Pharmacotherapy for Marijuana Dependence: A Double‐blind, Placebo‐controlled Pilot Study of Divalproex Sodium

Levin, Frances R.; McDowell, David M.; Evans, Suzette M.; Nunes, Edward V.; Akerele, Evaristo; Donovan, Stephen J.; Vosburg, Suzanne K.

doi:10.1080/10550490490265280

Cited by 111 publications

(89 citation statements)

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“…In fact, divalproex did decrease marijuana craving during abstinence. However, the increased irritability, sleepiness, anxiety, and decreased social interaction during divalproex maintenance is consistent with the poor compliance and negative results obtained in a pilot clinical trial with divalproex (Levin et al, 2003). The impaired cognitive task performance is particularly problematic for a potential treatment medication, as this effect occurred throughout the entire divalproex maintenance period.…”

Section: Discussionmentioning

confidence: 54%

“…Compliance was also assessed quantitatively by plasma assays. The divalproex dose was chosen based on its use in previous studies as a mood stabilizer (eg Levin et al, 2003;Donovan et al, 2000;Giakas et al, 1990). Divalproex dosing started at 500 mg/day, which was increased every 2 days until a final maintenance dose (1500 mg/day) was achieved on the 9th day of administration.…”

Section: Pharmacotherapy Of Marijuana Withdrawal M Haney Et Almentioning

confidence: 99%

“…Adding voucher-based incentive programs to cognitive or motivational techniques appears to improve treatment compliance, as is the case for cocaine treatment (Budney et al, 2000). The one double-blind, clinical study testing a medication (divalproex) for marijuana dependence showed that few patients were able to maintain abstinence regardless of medication dose (Levin et al, 2003). Thus, marijuana dependence appears to be as difficult to treat as other drug dependencies.…”

Section: Introductionmentioning

confidence: 99%

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Marijuana Withdrawal in Humans: Effects of Oral THC or Divalproex

Haney

Hart

Vosburg

et al. 2003

Neuropsychopharmacol

241

228

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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.

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Section: Discussionmentioning

confidence: 54%

Section: Pharmacotherapy Of Marijuana Withdrawal M Haney Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Marijuana Withdrawal in Humans: Effects of Oral THC or Divalproex

Haney

Hart

Vosburg

et al. 2003

Neuropsychopharmacol

241

228

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“…Maintenance on two medications, the antidepressant, bupropion (Haney et al, 2001), and the mood stabilizer, divalproex (Haney et al, 2004), significantly worsened mood during marijuana withdrawal compared to placebo, suggesting that they would not show promise as treatment approaches. Similarly, a clinical pilot trial observed poor compliance and outcome using divalproex to treat marijuana dependence (Levin et al, 2004). The antidepressant, nefazodone, which is sedating compared to the stimulant-like bupropion, decreased a subset of marijuana withdrawal symptoms (Haney et al, 2003), but the medication that most effectively attenuated marijuana withdrawal was THC (dronabinol, Marinol).…”

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confidence: 99%

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

et al. 2007

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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 ...

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“…Thus far, clinical trials using psychotropic agents such as valproic acid and buspirone have been conducted with mixed results and no pharmacological intervention has demonstrated efficacy in reducing marijuana use (Levin et al, 2004;McRae et al, 2006). Human laboratory trials of the antidepressants nefazodone and bupropion for amelioration of marijuana withdrawal found nefazodone to be partially effective for control of marijuana withdrawal related anxiety and muscle pain while bupropion was ineffective, and aggravated marijuana withdrawal related mood symptoms (Haney et al, 2003;Haney et al, 2001).…”

mentioning

confidence: 99%

Atomoxetine for treatment of marijuana dependence: A report on the efficacy and high incidence of gastrointestinal adverse events in a pilot study

Tirado

Goldman

Lynch

et al. 2008

Drug and Alcohol Dependence

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Marijuana users consistently demonstrate impairments in attention, executive function and response inhibition, which resemble deficits seen in attention deficit hyperactivity disorder (ADHD). We hypothesized that targeting the cognitive deficits associated with chronic marijuana use through ADHD medications may help identify a therapeutic agent for marijuana dependence.Thirteen subjects participated in an 11-week open label study to determine the feasibility, safety and tolerability of atomoxetine for individuals seeking treatment for marijuana dependence. The Time-Line Follow-Back measured marijuana use 90 days prior to study entry (p-TLFB) and weekly during the study (s-TLFB) along with weekly qualitative urine drug screen (UDS). For the eight subjects who completed the trial, the TLFB data showed a trend toward reduction in use with an increase in percent days abstinent (p=0.06). Analysis of weekly UDSs did not confirm the TLFB trend with 94% of all possible UDSs positive for THC through out the study.Marijuana dependent subjects taking atomoxetine experienced an inordinate number of gastrointestinal (GI) adverse events. Overall, 10 of 13 subjects (77%) experienced a mild to moderate GI adverse event defined as nausea, vomiting, dyspepsia, and loose stools. Atomoxetine is of limited utility in the treatment of cannabis dependence and is associated with clinically significant GI adverse events.

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Pharmacotherapy for Marijuana Dependence: A Double‐blind, Placebo‐controlled Pilot Study of Divalproex Sodium

Cited by 111 publications

References 31 publications

Marijuana Withdrawal in Humans: Effects of Oral THC or Divalproex

Marijuana Withdrawal in Humans: Effects of Oral THC or Divalproex

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

Atomoxetine for treatment of marijuana dependence: A report on the efficacy and high incidence of gastrointestinal adverse events in a pilot study

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