Abstract:
The invention provides methods for treating or suppressing marihuana usage, withdrawal, or dependence involving administration of a therapeutically-effective amount of a cytosine-containing or cytidine-containing compound, uridine-containing compound, creatine-containing compound, adenosine-containing, or adenosine-elevating compound to a mammal.

Description:
BACKGROUND OF THE INVENTION 
     This invention relates to methods for the treatment or suppression of marihuana dependence, withdrawal, or usage. 
     Substance abuse disorders present unique complications for patients, clinicians, and care givers. These disorders are difficult to diagnose unequivocally and fear of societal condemnation, as well as lack of simple and effective therapies, often results in patients who are reluctant to disclose their symptoms to health professionals, leading to adverse societal and health consequences. Substance abuse disorders, e.g., marihuana usage or dependence, occur in people of all ages and backgrounds. 
     Use of substances such as marihuana often leads to addiction and dependence on these substances, causing a variety of adverse consequences, including clinical toxicity, residual neuropsychological impairment, memory loss, physical dependence and withdrawal symptoms, and an impaired ability to maintain social and professional relationships. In addition, marihuana is the most widely abused illicit drug in the world. The etiology of substance abuse or dependence is unknown, although factors such as the user&#39;s physical characteristics (e.g., genetic predisposition, age, weight), personality, or socioeconomic class have been postulated to be determinants. 
     Simple and effective pharmacological treatments for these disorders have proven scarce to date. It would be beneficial to provide pharmacotherapies suitable for administration to all populations, including children and pregnant women, for the treatment of marihuana dependence, withdrawal, or usage. 
     SUMMARY OF THE INVENTION 
     In general, the invention features methods of treating or suppressing marihuana dependence, withdrawal, or usage by administering a therapeutically-effective amount of a cytidine-containing, cytosine-containing, creatine-containing, uridine-containing, adenosine-containing, or adenosine-elevating compound to a mammal. Any of the cytidine-containing, cytosine-containing, creatine-containing, uridine-containing, adenosine-containing, or adenosine-elevating compounds of the invention may be administered separately or in combination. 
     Specific effects of dependence, withdrawal, or usage that may be treated by the methods described herein include psychomotor performance deficits, memory loss, sleep disorders, decreased appetite, emotional symptoms (e.g., increased aggression, anger, anxiety, irritability, nervousness, or restlessness), physical symptoms (e.g., tension, headache, hot flashes, nausea, chills, or sweating), and craving (e.g., caused by withdrawal, drug exposure, stress, or cues). The methods may also be used for primary or secondary treatment of neurobiological damage associated with chronic marihuana use, e.g., general memory deficits and impairment in learning, retention, and retrieval. 
     In preferred embodiments, the cytidine-containing compound is cytidine or CDP. The cytidine-containing compound may include choline, e.g., CDP-choline. The uridine-containing compound is, for example, uridine, UMP, UDP, UTP, or triacetyl uridine. The mammal is, for example, a human child (e.g., born to a dependent mother), adolescent, adult (e.g., a pregnant woman), or older adult. In other preferred embodiments, the CDP-choline is administered orally and the administration is chronic, e.g., treatment occurring over a period of greater than 1, 2, 3, 4, 5, 6, 7, 14, 21, 30, 60, 90, or 180 days or even over a period of greater than one year. In one embodiment, treatment of marihuana withdrawal occurs over at least 10 days, e.g., for one month. 
     The method may also include diagnosing the mammal with marihuana dependence, withdrawal, or usage prior to administration of a therapeutic compound. In addition, the mammal may remain under the care of a physician during treatment. Treatment may further include psychological intervention, such as cognitive behavioral therapy for treating insomnia or Group Drug Counseling. 
     The methods of the invention may treat or suppress marijuana dependence, withdrawal, or usage in a mammal that may or may not have a co-morbid condition. Such co-morbid conditions include co-morbid drug use or dependence, e.g., from alcohol, nicotine, cocaine, opiates, or caffeine; neurological or psychiatric conditions, e.g., depression, dysthymia, and attention-deficit hyperactivity disorder; sleep disorders, e.g., insomnia, constructive or obstructive sleep apnea, restless leg syndrome, periodic limb movements, problem sleepiness, or narcolepsy; or a physical condition. The methods of the invention may also be employed on mammals that are otherwise physically and/or mentally healthy. 
     In other preferred embodiments, a brain phospholipid (e.g., lecithin) or a brain phospholipid precursor (e.g., a fatty acid or a lipid) is also administered to the mammal. An antidepressant may also be administered to the mammal. 
     By use of “marihuana” is meant use of any form of marihuana including cigarettes and brownies. The term also encompasses formulations including a tetrahydrocannabinol (e.g., Δ 1 -3,4-trans isomer or Δ 6 -3,4-trans isomer), the active ingredients in marihuana. 
     By “abuse” is meant excessive use of a substance, particularly one that may modify body functions. 
     By “dependence” or “dependency” is meant any form of behavior that indicates an altered or reduced ability to make decisions resulting, at least in part, from the use of marihuana. Representative forms of dependency behavior may take the form of antisocial, or inappropriate behavior and include those behaviors directed at the desire, planning, acquiring, and use of marihuana. This term also includes the psychic craving for marihuana that may or may not be accompanied by a physiological dependency, as well as a state in which there is a compulsion to use marihuana, either continuously or periodically, in order to experience its psychic effects or to avoid the discomfort of its absence. Forms of dependency include habituation, that is, an emotional or psychological dependence on marihuana to obtain relief from tension and emotional discomfort; tolerance, that is, the progressive need for increasing doses to achieve and sustain a desired effect; addiction, that is, physical or physiological dependence which is beyond voluntary control; and use of marihuana to prevent withdrawal symptoms. Dependency may be influenced by a number of factors, including physical characteristics of the user (e.g., genetic predisposition, age, gender, or weight), personality, or socioeconomic class. 
     By marihuana “usage” is meant the intake of marihuana by any route. The term also includes marihuana abuse. 
     By “treating” is meant the medical management of a patient with the intent that a cure, amelioration, or prevention of a disease, pathological condition, or disorder will result. This term includes active treatment, that is, treatment directed specifically toward improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventive treatment, that is, treatment directed to prevention of the disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the disease, pathological condition, or disorder. The term “treating” also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of the disease, pathological condition, or disorder. 
     By “suppressing” is meant reducing the desire, need, or number of usages of marihuana. 
     By “therapeutically-effective amount” is meant an amount of a cytidine-containing, cytosine-containing compound, a uridine-containing compound, a creatine-containing compound, an adenosine-containing compound, and an adenosine-elevating compound sufficient to produce a healing, curative, prophylactic, stabilizing, preventative, or ameliorative effect in the treatment or suppression of marihuana usage, withdrawal, or dependence. 
     By “cytidine-containing compound” is meant any compound that includes, as a component, cytidine, CMP, CDP, CTP, dCMP, dCDP, or dCTP. Cytidine-containing compounds can include analogs of cytidine. Preferred cytidine-containing compounds include, without limitation, CDP-choline and cytidine 5′-diphosphocholine, frequently prepared as cytidine 5′-diphosphocholine [sodium salt] and also known as citicoline. 
     By “cytosine-containing compound” is meant any compound that includes, as a component, cytosine. Cytosine-containing compounds can include analogs of cytosine. 
     By “adenosine-containing compound” is meant any compound that includes, as a component, adenosine. Adenosine-containing compounds can include analogs of adenosine. 
     By “adenosine-elevating compound” is meant any compound that elevates brain adenosine levels, for example, compounds which inhibit or alter adenosine transport or metabolism (e.g., dipyridamole or S-adenosylmethionine). 
     By “uridine-containing compound” is meant any compound that includes as a component uridine or UTP. Uridine-containing compounds can include analogs of uridine. Exemplary uridine-containing compounds include uridine, orotic acid, mono-, di- or tri-esters of uridine, including mono-, di-, and triacetyl uridine, and mono, di- or tri-phosphates of uridine including UMP, UDP, and UTP. 
     By “creatine-containing compound” is meant any compound that includes as a component, creatine. Creatine-containing compounds can include analogs of creatine. 
     By “phospholipid” is meant a lipid containing phosphorus, e.g., phosphatidic acids (e.g., lecithin), phosphoglycerides, sphingomyelin, and plasmalogens. By “phospholipid precursor” is meant a substance that is built into a phospholipid during synthesis of the phospholipid, e.g., fatty acids, glycerol, or sphingosine. 
     By “child or adolescent” is meant an individual who has not attained complete growth and maturity. Generally, a child or adolescent is under twenty-one years of age. 
     By “older adult” is meant an individual who is in the later stage of life. Generally, an older adult is over sixty years of age. 
     The compounds utilized herein are relatively non-toxic, and CDP-choline, uridine, and triacetyl uridine, in particular, are pharmacokinetically understood and known to be well tolerated by mammals. The present invention, therefore, provides treatments that are likely to have few adverse effects and may be administered to children and adolescents, as well as the elderly, or those whose health is compromised because of existing physical conditions. 
     Other features and advantages will be apparent from the following description and the claims. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a graph of a time course of weekly marihuana use in citicoline- and placebo-treated cocaine-dependent subjects. Subjects were treated with either citicoline or placebo for 8 weeks and then asked to keep track of their drug use patterns via a daily diary. Follow up weeks were conducted under a no drug condition. 
         FIG. 2  is a graph of activity of a representative cocaine dependent person two weeks prior to (Baseline) and two weeks after (Citicoline) treatment with citicoline. The graph shows a detailed distribution of sleep wake activity (vertical black lines), marihuana use (arrows), and citicoline treatment (dots) in a representative subject. Marihuana cigarettes are depicted by the arrows. Each strip recording is a 24 hour period of consecutive days. Activity was determined by use of an accelerometer worn on the subject&#39;s wrist (ActiWatch Score). 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The invention described herein features methods for the treatment or suppression of marihuana dependence, withdrawal, or usage. 
     To this end, the invention features the use of cytidine-containing, cytosine-containing, uridine-containing, creatine-containing, adenosine-containing, and adenosine-elevating compounds to alleviate symptoms of these disorders. A preferred cytidine-containing compound is CDP-choline (also referred to as citicoline or CDP choline [sodium salt]), a preferred adenosine-containing compound is S-adenosylmethionine (SAMe), and a preferred uridine-containing compound is triacetyl uridine. Compounds useful in the methods described herein also include encapsulated compounds, e.g., liposome- or polymer-encapsulated cytidine-containing, cytosine-containing, uridine-containing, creatine-containing, adenosine-containing, and adenosine-elevating compounds. Useful compounds further include those linked (e.g., covalently or non-covalently) to various antibodies, ligands, or other targeting and enveloping or shielding agents (e.g., albumin or dextrose), to allow the cytidine-containing, cytosine-containing, uridine-containing, creatine-containing, adenosine-containing, or adenosine-elevating compound to reach the target site (e.g., the central nervous system) prior to being removed from the blood stream, e.g., by the kidneys and liver, and prior to being degraded. 
     The cytidine-containing, cytosine-containing, uridine-containing, creatine-containing, adenosine-containing, or adenosine-elevating compounds may also be co-administered with other compounds that are precursors for the synthesis of brain phospholipids, e.g., fatty acids, lipids, or lecithin. 
     Marihuana Usage, Withdrawal, or Dependence 
     Surprisingly, we have discovered that CDP-choline is useful for the treatment of marihuana dependence, withdrawal, or usage, and believe that other, related compounds may be similarly useful.  FIG. 1  shows data collected from daily diaries that marihuana use in the subjects typically ranged from 5-10 cigarettes per week. Compared to placebo treatment, marihuana use was reduced during citicoline treatment (weeks 3-10) as reported using the daily diaries. Marihuana use during placebo treatment, while variable, did not decline below baseline levels. There is a group difference at baseline; this difference occurred because subjects were not matched for marihuana use in this study, and these subjects were not dependent on cannabis. Despite this difference, these data revealed an effect on marihuana intake between treatment with citicoline and placebo. 
     Data in  FIG. 2  also show a decrease in the number of marihuana cigarettes smoked and a more normalized, diurnal sleep pattern after treatment with citicoline. Subjects were given either placebo or 500 mg, twice daily of citicoline. This subject, and other cocaine-dependent subjects, displayed a disrupted degree of physical activity, as seen by a low amplitude of the accelerometer (vertical lines), during active drug use typical of the baseline period (Baseline, top 5 tracings). The subject&#39;s binge use of marihuana (arrows on second day) is clearly defined. The bottom 4 tracings of  FIG. 2  show the same subject on days 10-14 of citicoline treatment. In addition to the reduced marihuana use, citicoline impacted the subject&#39;s sleep wake profile—the subject developed a more normalized diurnal pattern of sleeping at night and became more active during the day. This pattern continued throughout the 8 weeks of treatment for this subject. 
     The success of treatment may be monitored by methods known in the art, e.g., analytical methods (e.g., blood or urine tests), objective measures of sleep activity (e.g., from a wrist actigraphy device (ActiWatch); see also U.S. application Ser. No. 10/740,075), daily diaries, patient interview (e.g., via the Addictive Severity Index) and self evaluation (e.g., patients may evaluate the severity of symptoms on a numerical scale), and neurological function tests (such as Wisconsin Card Sorting, Trail Making Part B, Block Design, Digit Symbol Substitution Test (DSST), Digit Span, and Stroop). 
     Use of marihuana, especially chronic use or abuse, may result in symptoms such a psychomotor performance deficits, memory loss, sleep disorders, reduced cognitive performance, reduced selective attention, and neurobiological damage (such as general memory deficits and impairment in learning, retention, and retrieval). 
     Symptoms of marihuana withdrawal include increases in drug craving, decreased appetite, difficulty sleeping, memory loss, psychomotor performance deficits, emotional symptoms (such as increased anger, aggression, restlessness, nervousness, anxiety, irritability, and tension), and physical symptoms (such as headache, hot flashes, nausea, chills, and sweating) (Budney et al. Arch Gen Psychiatry 2001, 58:917). Symptoms of withdrawal are typically most pronounced in the first ten days, e.g., 1-7 days, after cessation of marihuana use. Treatment of withdrawal can be monitored by methods known in the art, e.g., by monitoring a Global Symptom Severity index (Kouri et al. Psychopharmacology 1999, 143: 302; Kouri et al. Exp Clin Psychopharmacol 2000, 8:483-492). 
     Marihuana craving may be a substantial factor in a subject&#39;s inability to reduce marihuana usage. Craving may occur through several mechanisms, e.g., withdrawal-related craving, cue-triggered craving (craving caused by reminders of past drug use), drug exposure triggered craving, and stress-triggered craving. End points for treating craving include preventing craving, reducing craving, and preventing drug use in the presence of craving. Craving may be measured by methods known in the art, such as a questionnaire (Heishman et al. Addiction 2001, 96:1023). 
     Cytidine-Containing and Cytosine-Containing Compounds 
     Useful cytidine-containing or cytosine-containing compounds may include any compound comprising one of the following: cytosine, cytidine, CMP, CDP, CTP, dCMP, dCDP, and dCTP. Preferred cytidine-containing compounds include CDP-choline and cytidine 5′-diphosphocholine [sodium salt]. This list of cytidine-containing and cytosine-containing compounds is provided to illustrate, rather than to limit the invention, and the compounds described above are commercially available, for example, from Sigma Chemical Company (St. Louis, Mo.). 
     CDP-choline is a naturally occurring compound that is hydrolyzed into its components of cytidine and choline in vivo. CDP-choline is synthesized from cytidine-5′-triphosphate and phosphocholine with accompanying production of inorganic pyrophosphate in a reversible reaction catalyzed by the enzyme CTP:phosphocholine cytidylyltransferase (Weiss, Life Sciences 56:637-660, 1995). CDP-choline is available for oral administration in a 500 mg oblong tablet. Each tablet contains 522.5 mg CDP-choline sodium, equivalent to 500 mg of CDP-choline. Matching placebo tablets are also available. Other excipients contained in both active and placebo tablets are talc, magnesium stearate, colloidal silicon dioxide, hydrogenated castor oil, sodium carboxy-methylcellulose, and microcrystalline cellulose. 
     Other formulations for treatment or suppression of marihuana usage or dependence may take the form of a cytosine-containing or cytidine-containing compound combined with a pharmaceutically-acceptable diluent, carrier, stabilizer, or excipient. 
     Adenosine-Containing and Adenosine-Elevating Compounds 
     Adenosine-containing or adenosine-elevating compounds also provide useful therapies. Useful adenosine-containing or adenosine-elevating compounds include, without limitation, any compound comprising one of the following adenosine, ATP, ADP, or AMP. One preferred adenosine-containing compound is S-adenosylmethionine (SAMe). 
     In addition, compounds are known that are capable of increasing adenosine levels by other mechanisms. For example, adenosine uptake can be inhibited by a number of known compounds, including propentofylline (described in U.S. Pat. No. 5,919,789). Another known compound that inhibits adenosine uptake is EHNA. 
     Other useful compounds that can be used to increase brain adenosine levels are those that inhibit enzymes that break down adenosine, (e.g., adenosine deaminase and adenosine kinase). Finally, administering compounds that contain adenosine or precursors of adenosine, which are released as adenosine in vivo, can also be used. 
     Uridine-Containing Compounds 
     Uridine and uridine-containing compounds provide useful therapies because these compounds can be converted to CTP, a rate-limiting factor in PC biosynthesis (Wurtman et al., Biochemical Pharmacology 60:989-992, 2000). Useful uridine-containing compounds include, without limitation, any compound comprising uridine, UTP, UDP, or UMP. A preferred uridine-containing compound is triacetyl uridine. Uridine and uridine-containing compounds and analogs are well tolerated in humans. 
     Creatine-Containing Compounds 
     Creatine and creatine-containing compounds provide useful therapies because these compounds, by virtue of increasing brain phospholipid levels, can raise the levels of ATP. Creatine and creatine-containing compounds are known to be well tolerated at relatively high doses in humans. 
     Administration 
     Conventional pharmaceutical practice is employed to provide suitable formulations or compositions for administration to patients. Oral administration is preferred, but any other appropriate route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracistemal, intraperitoneal, intranasal, or aerosol administration. Therapeutic formulations may be in the form of liquid solutions or suspensions (as, for example, for intravenous administration); for oral administration, formulations may be in the form of liquids, tablets, or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols. 
     Methods well known in the art for making formulations are described, for example, in “Remington: The Science and Practice of Pharmacy” (20th ed.) ed. A. R. Gennaro, 2000, Lippincott, Philadelphia, Pa. Formulations for parenteral administration may, for example, contain excipients, sterile water, saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. 
     If desired, slow release or extended release delivery systems may be utilized. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. 
     Preferably, the compounds of the invention, such as CDP-choline, are administered at a dosage of at least 500 mg, e.g., 1000 or 2000 mg, twice daily by oral administration. Orally administered CDP-choline is bioavailable, with more than 99% of CDP-choline and/or its metabolites absorbed and less than 1% excreted in feces. CDP-choline, administered either orally or intravenously, is rapidly converted into the two major circulating metabolites, choline and cytidine. Major excretion routes are lung (12.9%) and urine (2.4%); the rest of the dose (83.9%) is apparently metabolized and retained in tissues. 
     In general, the compounds of the invention, such as CDP-choline, uridine, UTP, creatine, or SAMe, are administered at a dosage appropriate to the effect to be achieved and are typically administered in unit dosage form. The dosage preferably ranges from 50 mg per day to 4000 mg per day. The exact dosage of the compound may be dependent, for example, upon the age and weight of the recipient, the route of administration, and the severity and nature of the symptoms to be treated. In general, the dosage selected should be sufficient to treat or suppress marihuana usage or dependence, or one or more symptoms thereof, without producing significant toxic or undesirable side effects. As noted above, the preferred route of administration for most indications is oral. 
     In the case of CDP-choline, there have been no reported cases of overdoses. CDP-choline toxicity is largely self-limiting, ingestion of large amounts in preclinical studies shows common cholinergic symptoms (salivation, lacrimation, urination, defecation, and vomiting). 
     Combination with Other Therapies 
     The cytidine-containing, cytosine-containing, uridine-containing, creatine-containing, adenosine-containing, and adenosine-elevating compounds of the invention may be administered as a monotherapy, in combination with each other, or in combination with other therapies for the treatment of substance abuse disorders, including therapies for the treatment or suppression of marihuana usage, withdrawal, or dependence, or other associated physiological or psychological conditions. 
     The compounds of the invention, may be administered in conjunction with lower doses of other therapeutic compounds for these disorders, including stimulants and antidepressants. For example, the compounds of the invention may be administered with phospholipids, e.g., lecithin, or with brain phospholipid precursors, e.g., fatty acids or lipids, or may be administered as an adjunct to standard therapy for the treatment of substance abuse disorders. 
     In one particular example, the compound of the invention may be administered in combination with an antidepressant, anticonvulsant, antianxiety, antimanic, antipyschotic, antiobsessional, sedative-hypnotic, stimulant, or anti-hypertensive medication. Examples of these medications include, but are not limited to, the antianxiety medications, alprazolam, buspirone hydrochloride, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, desipramine hydrochloride, diazepam, halazepam, hydroxyzine hydrochloride, hydroxyzine pamoate, lorazepam, meprobamate, oxazepam, prazepam, prochlorperazine maleate, prochlorperazine, prochlorperazine edisylate, and trimipramine maleate; the anticonvulsants, amobarbital, amobarbital sodium, carbamazepine, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam, divalproex sodium, ethosuximide, ethotoin, gabapentin, lamotrigine, magnesium sulfate, mephenytoin, mephobarbital, methsuximide, paramethadione, pentobarbital sodium, phenacemide, phenobarbital, phenobarbital sodium, phensuximide, phenytoin, phenytoin sodium, primidone, secobarbital sodium, trimethadione, valproic acid, and clonazepam; the antidepressants, amitriptyline hydrochloride, amoxapine, bupropion hydrochloride, clomipramine hydrochloride, desipramine hydrochloride, doxepin hydrochloride, fluoxetine, fluvoxamine, imipramine hydrochloride, imipramine pamoate, isocarboxazid, lamotrigine, maprotoline hydrochloride, nortriptyline hydrochloride, paroxetine hydrochloride, phenelzine sulfate, protriptyline hydrochloride, sertraline hydrochloride, tranylcypromine sulfate, trazodone hydrochloride, trimipramine maleate, and venlafaxine hydrochloride; the antimanic medications, lithium carbonate and lithium citrate; the antiobsessional medications, fluvoxamine, and clomipramine hydrochloride; the antipsychotic medications, acetophenazine maleate, chlorpromazine hydrochloride, chlorprothixene, chlorprothixene hydrochloride, clozapine, fluphenazine decanoate, fluphenazine enathrate, fluphenazine hydrochloride, haloperidol decanoate, haloperidol, haloperidol lactate, lithium carbonate, lithium citrate, loxapine hydrochloride, loxapine succinate, mesoridazine besylate, molindone hydrochloride, perphenazine, pimozide, prochlorperazine maleate, prochlorperazine, prochlorperazine edisylate, promazine hydrochloride, risperidone, thioridazine, thiolidazine hydrochloride, thiothixene, thiothixene hydrochloride, and trifluoperzine hydrochloride; the sedative-hypnotic medications, amobarbital, amobarbital sodium, aprobarbital, butabarbital, chloral hydrate, chlordiazepoxide, chlordiazepoxide hydrochloride, clorazepate dipotassium, diazepam, diphenhydramine, estazolam, ethchlorvynol, flurazepam hydrochloride, glutethimide, hydroxyzine hydrochloride, hydroxyzine pamoate, lorazepam, methotrimeprazine hydrochloride, midazolam hydrochloride, non prescription, oxazepam, pentobarbital sodium, phenobarbital, phenobarbital sodium, quazepam, secobarbital sodium, temazepam, triazolam, and zolpidem tartrate; the stimulants, dextroamphetamine sulfate, methamphetamine hydrochloride, methylphenidate hydrochloride, and pemoline; and the anti-hypertensive, clonidine. 
     Compounds of the invention may also be administered in combination with a psychological intervention. In one embodiment, therapeutic treatment is combined with cognitive behavioral treatment for insomnia because insomnia is a common complaint of subjects suffering from marihuana withdrawal. Psychological intervention for insomnia provides a safe, effective alternative to pharmacotherapy. Cognitive Behavioral Therapy (CBT) (Morin  Insomnia: Psychological Assessment and Management . Guilford Press, New York, 1993; Morin et al. Clin Psychol Rev 1996, 16:521-542) includes the following treatment components: 
     Behavior Therapy: To change maladaptive sleep habits 
     Cognitive Therapy: To reframe dysfunctional beliefs and attitudes 
     Education: To promote good sleep hygiene practices 
     Medication: To facilitate discontinuation of hypnotic medications 
     The behavioral component typically includes one or more of stimulus control and sleep restriction techniques (Bootzin Proceedings of the American Psychological Association, 1972, 7:395-396; Bootzin et al.  Progress in Behavior Modification  New York: Academic Press 1978, Vol. 6, pp. 1-45; Spielman et al. Sleep 1987, 10:45-56). Exemplary stimulus control instructions include:
         1. Lie down intending to go to bed at night only when you are sleepy. Do not adhere to an arbitrary set bedtime.   2. Use the bed/bedroom for sleep and sex only. Do not watch TV, listen to the radio, eat, or read in bed.   3. Get out of bed if you cannot fall asleep or go back to sleep within an estimated 10-15 minutes (do not look at the clock); return to bed only when you feel sleepy, with the intention of seeing if sleep happens, rather than the intention of “trying” actively to fall asleep.   4. If you still cannot fall asleep, repeat step 3 as often as is necessary during the night.   5. Set your alarm and maintain a regular arising time in the morning, irrespective of how much sleep you got during the night, or how tired you may feel. Do not lie in bed awake.   6. Do not nap during the day.   7. Follow these steps consistently, recognizing that it is difficult to change any behavior, and change takes time.
 
Exemplary sleep hygiene recommendations include:
   1. Caffeine is a stimulant and should be discontinued 4-6 hours before bedtime.   2. Nicotine is a stimulant and should be avoided near bedtime and at awakenings.   3. Alcohol is a depressant that can facilitate sleep onset but can disrupt sleep later in the night. It should be avoided in close proximity to bedtime.   4. A heavy meal too close to bedtime can interfere with sleep and should be avoided. A light snack is acceptable.   5. Regular exercise in the late afternoon or early evening may deepen sleep, while exercise too close to bedtime may disrupt sleep.   6. Minimize light, noise, and excessive temperature during sleep.   7. Do not look at the clock when awake at night; this only serves to heighten anxiety and frustration about not sleeping.   8. Establish a 20-30 minute regular “worry time” during the daytime. Find a quiet place, relax, let worries come, and address them at this time, instead of at bedtime. This practice can help decrease worry and mind-racing at bedtime, by re-routing this kind of thinking to a time during the day.       

     The second component includes cognitive restructuring and is based on the rationale that insomniacs tend to have more anxious affect, worrisome cognitive style, and negative, maladaptive thoughts regarding sleep which adversely effect sleep (Borkovec et al. J. Abnormal Psychology 1981, 90:607-609; Kales et al.  Evaluation and Treatment of Insomnia  New York: Oxford University Press 1984; Van Egeren et al. Journal of Behavioral Medicine 1983, 6:217-232). Their expectations about sleep need and the consequences of insomnia are often unrealistic or invalid. These dysfunctional cognitions are associated with sleep disturbance in that the maladaptive thoughts produce emotional arousal that perpetuates insomnia. The focus of cognitive restructuring to treat insomnia is to alter the underlying dysfunctional thought processes and associated affective responses to produce more healthy, realistic thoughts about sleep and insomnia, thereby decreasing the emotional arousal which can lead to insomnia. 
     The third element of the approach addresses the lifestyle and environmental factors that can adversely affect sleep. Sleep hygiene instructions are conveyed in a common sense approach with the goal of helping insomniacs better manage these factors such that they optimize rather than deter from sleep. 
     The fourth component involves medication management and withdrawal. Chronic hypnotic use undermines the development of self-management skills to cope with insomnia. A schedule of gradual titration from sleep aids at the beginning of the cognitive-behavioral treatment program is advocated. 
     The program is typically brief in duration, inexpensive, and effective. It can be performed in group or individual format. Cognitive-behavior therapy for insomnia provided on an individual basis may produce superior results than group therapy, although there are advantages to the group format. The program typically consists of ten total sessions, the first two of which are devoted to thorough assessment, essential for successful triage and therapy. One focus of the multi-modal approach is helping insomniacs to develop a greater sense of self-efficacy about managing their own sleep difficulties. The sessions of treatment serve to consolidate treatment gains, integrate the therapies, and instruct patients as to how to avoid and cope with potential problems and relapse. With these therapy tools and relapse prevention strategies, patients gain the confidence and ability to address their insomnia and to see it as an inconvenience to be dealt with, rather than feeling victim to it and its effects on all other aspects of their lives. 
     In addition, subjects undergoing treatment with therapeutic compounds may be enrolled in psychological treatment programs, such as Group Drug Counseling. General group counseling is non-specific “talk therapy” during which a number of elements of the person&#39;s life are discussed with no emphasis on the marihuana abuse. Such efforts often serve as a control for meeting with a therapist. 
     Other Embodiments 
     All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference. 
     While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the appended claims. 
     Other embodiments are within the claims.