-like criteria that summarize the addiction hallmarks according to the DSM-5 (Deroche-Gamonet et al., 2004; Piazza and Deroche- Gamonet, 2013; Domingo-Rodriguez et al., 2022). The addiction score developed was then attributed based on the results of these three criteria, each determined by the respective behavioural test.

2.1.3.1 Persistence of response

The number of non-reinforced active responses during the 15 min drug-free period was measured as the persistence of drug-seeking behaviour. Mice were scored on the three consecutive days before the progressive ratio (PR).

2.1 .3.2 Motivation

The PR schedule of reinforcement evaluated the motivation towards the reinforcer. The responses required to receive one drug infusion escalated following this series: 1 , 5, 12, 21 , 33, 51 , 75, 90, 120, 155, 180, 225, 260, 300, 350, 410, 465, 540, 630, 730, 850, 1000, 1200, 1500, 1800, 2100, 2400, 2700, 3000, 3400, 3800, 4200, 4600, 5000, and 5500. The breaking point, the maximal number of responses mice perform to obtain one infusion, is defined as the motivation value and corresponds to the last ratio completed. The duration of the PR session was a maximum of 4h or until mice stopped responding to any nose-poke within 1 h.

2.1 .3.3 Compulsivity

Resistance to punishment, now defined as compulsive-like behaviour, corresponded to the maintenance of active responding behaviour despite its association with a negative consequence. It was measured by the total number of shocks obtained in a 50 min shock test, during which each drug delivered was associated with a foot-shock-induced punishment. This shock session was performed after a stabilizing FR2 self-administration session following the PR test. Mice were placed in a different operant box than the one regularly used for the operant sessions. Then mice underwent an FR2 self-administration schedule of reinforcement for 50 min with two scheduled changes: after one active response, mice received an electric foot shock (0.18 mA, 2 s), while after the second response, the electric foot-shock was paired with the drug delivery and the associated cue light. In parallel, if the second response was not completed within a min after completing the first response, the sequence was reinitiated.

2.1 .4 Establishment of mice subpopulations

After the three behavioural tests were performed, mice were categorized into “addicted” and “nonaddicted” animals based on the number of positive criteria achieved. A mouse was considered to be positive for an addiction-like criterion when the score of the behavioural test was equal to or beyond the 75th percentile of the normal distribution of the saline group. Mice that achieved 2 or 3 criteria were considered addicted and categorized as vulnerable, whereas those reaching 0 or 1 criterion were considered non-addicted and categorized as resilient.

2.1.5 Extinction and parameters related with craving

Only mice with patent catheters that reached all acquisition criteria continued to the extinction phase. After thiopental testing, mice were allowed to rest for 1 day, during which they underwent a 2-h locomotion test in individual locomotor activity boxes (10.8 x 20.3 x 18.6 cm, Imetronic, Pessac, France) equipped with infrared sensors to detect locomotor activity and an infrared plane to detect rearings. During the extinction period, neither WIN 55,212-2 infusions, priming infusions, nor the associated environmental cues were delivered after nose-poking on the active hole. Mice were exposed to 2-h daily sessions for 10 consecutive days in the same operant chamber as the selfadministration sessions. During this period, mice reached the extinction criterion when responses to the active nose-poke were < 35% of the mean responses obtained during the last 3 days of WIN 55,212-2 self-administration across three consecutive extinction sessions. A total of 14 extinction sessions were performed. Only mice that achieved the extinction criterion were evaluated for the following test of drug-seeking behavior. Two parameters related to craving were evaluated before and after this extinction period, resistance to extinction and drug-seeking behavior.

2.1 .5.1 Resistance to extinction

Number of active responses in 2 h during the first extinction session. Animals with significant sensitivity to drug withdrawal will increase their resistance to extinction by increasing the number of active nose-pokes to seek the drug when access is prevented.

2.1.5.1 Drug-seeking behaviour

The day after achieving the extinction criterion, we performed a single cue-induced reinstatement session in the same operant chamber to test reinstatement of drug-seeking behavior upon exposure to the environmental stimuli after a period of abstinence. The cue test was conducted under the same conditions used in the acquisition phase, except that active responding was not reinforced by the drug. This meant that mice were subject to a 2-h FR2 session, where nose-poking on the active hole resulted in the presentation of all the environmental cues associated (cue light, pump noise, and priming injection light) but not the delivery of WIN 55,212-2 (Martin-Garcia et al. 2009, PMID: 18752721).

2.1 .6 Behavioural tests to evaluate addiction-like phenotypic traits

Two additional phenotypic traits were also evaluated as factors of vulnerability to addiction:

2.1.6.1 Impulsivity

The number of non-reinforced active responses during the timeout periods (10 s) after each WIN 55,212-2 delivery was measured as impulsivity-like behavior, which indicated the inability to stop a response once it is initiated. The three consecutive days before the PR test were considered for this criterion.

2.1 .6.2 Sensitivity to reward

The number of reinforcers obtained in 2h sessions during the last three consecutive FR2 operant conditioning sessions maintained by WIN 55,212-2. Animals with higher levels of sensitivity to reward will obtain a higher number of reinforcers.

2.2. Statistical analysis

2.2.1. Statistical analysis of behavioural data

The number of animals (n) in each experimental condition is indicated in the figure legends. All statistical comparisons were performed with SPSS (IBM, version 25). Comparisons between groups were performed by Student’s t-test or U Mann-Whitney test according to the distribution defined by the Kolmogorov-Smirnov normality test. ANOVA with repeated measures was used when necessary to test the evolution over time, followed by post hoc analysis (Fisher LSD) for multiple-group comparison. The Pearson correlation coefficient was performed to analyze the relationships between values in each addiction-like criterion and the final criteria achieved. The chi-square analysis was used to compare the percentage of addicted and non-addicted mice. Results were expressed as individual values with the median and the interquartile range or with the mean ± S.E.M, which is specified in the figure legend. A p-value <0.05 was applied to determine statistical significance. The sample size was calculated based on the power analysis. The significance criterion (alpha) was set at 0.050, and the statistical test utilized was a two-sample t-test. With the sample size of 9 (vehicle) or 12 (treated) mice per group, our studies achieved a power superior to 80%.

3. Results

The inventors used the new operant model of WIN 55,212-2 self-administration recently validated as a new mouse model of CUD that recapitulates the diagnostic criteria used in DSM-5 to define this human disorder, based on the three main behavioural hallmarks of addiction that englobe DSM-5 addiction criteria: persistence of response, motivation for the drug and compulsive-like behaviour defined as a disruption of inhibitory control despite negative consequences.

This novel model was used to evaluate the effects of the peptide of SEQ ID NO: 1 on CUD. Peptide of SEQ ID NO: 1 orally administered at the dose of 10 and 20 mg/kg decreased the percentage of mice that reached the addiction criteria, and the dose of 10 mg/kg significantly decreased the motivation to seek for the synthetic cannabinoid agonist WIN 55,212-2.

FIG. 2 shows WIN 55,212-2 operant conditioning in male mice. A. Number of infusions obtained by Vehicle and the peptide of SEQ ID NO: 1 treated groups (10 or 20 mg/kg) during 2h of operant selfadministration maintained by intravenous infusions of WIN 55,212-2 in both FR1 and FR2 schedules of reinforcement (mean ± S.E.M., FR2 repeated measures ANOVA, treatment effect ** P<0.01 , Vehicle vs. 10 mg/Kg). B. Impulsivity as a behavioural phenotypic trait of vulnerability to addictionlike behaviour (individual data with median and interquartile range): number of responses to the active nose-poke during the 10 s time-out period (Student t-test, **P<0.01 , Vehicle vs. 10 mg/Kg). The sample size is n =9 for Vehicle mice, n =12 for 10 mg/Kg of peptide of SEQ ID NO: 1 , and n =12 for 20 mg/Kg peptide of SEQ ID NO: 1 .

FIG. 3 shows the responses in the three addiction-like criteria tests (individual data with median and interquartile range): A. Persistence of response: Number of responses to the active nose-poke during the 15 min drug-free period. B. Motivation: Breaking point determined during a 4 h progressive ratio schedule of reinforcement. The breaking point is the maximum number of responses an animal is willing to do to obtain one drug infusion (U Mann-Whitney, *P<0.05, Vehicle vs. 10 mg/Kg and #P<0.05, 10 mg/Kg vs. 20 mg/Kg). C. Compulsivity: Number of shocks received in the 50 min shock test. The dashed horizontal line indicates the 75th percentile of the distribution of the vehicle group, used as the threshold to consider a mouse positive for one criterion. D. Percentage of mice categorized as addicted or non-addicted for the Vehicle and peptide of SEQ ID NO: 1 treated groups (10 or 20 mg/kg). The sample size is n =9 for Vehicle mice, n =12 for 10 mg/Kg of peptide of SEQ ID NO: 1 , and n =12 for 20 mg/Kg of peptide of SEQ ID NO: 1 .

EXAMPLE 2. Peptide synthesis and purification

Peptides were assembled on 0.1 mmol (0.182 g; 0.55 mmol/g) of Rink Amide ProTide Resin (OEM Corporation), using a Liberty BlueTM 2.0 (CEM Corporation) microwave-assisted peptide synthesizer, running optimized Fmoc synthesis protocols.

Incorporation of Fmoc-D-amino acids (0.2 M) was achieved by double couplings with an excess of ethylcyano(hydroxyimino)acetate (1 M), in the presence of an excess of N,N’- diisopropylcarbodiimide (0.5 M) at each coupling step, with dimethylformamide as solvent.

Side chain protections of trifunctional residues were Boc (D-Lys and D-Trp), 2, 2, 4, 6, 7 pentamethyldihydrobenzofuran-5-sulfonyl (D-Arg), and t-butyl (D-Tyr).

Final deprotection and cleavage were performed with a trifluoroacetic acid/water/3,6-dioxa-1 ,8- octanedithiol/triisopropylsilane (94:2.5:2.5:1 v/v) cocktail for 90 min. Peptide analysis and purification followed the procedures outlined in WQ2021/064165. Fractions of satisfactory purity (>95%) by analytical high-performance liquid chromatography (HPLC) were pooled, lyophilized, and analyzed for identity by HPLC-MS as detailed in WQ2021/064165. REFERENCES

WO2021064165A1

Deroche-Gamonet V, et al. “Evidence for addiction-like behavior in the rat” Science 2004;305(5686), 1014-7

Piazza, P.V., et al. “A multistep general theory of transition to addiction” Psychopharmacology (Bed) 2013;229(387-413)

Domingo-Rodriguez L, et al. “Differential expression of miR-1249-3p and miR-34b-5p between vulnerable and resilient phenotypes of cocaine addiction.” Addict Biol. 2022;27(5)

Cajiao-Manrique MDM et al. “A male mouse model of WIN 55,212-2 self-administration to study cannabinoid addiction” Front Pharmacol. 2023;14:1143365

Cajiao-Manrique MDM. et al., “THC exposure during adolescence increases impulsivity-like behavior in adulthood in a WIN 55,212-2 self-administration mouse model” Front Psychiatry. 2023;14:1148993

Mendizabal, V. et al. “Involvement of K/Dynorphin System in WIN 55,212-2 Self-Administration in Mice” Neuropsychopharmacol. 2006; 31 , 1957-1966

Martin-Garcia E. et al. “Differential Control of Cocaine Self-Administration by GABAergic and Glutamatergic CB1 Cannabinoid Receptors” Neuropsychopharmacology. 2016;41 (9):2192-2205

Flores A, et al. “THC exposure during adolescence does not modify nicotine reinforcing effects and relapse in adult male mice” Psychopharmacology (Bed). 2020;237(3):801-809

Claims

1. Compound of formula (I)

AA¹-AA²-D-lle-D-Tyr-AA³-D-Tyr-D-Ala-D-Tyr-D-Val-D-Ala-Gly-D-lle-D-Leu-D-Lys-D-Arg-D-Trp-NH₂

(I) wherein,

AA¹ represents an amino acid selected from the group consisting of D-Tryptophan (D-Trp), D-

1 -naphthylalanine (D-1-Nal) and D-2-naphthylalanine (D-2-Nal);

AA² represents an amino acid selected from the group consisting of D-Leucine (D-Leu), D-Norleucine (D-Nle) and D-Phenylalanine (D-Phe); and

AA³ represents an amino acid selected from the group consisting of D-Methionine (D-Met) and D-Norleucine (D-Nle), or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cannabis use disorder in a subject.

2. Compound for use according to claim 1 , wherein AA¹ represents D-Tryptophan (D-Trp).

3. Compound for use according to any of claims 1-2, wherein AA² represents D-Leucine (D-Leu).

4. Compound for use according to any of claims 1-3, wherein AA³ represents D-Methionine (D-Met).

5. Compound for use according to any of claims 1-4, wherein the compound is:

D-Trp-D-Leu-D-lle-D-Tyr-D-Met-D-Tyr-D-Ala-D-Tyr-D-Val-D-Ala-Gly-D-lle-D-Leu-D-Lys-D-Arg-D- Trp, or a pharmaceutically acceptable salt thereof.

6. Compound for use according to any of claims 1-5, wherein the treatment of cannabis use disorder comprises decreasing the persistence of response, the motivation for the drug and/or the compulsive-like behaviour in the subject.

7. Compound for use according to any of claims 1-6, wherein the subject is a recreational cannabis and/or cannabinoids user.

8. Compound for use according to any of claims 1-7, wherein the subject is simultaneously, sequentially or separately treated with cannabis and/or a cannabinoid-based medicine.

9. Compound for use according to any of claims 7-8, wherein the subject is administered with cannabis and/or a cannabinoid selected from the group consisting of 2-arachidonoylglycerol (2-AG),

2-arachidonyl glyceryl ether (2-AGE, noladin ether), anandamide (N-arachidonoylethanolamine or AEA), N-arachidonoyl dopamine, palmitoylethanolamide (PEA); 11-hydroxy-A⁸-tetrahydrocannabinol, 11-hydroxy-A⁹-tetrahydrocannabinol, Cannabinol, A⁸-tetrahydrocannabinol, A⁹-tetrahydrocannabinol (Dronabinol, THC or A⁹-THC), AM-2201 (1-(5-fluoropentyl)-3-(1-naphthoyl)indole), AM-678 (1- pentyl-3-(1-naphthoyl)indole), arachidonyl-2’-chloroethylamide (ACEA), CP 55,940 ([(-)-cis-3-[2- hydroxy-4-(1 ,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)-cyclohexanol]), HU-210, JWH-018 (1-pentyl-3-(1-naphthoyl)indole), JWH-073, linoleyl ethanolamide, levonantradol (CP 50,556-1), Nabilone, Nabiximols, WIN 55,212-2, cannabigerol, cannabivarin, A⁹-tetrahydrocannabivarin, marinol, and mixtures thereof.

10. Compound for use according to claim 9, wherein the cannabinoid is A⁹-tetrahydrocannabinol (Dronabinol, THC or A⁹-THC).

11. Compound for use according to any of claims 1-10, wherein the dose of the compound is from 0.1 to 250 mg/daily.

12. Compound for use according to claim 11 , wherein the dose of the compound is from 1 .75 to 150 mg/daily.

13. Compound for use according to claim 12, wherein the dose of the compound is from 7 to 70 mg/daily.