MXPA99010187A - Method of improving disturbed behavior and elevating mood in humans - Google Patents

Abstract

A method for improving disturbed behavior and negative mood in animals suffering from dementia, particularly humans suffering from Alzheimer's type dementia, by administration of dronabinol.

Description

METHOD TO IMPROVE DISRUPTIVE BEHAVIOR AND TO RAISE HUMAN ENCOURAGEMENT RELATED APPLICATIONS This application claims priority over the US provisional patent application No. of. Series 60 / 045,813, which was filed on May 7, 1997 and on the American utility patent application Serial No. 08/866, 511, which was filed on May 30, 1997. GOVERNMENT SUPPORT This invention was conducted with the support of the Government through the Department of Veterans Affairs. The Government may have certain rights over this invention. TECHNICAL FIELD OF THE INVENTION The present invention relates, in general terms, to methods for improving deranged behavior and bad mood in animals, and more specifically said invention relates to methods for improving deranged behavior and bad mood in humans. who suffer from dementia, especially of the Alzheimer type. BACKGROUND OF THE INVENTION Dementia usually refers to a clinical syndrome composed of memory deficiency and loss of other intellectual functions due to chronic progressive degenerative brain disease. Dementia is usually characterized by the gradual loss of intellectual abilities. However, certain abnormalities of behavior and changes in personality are also associated with dementia. There are several states of dementia of multiple causes and different mechanisms. The chronic degeneration of neurons is one of many causes. The majority of dementia diseases appear during semen and many others appear during late adult life. Since the elderly population increases both in percentage of population and in absolute numbers in the Western world, the magnitude of the medical problems presented is alarming. However, dementias are not a consequence of aging. They are diseases linked to age. One of the most common dementias is Alzheimer's dementia (DAT). Alzheimer's disease is a degenerative disease that occurs frequently and that has a devastating nature. Although the disease is very rare in young people, (except in the case of young people with Down syndrome) and it is a rare disease in adults, it is the most frequent cause of dementia in the elderly and is related to depression for patients and their families as well as economic losses resulting from the costs related to the long-term care of patients disabled by the disease. Its prevalence in people older than 80 years is higher than 20%. Alzheimer's disease is frequently associated with a loss of initiative, irritability, loss of interest, forgetfulness, mood swings that often take the form of apathy, as well as excessive mood swings (ie, easy fluctuation between laughter and tears). at the least provocation). Dementia of the Alzheimer type also causes a progressive loss of learned behaviors such as the ability to feed, speech and language disorders, and lack of coordination of voluntary movement. There is therefore a need to have a method to improve the deranged behavior and to improve the mood of patients suffering from dementia. Dronabinol is a cannabinoid that has the chemical designation: (6aR-trans) -ßa, 7, 8, 10a-tetrahydro-6, 6, 9-trimethyl-3-pentyl-6H-dibenzo (b, d) pyran-1 -ol and is also known as delta-9-tetrahydrocannabinol (delta-9-THC). It occurs in nature and has been extracted from Cannabis sativa L. (marijuana). It can also be chemically synthesized. Dronabinol is currently marketed in a formulation having the trademark Marinol® for the treatment of anorexia associated with weight loss in patients with AIDS, and for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have not responded adequately to conventional antiemetic treatments. See Physicians Desk Reference 1997. Studies in patients with AIDS have shown good mood or a feeling of well-being after treatment with dronabinol. Gorter, R., Oncology, 5 (Supplement): 13-17 (1991); Beal et al., J. Pain Sympt. Manag., 10: 89-97 (1995). However, prior to the present invention, dronabinol had not been used or suggested for use in patients with dementia, Alzheimer's patients, particularly, to improve the deranged behavior or to elevate the mood of these patients. Accordingly, it is an object of the present invention to provide a method for improving deranged behavior and for improving mood in patients suffering from dementia, especially of the Alzheimer type. SUMMARY OF THE INVENTION In accordance with the present invention, it has now been discovered that certain manifestations associated with dementias can be effectively treated with dronabinol. Specifically, the present invention focuses on a method for improving the deranged behavior of humans suffering from dementia, said method comprising administering an effective amount of dronabinol. The present invention also provides a method for improving negative mood in humans suffering from dementia, said method comprising administering an effective amount of dronabinol. The methods of the present invention are especially beneficial when applied to patients suffering from Alzheimer's dementia. In the methods of the present invention, dronabinol can be administered alone or in combination with a pharmaceutically effective carrier or other pharmaceutically acceptable additives. In addition, the methods of the present invention can be administered in any suitable manner, including oral, buccal, sublingual, subcutaneous, intramuscular, intravenous, transdermal, and rectal administration, as well as other methods. The amount of dronabinol administered can vary widely. For example, the amount may be from about 0.01 to 35 mg / kg of body weight administered one to five times a day. In addition, dronabinol can be administered concurrently or successively with other drugs, such as, for example, psychoactive drugs. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph identifying changes in the outcome of the Cohen-Mansfield Agitation Inventory during the period of placebo treatment and the period of dronabinol treatment. Figure 2 is a graphical representation identifying changes in the Negative Affectation result during the period of placebo treatment and the period of dronabinol treatment. DETAILED DESCRIPTION OF THE INVENTION In general, the present invention focuses on a method for improving deranged behavior in humans suffering from dementia by administering an effective amount of dronabinol. The present invention also focuses on a method for improving negative mood in humans suffering from dementia through the administration of an effective amount of dronabinol. The method of the present invention can be used to treat any type of deranged behavior or negative mood, but more preferably it is used to treat the deranged behavior and negative mood associated with dementia in humans. There are several diseases and medical conditions associated with human dementia for which dronabinol may be useful, including Alzheimer's disease, Pick's disease, Huntington's chorea, leukodystrophies, lipid storage diseases such as lipofusinosis, Creutzfeltd-Jakob, dementia due to multiple infarction, post-traumatic dementia, intracranial masses, normal pressure hydrocephalus. Particularly, the method of the present invention improves deranged behavior and elevates mood in patients suffering from Alzheimer's dementia. Although dementias are associated with various clinical manifestations, in a preferred embodiment of the methods of the present invention, dronabinol can improve the various deranged behaviors found in patients affected by dementia., including, but not limited to, aimless displacement, inappropriate dressing, spitting, uttering high-sounding words or verbal aggression, constant unjustified request for attention or help, repetitive prayers or questions, beating, kicking, grabbing people, pushing, throwing things, making strange noises, screaming, biting, scratching, trying to get to a different place, fall intentionally, complain, be negative, eat / drink inappropriate substances, injure or injure others, handle things inappropriately , hide things, store things, break things, or destroy property, perform repetitive movements, make sexual proposals, general restlessness, and strange movements or make faces. In addition, the method of the present invention can raise the mood of patients suffering from any of the following mood states, including, but not limited to, anger, anxiety or fear, and depression or sadness. Although many types of dementia frequently affect humans 65 years and older, the method of the present invention can be applied to any insane patient regardless of age. Dronabinol can also be administered to a demented patient regardless of the duration of the period of time during which the patient has been affected by said dementia, either one day or many years. In addition, dronabinol can be administered to a demented patient for the entire time required up to improvement of the deranged behavior or elevation of the patient's mood. Dronabinol is a cannabinoid that has complex effects on the central nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. It is believed that these receptors can play a role in measuring the effects of dronabinol on the central nervous system. Alzheimer's disease and other progressive dementias cause the death of nerve cells. This causes the brain to have no substances, such as neurotransmitters, which are necessary for normal brain function. These substances stimulate specific receptors and coordinate the function of brain cells. Even though the endogenous transmitter that stimulates cannabinoid receptors is unknown, it is believed to exist. Therefore, it is postulated that certain symptoms observed in Alzheimer's disease are due to the lack of this endogenous transmitter. The administration of dronabinol can replace the lack of this endogenous transmitter. It is theoretically stated that the administration of dronabinol can replace the lack of this endogenous transmitter and improve brain function affected by cell loss. It is further considered that dronabinol may have a prolonged effect on deranged behavior and bad mood. For example, it has been reported that tetrahydrocannabinol metabolites are present in the urine up to 77 days after the ingestion of marijuana (Ellis et al., Clin. Pharmacol. Ther., 38: 572-78 (1985)). The pharmacokinetic characteristics of dronabinol can be described through a four compartment model, with an initial half-life of four hours and a terminal half-life of 25-36 hours (Aguerrí et al., Pharmacol. Rev., 38: 21-43 (1986)). However, low levels of dronabinol metabolites have been detected in urine and faeces 2-5 weeks after the onset of supervised abstinence (Dackis et al., Am. J. Psychiatry, 139: 1196-98 (1982) ). Even though dronabinol affects the central nervous system, it is not believed to increase paranoid reactions and hallucinations, confusion, ataxia, or speech difficulties that would affect the cognitive or functional abilities of Alzheimer's patients. In accordance with the methods of the present invention, dronabinol can be administered in the form of a composition, including a pharmaceutical composition, comprising dronabinol. Preferably, the composition additionally comprises a pharmaceutically acceptable carrier. One skilled in the art will observe that suitable methods of administration of dronabinol compositions of the present invention to an animal, such as a mammal, are available and, although more than one route of administration of a particular composition may be employed, a A particular route can cause a more immediate and more effective reaction than another route. Pharmaceutically acceptable carriers are also well known to those skilled in the art. The choice of the vehicle will be determined, in part, both by the particular composition and by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical compositions of the present invention. Suitable specific forms of administration include oral forms, buccal and sublingual forms of administration, subcutaneous, transdermal, intramuscular or intravenous forms of administration and rectal forms of administration, as well as forms by inhalation. For topical application, the compounds according to the present invention can be used in creams, ointments or lotions. The pharmaceutical compositions of the present invention for oral, buccal, nasal, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal administration, dronabinol can be administered in prolonged or controlled release forms or in unitary administration forms mixed with carriers. Pharmaceutical standards to humans or animals. The formulations can conveniently be prepared by any of the methods well known in the art. Formulations suitable for oral administration may consist of (a) liquid solutions, such as for example an effective amount of dronabinol dissolved in diluents such as water, oil or saline, (b) capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient, such as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions. The tablet forms may include one or more of the following: lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, wetting agents, preservatives, flavors, and pharmacologically compatible vehicles. The tablets may comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as tablets comprising the active ingredient in an inert base, such as for example gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing , in addition to the active ingredient, these vehicles as is known in the art. Dronabinol, alone or in combination with other suitable components, can be prepared in aerosol formulations for administration by inhalation. These aerosol formulations can be placed in acceptable propellants under pressure, such as, for example, dichlorodifluoromethane, propane, nitrogen, and the like. Formulations suitable for parenteral administration include aqueous and non-aqueous solutions, sterile isotonic injection solutions, which may contain anti-oxidants, regulators such as for example acetate and phosphate, toxicity adjusting agents, such as for example sodium chloride, pH, such as for example hydrochloric and phosphoric acid, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient, as well as sterile aqueous and non-aqueous suspensions which may include suspending agents, solubilizers, thickening agents, stabilizers and preservatives. The formulations may be presented in single dose or multiple dose sealed containers, such as ampoules and flasks, and may be stored in a lyophilized condition that requires only the addition of the sterile liquid vehicle, eg, water for injections, immediately prior to use. . Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type previously described. In a preferred embodiment, the dronabinol is administered in the form of an oral capsule composition containing 2.5 mg, 5 mg, or 10 mg of dronabinol, sesame oil, gelatin, glycerin, methyl paraben, propyl paraben, and titanium dioxide. The dose administered to an animal, particularly a human being, in the context of the present invention should be sufficient to obtain a therapeutic response within a reasonable time frame. The dose is determined by the strength of the particular compositions employed and the condition of the person, as well as the body weight of the person to be treated. The size of the dose will also be determined by the existence, nature, and magnitude of the adverse side effects that may accompany the administration of a particular composition. A suitable dosage for internal administration is 0.01 to 100 mg / kg per day. The preferred dosage is 0.01 to 35 mg / kg per day. A more preferred dosage is 0.05 to 5 mg / kg per day. A suitable concentration of dronabinol in pharmaceutical compositions for oral administration is 0.05 to 15% (by weight). A preferred concentration is 0.02 to 5%. A more preferred concentration is from 0.1 to 4%. They are especially orally administered from 0.03 to 0.06 mg / kg of body weight per day, and more preferably, a dosage form of oral 2: 5 mg is administered twice a day. The most preferred dosage for extracorporeal administration is within a range of about 0.1 mg / kg to 5 mg / kg of body weight per day.

In the case of rectal administration route, topical (including buccal and sublingual) or transdermal, the preferred dosage (estimated as the base) is within a range of 0.05 mg / kg to 20 mg / kg of body weight per day. Even when dronabinol can be administered as needed, preferably dronabinol is administered one to five times a day. Dronabinol can be administered concurrently with other necessary medications. For example, one or several psychoactive medications can be administered before, concurrently and after treatment with dronabinol. Examples of psychoactive drugs of this type include, but are not limited to, antidepressants, neuroleptics and benzodiazepines. Specific neuroleptic drugs include, but are not limited to, ferfenazine, thiothixene, haloperidol, and thioridazine. Specific benzodiazepines include, but are not limited to, lorazepam and alprazolam. Specific antidepressants include, but are not limited to, sertraline, trazodone and desipramine. Although the preferred embodiment of the present invention is the treatment of dementia, particularly of the Alzheimer's type, in humans, the methods of the present invention can be used to treat deranged behavior and to elevate mood in animals of any type. Examples of suitable animals include, but are not limited to, dogs, pigs, sheep, horses, cows and cats. All publications mentioned or referenced here are incorporated by reference in their entirety. The present invention will be further illustrated through the following example. This example serves to further illustrate the present invention and is not intended to limit the scope of said invention. EXAMPLE Each patient in this example was diagnosed with "probable" DAT by a neurologist in accordance with DSM III-R and criteria NINCDS-ARDDA. These generally accepted criteria include deficits in two or more areas of cognition, progressive worsening of memory and other cognitive functions, no disturbances of consciousness, absence of systemic disorders, and other brain diseases that, in themselves, could explain the progressive deficits of memory and cognition. (McKhann et al., Neurology, 34: 939-944 (1984).) Each patient underwent a physical examination and a laboratory examination including complete blood count with differential liver function tests, thyroid function tests including TSH , BUN iron binding capacity, creatinine, and electrolytes The severity of dementia in each patient was measured by the Mini-mental Status Examination (MMSE) .The MMSE is generally known in the art and is is described in Folstein et al., J. Psychiatr Res., 12: 189-198 (1975), Katz Activity of Daily Living scale (Katz ADL) (Katz et al., JAMA, 185: 914-19 (1963) , and Bedford Alzheimer's ursing Scale-Sverity (BANS-S) (Bedford's Alzheimer's Care severity scale) (Volicer et al., J. Gerontol., 49: M223-26 (1994).) These data are reported in Table 1 Table 1 Average characteristic + deviation standard range * Age (years) 72.7 + 4.9 65 - 82 Sex 11 male sex 1 female DAT duration (years) 7.0 + 4.1 2 - 16 Duration of care of 17.4 _ + 21.9 2.6 - 81.0 long term before the start of the study (months) Result of mini-examination of 4.0 + 7.4 0 - 20 mental state (11) Result of the activity 5.7 + 0.6 4 - 6 of Katz of the daily life (12) severity score according to 17.5 + 3.0 13 - 22 Bedford's Alzheimer's care scale (13) * SD it refers to the standard deviation. The patients included in the analysis were all 65 years of age or older and all patients except one were men. The duration of DAT ranged from 2 to 16 years and most patients had undergone institutional long-term care for many months before the start of the study. Most of them looked like severe dementia; the result of MMSE was 0 in 8 patients. The patients also had affected activities of daily life; 9 were dependent on the 6 activities. The results of BANS-S, which detect the progression of the disease even in the severe stage, indicated a moderate to severe affectation. Eleven of the patients were taking a psychoactive drug before the start of the study with dronabinol and they continued with the ingestion of this drug during the study period. Four patients were receiving regular doses of neuroleptics (perphenazine, thiothixene, haloperidol or dflfc thioridazine), 4 patients were receiving regular doses of benzodiazepines (3 received lorazepam and 1 alprazolam), and 8 patients were receiving regular doses of antidepressants. Antidepressants included sertraline (8 patients), trazodone (4 patients) and desipramine (1 patient), 9 three patients were receiving both sertraline and trazodone, and one patient was switched from trazodone to doxephema.Treatment with antidepressants was initiated at least 4 weeks before the start of the study and the average duration of antidepressant treatment before the start of the study was 7 months. Eleven patients presented orders for psychoactive drugs as needed (PRN). These drugs included lorazepam in 4 patients and alprazolam, trazodone, doxepin, haloperidol, perphenazine and thioridazine in one patient each. Patients received these drugs very rarely, on average 9.7 doses / 6 weeks during the administration of placebo and 7.2 doses / 6 weeks during treatment with dronabinol. A double-blind placebo-controlled cross-over design was employed with each study period lasting 6 weeks. Dronabinol or placebo was administered in a fixed dose schedule, 2.5 mg capsule or placebo capsule with identical appearance every morning at 12 o'clock. Patients were randomly assigned to placebo groups first or dronabinol first. Possible side effects were determined each week by asking primary care staff if the patient had a list of possible symptoms. A list of these symptoms was observed in 12 patients over seventy weeks in accordance with what is identified in Table 2 below. Table 2 SYNTOMA DRONABI OL PLACEBO Patients Weeks Patients Weeks n * nnn Anxiety / 11 92 37 53 12 100 43 61 nervousness Affectation 11 92 32 46 10 83 36 51 emotional Tiredness 9 75 25 36 42 15 21 Sleepiness 8 67 29 41 4 33 12 17 Euphoria 7 58 31 44 5 42 16 23 Reaction 4 33 16 23 5 42 18 26 paranoid Hallucination 4 33 11 16 5 42 16 23 Depression 2 16 4 6 2 16 4 6 Ataxia 2 16 6 8 2 16 3 4 Pain 2 16 7 10 1 8 3 4 muscular Diarrhea 2 16 3 4 Blushing 1 8 2 3 2 16 2 3 Confusion 1 8 2 3 2 16 2 3 increasing sweat 1 8 2 3 1 8 1 1 Difficulty 1 8 1 1 increasing speech Headache 1 8 1 1 Nightmares 1 8 1 1 * refers to the number of patients who had the listed effect and% identifies the percentage of total patients who had the effect. In addition to the listed effects, an attack incidence was observed in a patient treated with dronabinol. The baseline measurements were taken one week prior to randomization and initiation of treatment. Behavioral measurements were obtained weekly during the 12-week duration of the trial. Repeated measurements of these variables were therefore available for six weeks of treatment with dronabinol and six weeks of placebo treatment for each patient. The magnitude of disordered behavior presented by each patient was determined each week through interviews with primary health care personnel, who were family members, based on the patient's behavior rating scales. Deranged behavior was measured by the Cohen-Mansfield Agitation Inventory (CMAI) (Cohen-Mansfield Agitation Inventory (Cohen-Mansfield et al., J. Gerontol, Med. Sci., 44: M77-84 (1989)) which It is a widely used instrument with good psychometric properties, Twenty-nine elements of this inventory are scored through frequency (1 = never and 7 = constantly or almost constantly) and by the level of disorder (from 1 = no disorder to 5 = disorder For each observation period, the total result was calculated by multiplying the frequency and impact of the disorder of the individual elements and by adding the products.The elements of CMAI observed are identified in Table 3 below: TABLE 3 - ELEMENTS OF BEHAVIOR OF CMAI OBSERVED Speed, displacement without direction Inappropriate dress, undress Spit (including during food) Use of high-sounding words or verbal aggression Constant unjustified request for attention or help Repetitive prayers or questions (beating (including self-kicking) Kicking Holding on to people Pushing Throwing things Strange noises (strange laughter or whining) Screaming Biting Scratching Attempting to get to a different place (for example, outside the ward) Intentional falling Complaints Negative condition Eating / drinking inappropriate substances Hurting yourself or others (hot water, for example) Handling things inappropriately Hide things Store things Break things or destroy properties Perform repetitive acts 5 Make unseemly verbal proposals General uneasiness Strange movements, making faces Acceptance of patients was measured using Lawton Observed Affect Scale - Past (Lawton et al., J. Gerontol.

(B), 51B: P3-14 (1996)). This scale consists of six elements, three that measure the positive affectation (pleasure, interest and happiness) and three that measure the negative affectation (anger, anxiety / fear and depression / sadness) on a scale of points (from 1 = never to 5 = more than 3 times a day). The 15 results of the positive and negative affectations were calculated by adding the results of the appropriate elements. Statistical analysis was carried out using Statistix 4. 1 (Analytic Software). Repeated ANOVA measurements during the 12 weeks of the study were carried out to test the effects of the variables of order, time and treatment under study. Figure 1 is a graphical representation showing the result of CMAI during the placebo and dronabinol phases of the study. Deranged behavior decreased during treatment with dronabinol (F (order x treatment) = 2.18, df = 1143, p = 0.12) and this decrease in deranged behavior persisted during the placebo period after treatment with dronabinol. When the results of CMAI were expressed as a percentage of the baseline, a significant order x time interaction was observed (F = 2.35 (order x time), df = 5.143, P = 0.05). Figure 2 is a graphic representation of the changes in the outcome of negative affectation during the placebo and dronabinol phases. Negative affectation decreased during the study period of 12 weeks (F (time) = 2.46, df = 5, 143, p = 0.045) and decreased more when patients were treated with dronabinol than when patients were treated with placebo (F (time x treatment) = 3.98, df = 5.143, p = 0.004). In addition, the decrease was greater in the case of patients who received dronabinol first, compared with patients who received placebo first (F (order x time) = 5.45, df = 5.143, p <0.0005). In contrast, the positive affectation remained similar during both treatments (dronabinol and placebo) and treatment periods (the six-week dronabinol phase and the six-week placebo phase). We observed a widespread agitation using two scales: CMAI and Observed Affect Scale (Scale of observed affectation). The negative phase of the Observed Affect Scale includes two elements (anger and anxiety / fear) that are commonly present in patients during agitated behaviors. The third element of pressure / sadness was rarely observed as can be seen from Table 2. Therefore, both scales measured similar deranged behaviors. It is possible that this effect is partially due to drowsiness, which is twice as common in patients treated with dronabinol than in patients receiving placebo. The effect of dronabinol on deranged behavior continued during the subsequent placebo period. No differences were observed in deranged behavior in the second treatment period. This prolonged change in disordered behavior could be due to a long-term effect of dronabinol. Treatment with dronabinol did not change the Positive Affectation, even when the euphoria as an adverse reaction was reported more frequently and in a larger number of patients during the treatment with dronabinol than during the periods in which the patients received placebo. It is possible that the elements of Positive Affectation represent more a degree of patient involvement than the patient's mood (Lawton et al., Psicol.Aging, 3: 469-477 (1995)).

While this invention has been described with emphasis on preferred embodiments, it will be apparent to those of ordinary skill in the art that variations as to the preferred methods of the present invention can be employed and that the possibility that the invention is practiced from a differently from what is specifically described here. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention, as defined in the following claims.

Claims (1)

1. REI INDICATIONS A method for the treatment of humsuffering from dementia, comprising the administration of a therapeutically effective amount of dronabinol to said human beings. The method of claim 1, wherein said dementia comprises Alzheimer's type dementia. The method according to claim 1, wherein said dronabinol is administered in combination with a pharmaceutically effective carrier. The method according to claim 1, further comprising the administration of a psychoactive drug. The method according to claim 4, wherein said psychoactive drug is selected from the group consisting of antidepressants, neuroleptics and benzodiazepines. The method according to claim 1, wherein dronabinol is administered to said human beings orally. The method according to claim 6, wherein the dronabinol is administered in an amount of about 0.03 to about 0.06 mg / kg of body weight per day. The method according to claim 6, wherein 2.5 mg of dronabinol are administered twice a day.