WO2012083414A1

WO2012083414A1 - Use of marihuana and compounds therein for treating obesity

Info

Publication number: WO2012083414A1
Application number: PCT/CA2011/001131
Authority: WO
Inventors: Bernard Le Foll; Yann Le Strat
Original assignee: Bernard Le Foll; Yann Le Strat
Priority date: 2010-12-20
Filing date: 2011-10-11
Publication date: 2012-06-28
Also published as: CA2726085A1; EP2654763A1; EP2654763A4

Abstract

A method for treating or preventing obesity or to facilitate weight loss, particularly in overweight individuals with a body mass index (BMI) of about 25 or greater or in obese individuals with a BMI of about 25 or greater, as well as nutraceutical or pharmaceutical compositions and supplements therefor. The methods involve administering to a subject in need thereof a therapeutically effective amount of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof.

Description

USE OF MARIHUANA AND COMPOUNDS THEREIN FOR TREATING OBESITY FIELD OF INVENTION

The present invention relates to methods of treating or preventing obesity, or to facilitate weight loss in a subject in need thereof, as well as compositions and supplements therefor. BACKGROUND OF THE INVENTION

The role of cannabis and endocannabinoids on appetite regulation has been extensively studied, but the impact of cannabis use on weight in the general population is not known.

In 2007-2008, the prevalence of obesity was 33.9% among adults in the United States¹, contributing to 13% of the total mortality². Clinical guidelines for obesity treatment recommend lifestyle approaches, including the promotion of physical activity and healthy diet . Pharmacological treatment may be appropriate to facilitate weight loss in patients with a BMI above 30 or a BMI above 27 in the presence of coexisting conditions. Seven drugs (orlistat, sibutramine, diethylpropion, phentermine, benzphetamine, phendimetrazine and mazindol) are currently approved for the treatment of obesity in the United States. Their mechanisms of action are based on elevating monoamine levels or lipase inhibition in the gastrointestinal tract.

The role of cannabis and endocannabinoids on appetite regulation has been extensively studied in the past 10 years⁴. Rimonabant, a selective antagonist/inverse agonist of the cannabinoid CB1 receptor, was approved in more than 30 countries for the treatment of obesity, but was withdrawn because of safety concerns. Thereafter, the development of other cannabinoid CB1 receptor antagonists has been stopped^{5 6}.

Based on the fact that cannabis use increases appetite, clinical trials suggested that cannabis- derivatives may be a useful treatment for anorexia and weight loss associated with Human Immunodeficiency Virus infection^{7 8}. In contrast to tobacco use and smoking cessation that have been associated with weight loss⁹ and gain¹⁰, respectively, no study has evaluated the impact of cannabis use on weight in the general adult population. The present invention accordingly relates to the prevalence of obesity as a function of cannabis use, and hence, to compositions and methods that can facilitate weight loss.

SUMMARY OF THE INVENTION

It is an object of the invention to provide methods, compositions and/or supplements that can be used to treat or prevent obesity, or facilitate weight loss in a subject in need thereof.

Accordingly, the invention relates at least in part to a method for the treatment or prevention of obesity. The method comprises administering to a subject in need thereof a therapeutically effective amount of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof.

Also provided, according to the invention, is a method for regulation of appetite,

normalization of the need to eat and/or facilitating weight loss. The method of facilitating weight loss comprises administering to a subject in need thereof a therapeutically effective amount of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof.

The above-described methods may further include, in non-limiting embodiments, additional steps of: obtaining the subject's weight or body mass index (BMI), and determining if the weight is normal or if the subject is overweight (BMI between 25 and 30) or if the subject is obese (BMI of about 30 or greater). The cannabis, at least one cannabinoid or derivative thereof, extract prepared from at least one cannabis plant, or combination thereof is then preferentially administered if the subject is determined to be overweight or obese or have a BMI of about 25 or greater.

There is also provided herein a nutraceutical composition or supplement comprising an effective amount of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof. The nutraceutical composition or supplement is particularly useful for regulating appetite, normalizing the need to eat and/or facilitating weight loss, or for the treatment or prevention of obesity in a subject in need thereof.

In addition, as a further aspect of the invention, there is provided a pharmaceutical

composition for the treatment or prevention of obesity, regulating appetite, normalizing the need to eat and/or facilitating weight loss. The composition comprises a therapeutically effective amount of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof, in addition to one or more pharmaceutically acceptable carriers, excipients or diluents.

Further provided herein is the use of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof, for the treatment or prevention of obesity, regulating appetite, normalizing the need to eat and/or facilitating weight loss in a subject in need thereof. The use may also involve the manufacture of medicaments for the noted therapies or treatments.

When the cannabis, at least one cannabinoid or derivative thereof, extract prepared from at least one cannabis plant, or combinations thereof are administered in effective amounts, and combined with appropriate dietary planning and nutrition, the above described methods, uses, nutraceutical compositions, supplements and pharmaceutical compositions can provide benefits to the subject, including regulation of appetite, normalization of the need to eat, and result in weight loss. The above-described methods, uses, nutraceutical compositions, supplements and

pharmaceutical compositions may be adapted for human or veterinary therapeutic purposes. As such, the subject may be a human or other mammal including, but not limited to horse, dog, cat, rat, or mouse. However, the methods, uses, nutraceutical compositions, supplements and pharmaceutical compositions are particularly beneficial for humans, especially overweight and obese humans with a BMI of about 25 or greater.

It is also envisioned that the above-described methods, uses, nutraceutical compositions, supplements and pharmaceutical compositions can be incorporated into a combination therapy. Such combination therapies would involve administering the cannabis, at least one cannabinoid or derivative thereof, extract prepared from at least one cannabis plant, or combinations thereof as described herein, together with one or more additional active agents effective for the treatment or prevention of obesity or for facilitating weight loss. In the above-described methods, uses, nutraceutical compositions, supplements and pharmaceutical compositions, the at least one cannabinoid or derivative thereof may, in certain non-limiting embodiments, be derived from Cannabis sativa, Cannabis

indica/afghanica, Cannabis ruderalis, other plants of the Cannabis genus, or other plants that contain at least one cannabinoid compound classically present in Cannabis sativa such as, for instance, delta-9-tetrahydrocannabinol (THC), cannabidiol or others. In further non-limiting embodiments, the at least one cannabinoid or derivative thereof may be in a substantially pure or isolated form, or obtained synthetically according to methods available in the art. In other non-limiting embodiments, the at least one cannabinoid or derivative thereof may incorporate or consist of a synthetic cannabinoid ligand with similar pharmacology to the naturally derived cannabinoids described above. Without wishing to be limiting, these synthetic cannabinoid ligands may be partial agonists for the CB 1 and/or the CB2 cannabinoid receptor.

In further non-limiting embodiments of the above-described methods, uses, nutraceutical compositions, supplements and pharmaceutical compositions, the extract prepared from at least one cannabis plant may be in the form of a botanical drug substance, and/or may comprise naturally occurring cannabinoids from the at least one cannabis plant.

It is also envisioned that the nutraceutical composition or supplement described above can further comprise one or more acceptable carriers, excipients or diluents, and/or may be in the form of a dietary supplement formulated as a food, a drink, or an additive for a food or drink.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. BRIEF DESCRIPTION OF THE DRAWINGS

These and other features of the invention will become more apparent from the following description in which reference is made to the following appended drawings.

FIGURE 1 : Adjusted prevalence of obesity among participants in the NESARC study (Panel A, N=43,093) and in the NCS-R study (panel B, N=9,282) by use of cannabis in the last 12 months. Estimates were weighted to be representative of the US population. PO.001 in both samples (Cochran-Mantel-Haenszel χ² test in adjusted prevalence of obesity with higher frequency of cannabis use). Error bars represent 95% confidence intervals.

DETAILED DESCRIPTION

A cross-sectional study was carried out to examine the association between the use of cannabis and obesity. The results of this study show that, despite evidence that cannabis use induces appetite in clinical trials and laboratory studies, the weight of cannabis users was lower as compared to the non-users in the general population.

Accordingly, there is provided herein methods, uses, nutraceutical compositions, supplements and pharmaceutical compositions for the treatment or prevention of obesity, regulating appetite, normalizing the need to eat and/or for facilitating weight loss. These methods, uses, nutraceutical compositions, supplements and pharmaceutical compositions involve administering to a subject in need thereof a therapeutically effective amount of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof.

The described nutraceutical compositions, supplements and pharmaceutical compositions may include the described active component(s) together with an acceptable carrier or excipient, or together with one or more separate active agents or drugs as part of a combination. In addition, the nutraceutical compositions, supplements and pharmaceutical compositions may be administered in a treatment regime with other drugs, nutraceutical compositions, supplements or pharmaceutical compositions, either separately or in a combined formulation. Such compositions will preferably be formulated with a vehicle acceptable for administration to a subject, preferably a human, in need thereof. Methods of formulation for such

compositions are well known in the art and taught in standard reference texts such as

Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 1985. A

composition may comprise a single compound, or a combination thereof.

Formulations expected to be useful in the present invention may include, but are not limited to, aqueous solutions (where water soluble), dispersions and powders that are stable under the conditions of manufacture and storage and will preferably be preserved against the

contaminating action of microorganisms such as bacteria and fungi. The vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerols, mono- and di-glycerols, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and oils (e.g., edible oils including but not limited to vegetable, fruit, nut, fish oils, and mineral oils). The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants.

Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In some cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Sterile solutions can be prepared by incorporating the composition in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filter sterilization. Generally, dispersions are prepared by incorporating the composition into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yield a powder, optionally plus any additional desired ingredient from a previously sterile-filtered solution thereof. Suspensions, in addition to the active agent or cell extract as described herein, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. Solid dosage forms for oral administration may include, but are not limited to, ingestible hard and soft capsules, tablets, pills, candy, chewing gum, lollipops, powders, granules, elixirs, suspensions, syrups, wafers, sublingual or buccal tablets, troches, and the like. In such solid dosage forms the compound is mixed with at least one inert, pharmaceutically acceptable excipient or diluent or assimilable edible carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, or incorporated directly into the subject's diet. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The percentage of the compound of the invention in the compositions and preparations may, of course, be varied. The amount of active agent in such compositions is such that a suitable dosage will be obtained. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the

pharmaceutical and nutraceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the compound(s) of the invention only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions, which can be used include polymeric substances and waxes. The compositions can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active agent of the invention, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, ground nut corn, germ olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral

compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the composition or extract as described herein, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Accordingly, the described nutraceutical compositions, supplements or pharmaceutical compositions can be administered to a subject, preferably a mammal, more preferably a human, to treat and/or prevent obesity, or for facilitating weight loss, regulating appetite, and/or normalizing the need to eat. The nutraceutical compositions, supplements or pharmaceutical compositions may be administered by various routes including, but not limited to, orally, through bucall sprays, intravenously, intramuscularly, intraperitoneally,

subcutaneously, nasally or by inhalation. The formulation and route of administration as well as the dose and frequency of administration can be selected routinely by those skilled in the art based upon the severity of the condition being treated, as well as patient-specific factors such as age, weight and the like. One skilled in the art recognizes that interspecies pharmacokinetic scaling can be used to study the underlining similarities (and differences) in drug disposition among species, to predict drug disposition in an untested species, to define pharmacokinetic equivalence in various species, and to design dosage regimens for experimental animal models, as discussed in Mordenti, Man versus Beast: Pharmacokinetic Scaling in Mammals, 1028, Journal of Pharmaceutical Sciences, Vol. 75, No. 11 , November 1986.

Extracts as described herein may be prepared, in certain non-limiting embodiments, using one or more liquid extraction steps. For instance, yet without wishing to be limiting, the source material may be extracted using solvents including alcohol(s) such as methanol (MeOH), ethanol (EtOH), isopropanol, or combinations thereof. In a one exemplary embodiment, the source material is extracted in a solvent system of about 5 to about 100 % alcohol such as EtOH. Liquid extraction steps may be carried out according to a variety of methods, which methods may include without limitation steps of mixing followed by separation. For instance, in a non-limiting embodiment, the source material may be mixed by vortexing followed by filtration or centrifugation to remove solid material. Multiple steps of mixing and separating may also be used, including 2, 3, 4, 5 or more steps. In an embodiment, which is not meant to be limiting in any way, the source material may be mixed by vortexing for up to about 2 minutes, followed by separation of the mixture by filtration or centrifugation. In non-limiting embodiments involving centrifugation, this/these step(s) may be carried out at sufficient time and speed to remove substantially all of the solid material from solution. Without wishing to be limiting in any way, a centrifugation step may be carried out at about 5,000 x g to about 20,000 x g, including any centrifugation speed within this range, preferably between about 10,000 x g to about 15,000 x g. The time required for the centrifugation step will typically be dependent upon the speed, and in certain non-limiting embodiments may be up to 1 hour or even more. The centrifugation time will typically be between about 5 minutes to about 30 minutes, more preferably about 15 minutes. Without limitation, the centrifugation steps as well as any of the additional separation steps may be carried out at room temperature or lower, preferably at about 4°C. Concentration of supernatant fractions may also be carried out in a variety of ways, including by lyophilization (freeze-drying), spray-drying, rota-evaporating or other evaporating technologies, and other non-limiting concentrating methods.

The extraction process may also include chromatographic separation steps, for instance but not limited to separation by high-pressure liquid chromatography (HPLC), to further separate bioactive components of the extracted materials. The extraction process may also include one or more quantification and identification steps to measure the content of the extract, including the content of cannabinoids as described herein.

Definitions:

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

The term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

A "pharmaceutical agent" or "drug" refers to a chemical compound or composition capable of inducing a desired therapeutic or prophylactic effect when properly administered to a subject.

As used herein, the term "about" refers to a +1-5% variation from the nominal value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to. Other chemistry terms employed herein are used according to conventional usage in the art, as exemplified by The McGraw Hill Dictionary of Chemical Terms (ed. Parker, S., 1985), McGraw Hill, San Francisco.

EXPERIMENTS: Methods

Data source:

We analyzed cross-sectional data from two population based national representative samples, the National Epidemiological Survey on Alcohol and Related Conditions" (NESARC) and the National Comorbidity Survey-Replication¹² (NCS-R). These studies have been described extensively in previous reports"^"14. Both samples are face-to-face surveys of adults aged 18 years and older from the civilian non-institutionalized population residing in the United States.

The NESARC is a survey of 43,093 respondents (response rate, 81%) conducted by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) from 2001-2002. The NCS-R is an independent survey of 9,282 respondents (response rate, 73.0%) conducted by the

National Institute of Mental Health Collaborative Psychiatric Epidemiology Surveys (CPES) from 2001-2003.

Measures:

Measure of current cannabis use In the NESARC, the frequency of cannabis use in the preceding 12 months among users was assessed with the question: "During the last 12 months, about how often did you use marijuana?", with the 5 following possible answers: (i) every day, (ii) 5 to 6 days a week, (iii) 3 to 4 days a week, (iv) 1 to 2 days a week, (v) 2 to 3 days a month, or (vi) once a month or less. In the NCS-R, the frequency of cannabis use in the preceding 12 months among users was assessed with the question: "on average, how often in the past 12 months have you used marijuana or hashish", with the following possible answers: (i) daily, (ii) almost daily (3 to 6 times a week), (iii) 1 or 2 days a week, (iv) several times a month (25 to 51 days a year), (v) 1 to 2 times a month (12 to 24 days a year), (vi) every other month or so (6 to 1 1 days a year), (vii) 3 to 5 days in past 12 months, or (viii) 1 or 2 days in past 12 months.

Based on responses to these two similar questions, respondents were grouped into four categories of cannabis use to increase consistency across the 2 studies: (i) no use in the last 12 months, (ii) at least once a year but less than once a month, (iii) at least once a month to twice a week, and (iv) 3 days a week to everyday.

Measurement of body mass index and obesity

Self-reported height and weight were available from 41,654 respondents in the NESARC and from 9,106 respondents in the NCS-R. Body Mass Index (BMI) was calculated by dividing weight in kilograms by square of height in meters. Individuals were considered obese if their BMI was 30.0 kg/m² or greater (N= 9,879 in the NESARC; N=2,283 in the NCS-R). Previous studies have found that self-reported weight and height are accurate, particularly when adjusting for socio-demographic factors^15"17. We used BMI as a continuous outcome for the linear regression analysis examining the relationship between the frequency of cannabis use and BMI. For all other analyses, we considered obesity as a categorical outcome. Measure of tobacco smoking

Past 12-month cigarette use was coded into 3 categories in both samples: (i) current smoker, defining someone who currently smokes cigarettes daily or occasionally, (ii) ex-smoker, defining a non-user who previously was a daily or occasional smoker, and (iii) never smoked, defining a non-user who has never used any tobacco. Other measures We also considered sociodemographic characteristics, including race, age, educational level and marital status, as well as the use of other drugs in the past 12 months. We did not include household income, since this data was available only in a sub-sample of the NCS-R dataset.

In both the NESARC and the NCS-R, age at interview was categorized into: (i) 18-29, (ii) 30-44, (iii) 45-64 and (iv) >65 years. Marital status was classified into: (i) married or common-law, (ii) widowed, divorced or separated, and (iii) never married. Educational level was classified into: (i) less than high school, (ii) high school graduate, and (iii) some college or higher. Region of residence was classified into: (i) Northeast, (ii) Midwest, (iii) South, and (iv) West. Race/ethnicity coding was different between the two samples. In the NESARC, race/ethnicity was categorized into: (i) white, (ii) black, (iii) Asian/Native Hawaiian Pacific Islander, (iv) Hispanic/Latino, and (5) American Indian/ Alaska Native. In the NCS-R, race/ethnicity was categorized into: (i) white, (ii) black, (iii) Asian, (iv) Hispanic/Latino, and (v) other (including American Indian/Pacific Islander). In the NESARC participants were asked whether they had used sedatives, tranquilizers, opiates, heroin, amphetamine, cocaine/crack, hallucinogens or inhaler in the past 12 months. In the NCS-R participants were asked whether they had used cocaine/crack or any other drug in the past 12 months. In both samples, drug use in the past 12 months was categorized into: (i) no use of other drugs (except tobacco, alcohol and cannabis), and (ii) other drug use in the past 12 months.

Statistical analyses

We first conducted univariate descriptive statistics for the cohorts characteristics across our 4 groups of interest defined according to the frequency of cannabis use last year (respectively: no use in the last 12 months, at least once a year but less than once a month, at least once a month to twice a week, and 3 days a week to everyday). We used Cochran-Mantel-Haenszel χ² statistic to examine the statistical significance of difference observed with categorical dependent variables. The threshold for statistical significance was P<0.05. This analysis was repeated including only the participants who had never smoked tobacco.

We then fit a logistic regression model with obesity as a categorical outcome and the frequency of cannabis use last year as the primary association of interest. We adjusted for sex and age in our first model, and for sex, age, race/ethnicity, educational level, marital status, region of residence, smoking status in our second model. These covariates were chosen because they were associated with the dependent variable in the bivariate analysis. Goodness of fit was determined with the use of the Hosmer-Lemeshow statistic.

We fit a linear regression model with BMI as an outcome and use of cannabis as well as its frequency of use last year as the primary association of interest, adjusting for sex and age.

For all analyses, data was weighted to reflect national population estimates and analyzed using SUDAAN software, version 10.01 (Research Triangle Park, NC), to adjust for the complex sampling design.

Results Of the 50,736 eligible respondents (41 ,633 in the NESARC; 9,103 in the NCS-R), 4.0% of the participants in the NESARC and 7.3% of the participants in the NCS-R reported using cannabis at least once in the past 12 months (Table 1 and 2). The prevalence of obesity was significantly lower in cannabis users vs non-users (16.1% vs 22.0%, respectively, in the NESARC, PO.001 ; 17.2% vs 25.3%, respectively, in the NCS-R, PO.001). Table 1. Characteristics of the NESARC sample.

Cannabis use No use in the past More than once a Once a month to 2 3 days a week to frequency 12 months year, less than days a week everyday once a month n % (SE) n % (SE) n % (SE) n % (SE)

Sex Male 17.161 47.8 329 60.9 350 69.2 309 71.5

(0.3) (2.2) (2.4) (2.4) Female 22,895 52.2 248 39.1 190 30.8 151 28.5

(0.3) (2.2) (2.4) (2.4)

Race/ White 23,756 70.9 387 76.3 318 68.8 240 65.8 ethnicity (1.6) (2.4) (2.8) (2.6)

Black 7,611 10.9 82 10.4 100 12.7 108 15.8

(0.6) (1.5) (1.8) (2.0)

American 631 2.1 (0.1) 10 1.9(0.6) 17 3.4 (0.9) 21 6.3 (1.6)

Indian/Alaska

Native

Asian/Native 1.244 4.4 (0.5) 20 4.0(1.2) 11 3.0(1.0) 7 2.8(1.2) Hawaiian /

Pacific Islander

Hispanic 7.814 11.7 78 7.3(1.2) 94 11.9 84 9.2(1.2)

(1.3) (1.9)

Age 18-29yr 7,562 20.4 306 55.8 264 53.0 278 60.2

(0.4) (2.6) (2.6) (3.1)

30-44 yr 12,412 30.8 202 33.9 187 32.4 129 27.7

(0.3) (2.3) (2.6) (2.8)

45-64 yr 12.145 31.7 70 10.2 84 14.2 56 11.7

(0.3) (1.4) (1.8) (1.9) 65 yr 7,937 17.0 0 0 (0.0) 6 0.4 (0.2) 2 0.1 (0.1)

(0.3)

Educational Less than high 3.165 6.3 (0.3) 8 1.6 (0.7) 11 1.8(0.6) 8 1.0 (0.4) level school

High school 15,787 38.5 198 35.5 225 41.7 269 59.8 graduate (0.6) (2.6) (2.7) (3.1)

Some college or 21.104 55.1 371 62.9 304 56.5 183 39.2 higher (0.6) (2.6) (2.7) (3.1)

Marital Married / 21.010 63.1 164 32.1 127 29.3 130 34.6 status common-law (0.5) (2.4) (2.3) (2.6)

Widowed, 10,486 17.6 99 14.1 112 17.1 67 11.6 divorced or (0.2) (1.9) (1.9) (1.7) separated Never married 8.560 19.3 314 53.7 301 53.7 263 53.7

(0.5 ) (2.5) (2.5) (2.7)

Region Northeast 7.593 19.6 106 19.3 1 10 22.2 92 21.1

(3.4) (3.9) (4.4) (4.2)

Midwest 8,343 23.1 141 25.8 126 24.7 87 18.5

(3.2) (3.8) (4.0) (3.6)

South 15, 163 35.6 156 25.9 128 23.2 132 27.6

(3.3) (3.3) (3.5) (3.9)

West 8.957 21.7 174 29.0 176 30.0 149 32.8

(3.5) (4.5) (4.4) (5.7)

Sample sizes are unweighted values, percentages are weighted values. All analyses are weighted to reflect national population estimates. χ2 statistics are used to compare respondent characteristics among the 4 sub-groups defined by cannabis use. All P values <0.001. Column total may not add to 100 due to rounding.

Table 2. Characteristics of the NCS-R sampk

Cannabis use No use in the More than once a Once a month 3 days a week to frequency past 12 months year, less than to 2 days a everyday once a month week n ^c >/o (SE) n % (SE) n % n %

(SE) (SE)

Sex Male 3,699 46.8 120 52.4 1 15 64.9 126 71.3

(0.5) (3.6) (3.7) (3.9)

Female 4,771 53.2 136 47.6 73 35.1 63 28.7

(0.5) (3.6) (3.7) (3.9)

Race/ White 6, 138 73.7 189 72.5 129 69.7 126 64.8 ethnicity (2.0) (4.6) (4.5) (3.2)

Black 1 , 100 1 1 .3 26 8.7 39 19.6 33 15.0

( 1.2) (1.9) (3.4) (3.0)

Asian 175 2. 1 5 2.4 3 2.0 3 1.9

(0.3) ( 1.2) ( 1.4) (1.3)

Hispanic/ 799 10.7 32 14.4 12 6.9 15 13.3

Latino ( 1.0) (3.7) (2.8) (3.1 )

Others 258 2.2 4 2.0 5 1.8 12 4.9

(0.3) ( 1.1 ) (0.9) ( 1.4)

Age 18-29 yr 1 ,724 20.6 125 53.9 99 57.1 1 13 62.4 ( 1.1 ) (4.2) (4.7) (3.5)

30-44 yr 2,675 29.6 89 30.2 63 30.8 56 26.7

(0.7) (3.6) (3.7) (3.9)

45-64 yr 2,630 32.5 42 15.9 26 12.1 20 10.9

(0.9) (2.8) (2.5) (2.3)

> 65 yr 1 ,441 17.4 0 0.0 0 0.0 0 0.0

(0.5) (0.0) (0.0) (0.0)

Educational Less than high 1 ,235 16.1 21 9.9 3 1 14.3 54 29.1 level school (0.7) (3.1 ) (2.7) (4.3)

High school 2,568 32.3 57 27.8 60 37.6 53 28.4 graduate (1.2) (3.1 ) (3.8) (4.7)

Some college 4,667 51.6 178 62.3 97 48.2 82 42.5 or higher (1.7) (4.3) (4.3) (4.7)

Marital Married / 4,976 57.8 100 33.2 67 27.3 76 32.2 status common-law (1.2) (3.7) (3.5) (3.8)

Widowed, 1 ,887 21.1 45 14.8 23 10.5 28 13.1 divorced or (0.6) (2.6) (2.7) (2.9) separated

Never married 1 ,607 21.1 1 1 1 51.9 98 62.1 85 54.6

(1.1 ) (4.4) (3.4) (3.5)

Region Northeast 1 ,537 19.0 62 26.9 41 23.6 37 19.4

(3.5) (5.7) (3.8) (3.6)

Midwest 2,263 23.2 63 20.3 50 22.3 51 22.3

(1 .8) (3.3) (3.4) (3.4)

South 2,978 36.6 66 27.1 48 25.8 49 24.7

(2. 1 ) (3.7) (3.6) (3.4)

West 1 ,692 21.1 65 25.7 49 28.3 52 33.6

(2.1 ) (3.2) (5.0) (6.7)

The proportion of obese participants decreased with the frequency of cannabis use (Cochran- Mantel-Haenszel χ² test, PO.001 in both samples, Figure 1 ). The prevalence of obesity in participants of the NESARC who reported no cannabis use in the past 12 months was 22.0%, but was only 14.3% in participants who "used cannabis 3 days a week or more" (percentages are weighted and adjusted for survey design). Similarly, the prevalence of obesity in participants of the NCS-R who reported no cannabis use in the past 12 months was 25.3%, but was only 17.2% in participants who "used cannabis 3 days a week or more". The odds ratio of obesity was significantly lower for all groups of cannabis users, in both samples in comparison with those who had not used cannabis in the last 12 months, except from the subgroup of participants of the NCS-R who "used cannabis once a month to 2 days a week" (Table 3).

Table 3. Outcome of multivariate analysis of obesity in the NESARC and NCS-R.

NESARC NCS-R

Adjusted Adjusted Adjusted Adjusted

Cannabis use Crude Crude

Odds ratio³ Odds ratio^b Odds ratio" Odds ratio^b frequency Odds ratio Odds ratio

(95% CI) (95% CI) (95% CI) (95% CI)

No use in the 1 1 1 1 1 1 past 12 months (reference) (reference) (reference) (reference) (reference) (reference)

More than once 0.71 0.76 0.82 0.56 0.61 0.70 a year, less than (0.54-0.92) (0.58-0.98) (0.63- 1.05) (0.36-0.86) (0.38-0.96) (0.44- 1.1 1 ) once a month

Once a month 0.73 0.77 0.79 0.69 0.75 0.84 to 2 days a (0.57-0.93) (0.60-0.98) (0.62- 1.01 ) (0.44- 1.07) (0.49-1.14) (0.54-1.31 ) week

3 days a week 0.59 0.63 0.61 0.61 0.67 0.73 to everyday (0.44-0.79) (0.47-0.84) (0.46-0.82) (0.38-0.99) (0.40- 1.10) (0.43-1.23) Abbreviation: CI, confidence interval. All analyses are weighted to reflect national population estimates. ^a Adjusted for sex and age. ^b Adjusted for sex, age, race/ethnicity, educational level, marital status, region and tobacco smoking status.

When a regression analysis was used to control for the confounding effects of age and sex, the odds ratio of obesity was significantly lower for all groups of cannabis users compared to participants who had not smoked cannabis in the last 12 months in the NESARC (Table 3).

The same regression analysis on the NCS-R sample showed that when controlling for the confounding effect of sex and age, the odds-ratio of obesity was significantly lower in the group of participants using cannabis "more than once a year but less than 1 a month" compared to those who had not smoked cannabis in the last 12 months.

In the NESARC, 53.2% of the participants had never smoked tobacco and 19.2% were ex- smokers. In the NCS-R, 50.5% of the participants had never smoked tobacco and 24.5% were ex-smokers. Table 4 presents the data on tobacco smoking status by the frequency of cannabis use in the last 12 months in both samples. Frequent cannabis users were more likely to be current or ex-smokers (χ² test for heterogeneity, PO.001 in both samples).

Table 4. Tobacco smoking by frequency of cannabis use in the NESARC and NCS-R.

Sample sizes are unweighted and unadjusted values, percentages are weighted values. All analyses are weighted to reflect national population estimates. χ2 statistics are used to compare respondent characteristics among the 4 subgroups defined by cannabis use. All P values <0.001. Column total may not add to 100 due to rounding.

When a regression analysis was used to control for the confounding effect of tobacco smoking status, as well as other sociodemographic variables (sex, age, race/ethnicity, educational level, marital status and region), the odds ratio of obesity was significantly lower in the group of participants using cannabis "more than 3 days a week" than in those who had not smoked cannabis in the last 12 months in the NESARC (Table 3). The same regression analysis in the NCS-R sample showed that when controlling for the confounding effects of smoking status as well as other sociodemographic variables, the odds- ratio were in the same range as those of the NESARC, but not statistically significant. The data were well fitted by the model (P=0.33 in the NESARC, P=0.43 in the NCS-R by the Hosmer-Lemeshow test). We repeated all analyses taking into account the household income in the NESARC sample and in a subsample of 4,591 participants for which this information was available in the NCS-R, and this did not affect the significance of the results (data not shown).

Given that cannabis is often used concurrently with tobacco, and that tobacco smoking affects weight, we also examined the sub-sample of 28,896 participants who reported no use of tobacco in the past 12 months in the NESARC. We found that the use of cannabis was associated with lower rates of obesity in this sub-sample (χ² test for linear trend, PO.01), with obesity rates being 1 1.8% in participants using cannabis "more than 3 days a week", 10.1% in participants using cannabis "1 to 2 times a month", 17.7% in participants reporting using cannabis "at least once a year but less than once a month," and 20.8% in participants who did not use cannabis in the past 12 months. These results remained significant after controlling for sex and age (Cochran-Mantel-Haenszel χ² test, P<0.05). The sample size of the NCS-R was too small to conduct this analysis.

Smoking cannabis was associated with a significantly lower BMI in both samples (β= -1.08 (95% confidence interval [CI], -1.40 to -0.75) and β= -1.21 (95% CI, -1.78 to -0.65), adjusted for sex and age in the NESARC and in the NCS-R, respectively). The relationship between the frequency of cannabis use and BMI showed that smoking cannabis once a year or more was associated with a significantly lower BMI in the NESARC (Table 5). In the NCS-R this association was significant only in the subgroups using cannabis "at least once a year, less than 1 a month" and "more than 3 times a week."

Table 5. Adjusted differences in BMI and frequency of cannabis use in the NESARC and NCS-R. No use in the More than once Once a month to 3 days a week to

past 12 a year, less than 2 days a week everyday

months once a month

Adjusted β Adjusted β Adjusted β Adjusted β

coefficient coefficient coefficient coefficient

(95% Cl) ^a (95% CI) (95% CI) (95% CI)

NESARC Reference -0.73 -1.24 -1.35

(- 1.22 to -0.23) (-1 .82 to -0.65) (-1.90 to -0.80)

NCS-R Reference - 1 .54 -0.74 - 1.25

(-2.38 to -0.71 ) (- 1 .53 to 0.05) (-2.08 to -0.42)

Abbreviation: CI, confidence interval. All analyses are weighted to reflect national population estimates.

"Adjusted for sex and age.

We repeated all analyses on the NESARC sample after excluding women who were pregnant (n= 1,524; information not available in the NCS-R dataset) and this did not affect the significance of the results (P<0.001, Cochran-Mantel-Haenszel χ² test). Due to the suppressive effect of psychostimulants drugs on appetite, a similar analysis excluding participants who reported any illicit drug use other than cannabis in the last 12 months (N=l,408 in the NESARC; N=184 in the NCS-R) has been performed. Excluding those participants did not change the significance of the results (P<0.001 in both samples, Cochran- Mantel-Haenszel χ² test).

This cross-sectional analysis indicates that, despite evidence that cannabis use induces appetite in clinical trials and laboratory studies, cannabis users are actually less likely to be obese than non-users in the general population.

When interpreting these results the following factors were considered. Firstly, information on cannabis use, height and weight were based on self-reports and not confirmed by direct measurement. While self reports tend to underestimate BMI^{I? u}\ they are unlikely to influence conclusions about associations since they are subject to random misclassification. Furthermore, the adjustments made for sociodemographic characteristics in the present study further decreased the risk of misclassification^{16 17}. Secondly, these findings could reflect a cohort effect. However, if obese participants in the NESARC were to avoid a substance because of its effect on weight, obesity would be associated with a lower rate of use of other drugs classically associated with weight gain, such as alcohol. At variance with this hypothesis, alcohol use frequency has been correlated to the BMI in the NESARC^{18 26}.

Nevertheless, the cross-sectional design of this study does not allow for attribution of causality. Taken together, these results show that people using cannabis are less likely to be obese than people who do not use cannabis, even if cannabis consumption increases appetite.

One or more currently preferred embodiments have been described by way of example. It will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims. All documents cited herein are hereby incorporated by reference.

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Claims

1. Use of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof, for the manufacture of a medicament for the treatment or prevention of obesity, regulating appetite, normalizing the need to eat and/or facilitating weight loss in a subject in need thereof.

2. The use of claim 1 , wherein the at least one cannabinoid or derivative thereof is from

Cannabis sativa, Cannabis indica/afghanica, Cannabis ruderalis, other plants of the Cannabis genus, or other plants that contain at least one cannabinoid compound present in Cannabis sativa.

3. The use of claim 1 , wherein the at least one cannabinoid or derivative thereof is a

cannabinol.

4. The use of claim 1, wherein the cannabinol is delta-9-tetrahydrocannabinol or cannabidiol.

5. The use of claim 1 , wherein the at least one cannabinoid or derivative thereof is in a

substantially pure or isolated form.

6. The use of claim 1 , wherein the at least one cannabinoid or derivative thereof is in a

synthetic form.

7. The use of claim 1, wherein the extract prepared from at least one cannabis plant is in the form of a botanical drug substance.

8. The use of claim 1 , wherein the extract prepared from at least one cannabis plant

comprises naturally occurring cannabinoids in said at least one cannabis plant.

9. The use of claim 1 , wherein the subject is a human.

10. The use of claim 1 , wherein said cannabis, at least one cannabinoid or derivative thereof, extract prepared from at least one cannabis plant, or combination thereof is for administration if the subject is overweight with a BMI of about 25 or greater, or obese with a BMI of about 30 or greater.

1 1. A nutraceutical composition or supplement comprising an effective amount of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof.

12. The nutraceutical composition or supplement of claim 1 1, for regulating appetite,

normalizing the need to eat, facilitating weight loss and/or for the treatment or prevention of obesity in a subject in need thereof.

13. A pharmaceutical composition for the treatment or prevention of obesity, regulating

appetite, normalizing the need to eat and/or facilitating weight loss, the composition comprising a therapeutically effective amount of cannabis, at least one cannabinoid or derivative thereof, an extract prepared from at least one cannabis plant, or a combination thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents.

14. The nutraceutical or pharmaceutical composition of any one of claims 1 1 to 13, wherein the at least one cannabinoid or derivative thereof is from Cannabis sativa, Cannabis indica/afghanica, Cannabis ruderalis, other plants of the Cannabis genus, or other plants that contain at least one cannabinoid compound present in Cannabis sativa.

15. The nutraceutical or pharmaceutical composition of claim 14, wherein the at least one cannabinoid or derivative thereof is a cannabinol, preferably delta-9-tetrahydrocannabinol or cannabidiol.