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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.

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    • "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. "
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    • "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). "
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    • "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. "
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