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

Division on Substance Abuse, New York State Psychiatric Institute and Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, Unit 120, New York, NY, 10032, USA.
Psychopharmacology (Impact Factor: 3.99). 04/2008; 197(1):157-68. DOI: 10.1007/s00213-007-1020-8
Source: PubMed

ABSTRACT Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence.
The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an alpha(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.
Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (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 three 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.
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.
These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.

Download full-text


Available from: Richard Foltin, Jul 13, 2015
  • Source
    • "The authors concluded that dronabinol treatment might help individuals whose cannabis withdrawal is severe and a barrier to abstinence. Thus, dronabinol displays only some characteristics of an effective agonist replacement treatment, suggesting it would be preferable to combine dronabinol with medications that possess complementary mechanisms of action (Haney et al., 2008), including those that block both the unconditioned and conditioned reinforcing effects of marijuana. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The current study tested whether oral Δ(9)-tetrahydrocannabinol (THC: 0-, 10-, and 20-mg) pretreatment would attenuate polysensory cue-induced craving for marijuana. Cannabis dependent participants (7 males and 7 females, who smoked on average 5.4±1.1 blunts daily) completed 3 experimental sessions (oral THC pretreatment dose; counterbalanced order) using a placebo-controlled within-subject crossover design. During each session, participants completed a baseline evaluation and were first exposed to neutral cues then marijuana cues while physiological measures and subjective ratings of mood, craving, and drug effect were recorded. Following placebo oral THC pretreatment, marijuana (vs. neutral) cues significantly increased ratings of marijuana craving (desire and urge to use, Marijuana Craving Questionnaire (MCQ)-Compulsivity scale), anxious mood and feeling hungry. Males also reported feeling more "Down" during marijuana cues relative to females. Pretreatment with oral THC (10-mg and/or 20-mg vs. placebo) significantly attenuated marijuana cue-induced increases in craving and anxiety but not hunger. Oral THC attenuation of the cue-induced increase in MCQ-Compulsivity ratings was observed in females only. Oral THC produced statistically (but not clinically) significant increases in heart rate and decreases in diastolic blood pressure, independent of cues. These marijuana-cue findings replicate earlier results and further demonstrate that oral THC can attenuate selected effects during marijuana multi-cue exposure, and that some of these effects may be sex-related. Results of this study suggest oral THC may be effective for reducing marijuana cue-elicited (conditioned) effects. Further study is needed to determine whether females may selectively benefit from oral THC for this purpose. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Drug and Alcohol Dependence 02/2015; 149. DOI:10.1016/j.drugalcdep.2015.01.046 · 3.28 Impact Factor
  • Source
    • "The symptom rated as 'strong' or 'very strong' most frequently (37.9%) was craving (Preuss et al., 2010). Since the CWS in animal experiments and human studies can be alleviated by the administration of -9-tetrahydrocannabinol (THC; Budney et al., 2007; Haney et al., 2008; Vandrey et al., 2013), which is mainly responsible for the euphoric and reinforcing effects of cannabis (Cone and Huestis, 1993; Mechoulam, 1999), it is likely that a decrease in THC levels in the extracellular brain fluid is crucially involved in the formation of the syndrome. In 2006, to the time when our study started, there was only one small study available , which had investigated the course of plasma cannabinoids after initiation of abstinence in chronic cannabis users (8 men were followed for 10–15 days; Johansson et al., 1989). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the course of cannabis withdrawal syndrome (CWS) within a controlled inpatient detoxification setting and to correlate severity of CWS with the serum-levels of delta-9-tetrahydrocannabinol (THC) and its main metabolites 11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH).
    Drug and Alcohol Dependence 08/2014; 143. DOI:10.1016/j.drugalcdep.2014.07.027 · 3.28 Impact Factor
  • Source
    • "Note, ratings of 'high' from placebo capsules were elevated in this study (nearly 20% of maximum score), we suspect because of expectancy effects: capsule administration was doubleblind yet participants experienced each dosing condition so they may have come to expect that the capsule would produce effects. Typically, placebo capsules produce lower ratings of intoxication so the effects of nabilone (Bedi et al, 2012) or dronabinol (Haney et al, 2008) administration on ratings of intoxication are apparent. Yet even if marijuana smokers experience some positive subjective effects from nabilone, there is little to suggest that a long-acting, slow-onset oral medication will have abuse liability approaching that of smoked marijuana. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 analogue 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 M, 3 F), 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.Neuropsychopharmacology accepted article preview online, 26 February 2013; doi:10.1038/npp.2013.54.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2013; 38(8). DOI:10.1038/npp.2013.54 · 7.83 Impact Factor
Show more