Abstinence following daily marijuana use can produce a withdrawal syndrome characterized by negative mood (eg irritability, anxiety, misery), muscle pain, chills, and decreased food intake. Two placebo-controlled, within-subject studies investigated the effects of a cannabinoid agonist, delta-9-tetrahydrocannabinol (THC: Study 1), and a mood stabilizer, divalproex (Study 2), on symptoms of marijuana withdrawal. Participants (n ¼ 7/study), who were not seeking treatment for their marijuana use, reported smoking 6-10 marijuana cigarettes/day, 6-7 days/week. Study 1 was a 15-day in-patient, 5-day outpatient, 15-day in-patient design. During the in-patient phases, participants took oral THC capsules (0, 10 mg) five times/day, 1 h prior to smoking marijuana (0.00, 3.04% THC). Active and placebo marijuana were smoked on in-patient days 1-8, while only placebo marijuana was smoked on days 9-14, that is, marijuana abstinence. Placebo THC was administered each day, except during one of the abstinence phases (days 9-14), when active THC was given. Mood, psychomotor task performance, food intake, and sleep were measured. Oral THC administered during marijuana abstinence decreased ratings of 'anxious', 'miserable', 'trouble sleeping', 'chills', and marijuana craving, and reversed large decreases in food intake as compared to placebo, while producing no intoxication. Study 2 was a 58-day, outpatient/in-patient design. Participants were maintained on each divalproex dose (0, 1500 mg/day) for 29 days each. Each maintenance condition began with a 14-day outpatient phase for medication induction or clearance and continued with a 15-day in-patient phase. Divalproex decreased marijuana craving during abstinence, yet increased ratings of 'anxious', 'irritable', 'bad effect', and 'tired.' Divalproex worsened performance on psychomotor tasks, and increased food intake regardless of marijuana condition. Thus, oral THC decreased marijuana craving and withdrawal symptoms at a dose that was subjectively indistinguishable from placebo. Divalproex worsened mood and cognitive performance during marijuana abstinence. These data suggest that oral THC, but not divalproex, may be useful in the treatment of marijuana dependence.

Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence.Objectives-To determine if THC, a cannabinoid agonist, and lofexidine, an α 2 -adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence.Methods-Nontreatment-seeking, male volunteers (n=8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, THC (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first 3 inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake and sleep were measured.Results-THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep, and decreased marijuana withdrawal, craving and relapse in daily marijuana smokers relative to either medication alone.Conclusions-These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence. KeywordsMarinol; Britlofex; dependence; withdrawal; treatment; cannabinoid; norepinephrine Marijuana use is prevalent in American society, and the number of individuals who currently meet DSM-IV criteria for cannabis abuse or dependence has steadily increased since the 1990s (Compton et al., 2004). Although marijuana is less likely to produce dependence than drugs such as nicotine, alcohol or heroin (Anthony et al., 1994), the sheer number of marijuana smokers combined with the increasing potency of marijuana has NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2012 June 12.Published in final edited form as:Psychopharmacology (Berl). 2008 March ; 197(1): 157-168. doi:10.1007/s00213-007-1020-8. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript resulted in a significant number of individuals developing cannabis use disorders, i.e., approximately 1.5% of the U.S. population (Compton et al., 2004).A number of studies have demonstrated that there is a personal (i.e., not court-mandated) demand for marijuana treatment, particularly when marijuana-specific treatment programs are offered (Roffman et al., 1988;Stephens et al., 1993;Lang et al., 2000). Treatmentseekers report distress about their marijuana use, and repeatedly ...

Modafinil has been reported to reduce cocaine use in a clinical sample of infrequent users (2 days/week), but the effects of modafinil on cocaine self-administration in the laboratory have not been studied. The present study investigated the effects of modafinil maintenance on cocaine self-administration by frequent users (4 days/week) under controlled laboratory conditions. During this 48-day double-blind, crossover design study, the effects of modafinil maintenance (0, 200, and 400 mg/day) on response to smoked cocaine (0, 12, 25, and 50 mg) were examined in nontreatment-seeking cocaine-dependent individuals (n ¼ 8). Cocaine significantly increased selfadministration, subjective-effect ratings, and cardiovascular measures; modafinil at both doses (200 and 400 mg/day) markedly attenuated these effects. These findings agree with data from previous human laboratory and clinical investigations of modafinil as a potential cocaine abuse treatment medication. Thus, our data support the potential of modafinil as a pharmacotherapy for cocaine dependence.

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Abuse of prescription opioid medications has increased dramatically in the United States during the past decade, as indicated by a variety of epidemiological sources. However, few studies have systematically examined the relative reinforcing effects of commonly abused opioid medications. The current double-blind, placebo-controlled in-patient study was designed to compare the effects of intravenously delivered fentanyl (0, 0.0625, 0.125, 0.187, and 0.250 mg/70 kg), oxycodone (0, 6.25, 12.5, 25, and 50 mg/70 kg), morphine (0, 6.25, 12.5, 25, and 50 mg/70 kg), buprenorphine (0, 0.125, 0.5, 2, and 8 mg/70 kg), and heroin (0, 3.125, 6.25, 12.5, and 25 mg/70 kg) in morphinemaintained heroin abusers (N ¼ 8 completers maintained on 120 mg per day oral morphine in divided doses (30 mg q.i.d.)). All of the participants received all of the drugs tested; drugs and doses were administered in non-systematic order. All of the drugs produced statistically significant, dose-related increases in positive subjective ratings, such as 'I feel a good drug effect' and 'I like the drug.' In general, the order of potency in producing these effects, from most to least potent, was fentanyl4buprenorphineXheroin 4morphine ¼ oxycodone. In contrast, buprenorphine was the only drug that produced statistically significant increases in ratings of 'I feel a bad drug effect' and it was the only drug that was not self-administered above placebo levels at any dose tested. These data suggest that the abuse liability of buprenorphine in heroin-dependent individuals may be low, despite the fact that it produces increases in positive subjective ratings. The abuse liabilities of fentanyl, morphine, oxycodone, and heroin, however, appear to be similar under these experimental conditions.

Few individuals seeking treatment for marijuana use achieve sustained abstinence. The cannabinoid receptor agonist, Δ(9)-tetrahydrocannabinol (THC; dronabinol), decreases marijuana withdrawal symptoms, yet does not decrease marijuana use in the laboratory or clinic. Dronabinol has poor bioavailability, which may contribute to its poor efficacy. The FDA-approved synthetic analog of THC, nabilone, has higher bioavailability and clearer dose-linearity than dronabinol. This study tested whether nabilone administration would decrease marijuana withdrawal symptoms and a laboratory measure of marijuana relapse relative to placebo. Daily, nontreatment-seeking marijuana smokers (8 men and 3 women), who reported smoking 8.3±3.1 marijuana cigarettes/day completed this within-subject study comprising three, 8-day inpatient phases; each phase tested a different nabilone dose (0, 6, 8 mg/day, administered in counter-balanced order on days 2-8). On the first inpatient day, participants took placebo capsules and smoked active marijuana (5.6% THC) at six timepoints. For the next 3 days, they had the opportunity to self-administer placebo marijuana (0.0% THC; withdrawal), followed by 4 days in which active marijuana was available for self-administration (5.6% THC; relapse). Both nabilone dose conditions decreased marijuana relapse and reversed withdrawal-related irritability and disruptions in sleep and food intake (p<0.05). Nabilone (8 mg/day) modestly worsened psychomotor task performance. Neither dose condition increased ratings of capsule 'liking' or desire to take the capsules relative to placebo. Thus, nabilone maintenance produced a robust attenuation of marijuana withdrawal symptoms and a laboratory measure of relapse even with once per day dosing. These data support testing of nabilone for patients seeking marijuana treatment.

Background Few marijuana smokers in treatment achieve sustained abstinence, yet factors contributing to high relapse rates are unknown. Study 1: Methods Data from five inpatient laboratory studies assessing marijuana intoxication, withdrawal and relapse were combined to assess factors predicting the likelihood and severity of relapse. Daily, nontreatment-seeking marijuana smokers (n=51; 10 ± 5 marijuana cigarettes/day) were enrolled. Results 49% of participants relapsed the first day active marijuana became available. Tobacco cigarette smokers (75%), who were not abstaining from cigarettes, were far more likely to relapse than non-cigarette smokers (OR=19, p<0.01). Individuals experiencing more positive subjective effects (i.e. feeling “high”) after marijuana administration and those with more negative affect and sleep disruption during marijuana withdrawal were more likely to have severe relapse episodes (p<0.05). Study 2: Methods To isolate the effects of cigarette smoking, marijuana intoxication, withdrawal and relapse were assessed in daily marijuana and cigarette smokers (n=15) under two within-subject, counter-balanced conditions: while smoking tobacco cigarettes as usual (SAU) and after at least 5 days without cigarettes (Quit). Results Most participants (87%) relapsed to marijuana whether in the SAU or Quit phase. Tobacco cigarette smoking did not significantly influence relapse, nor did it affect marijuana intoxication or most symptoms of withdrawal relative to tobacco cessation. Conclusions Daily marijuana smokers who also smoke cigarettes have high rates of marijuana relapse and cigarette smoking versus recent abstinence does not directly influence this association. These data indicate that current cigarette smoking is a clinically important marker for increased risk of marijuana relapse.

Rationale Only a small percentage of individuals seeking treatment for their marijuana use achieves sustained abstinence, suggesting more treatment options are needed. Objectives To determine the effects of baclofen (Study 1) and mirtazapine (Study 2) in a human laboratory model of marijuana intoxication, withdrawal and relapse. Methods Study 1: Daily marijuana smokers (n=10), averaging 9.4 (± 3.9) marijuana cigarettes/day, were maintained on placebo and each baclofen dose (60, 90 mg/day) for 16 days. Study 2: Daily marijuana smokers (n=11), averaging 11.9 (± 5.3) marijuana cigarettes/day, were maintained on placebo and mirtazapine (30 mg/day) for 14 days each. Medication administration began outpatient prior to each 8-day inpatient phase. On the first inpatient day of each medication condition, participants smoked active marijuana (Study 1: 3.3% THC; Study 2: 6.2% THC). For the next 3 days, they could self-administer placebo marijuana (abstinence phase), followed by 4 days in which they could self-administer active marijuana (relapse phase); participants paid for self-administered marijuana using study earnings. Results Study 1: During active marijuana smoking, baclofen dose-dependently decreased craving for tobacco and marijuana, but had little effect on mood during abstinence and did not decrease relapse. Baclofen also worsened cognitive performance regardless of marijuana condition. Study 2: Mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease marijuana relapse. Conclusions Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine showed promise for the potential treatment of marijuana dependence.