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: 3.88). 04/2008; 197(1):157-68. DOI: 10.1007/s00213-007-1020-8
Source: PubMed


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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    • "Study medication, dronabinol or placebo, were given under double-blind conditions and dronabinol was administered twice daily at 10 AM and 9 PM with the following schedule of titration: Study Day 2: 10 mg in AM, Study Day 3: 10 mg in AM and PM, Study Day 4 onward: 15 mg in AM and PM. Dose selection was guided by the prior clinical trial's experience with dronabinol, the need to test the sufficiently high dose of dronabinol to test study's primary hypothesis, and tolerability that will permit its use on an outpatient basis in individuals who are intolerant to marijuana (Budney et al., 2007; Haney et al., 2008; Levin et al., 2011). "
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    ABSTRACT: Evidence suggests that the cannabinoid system is involved in the maintenance of opioid dependence. We examined whether dronabinol, a cannabinoid receptor type 1 partial agonist, reduces opioid withdrawal and increases retention in treatment with extended release naltrexone (XR-naltrexone). Opioid dependent participants were randomized to receive dronabinol 30mg/d (n=40) or placebo (n=20), under double-blind conditions, while they underwent inpatient detoxification and naltrexone induction. Before discharge all participants received an injection of XR-naltrexone, with an additional dose given four weeks later. Dronabinol or placebo was given while inpatient and for 5 weeks afterwards. The primary outcomes were the severity of opioid withdrawal, measured with the Subjective Opioid Withdrawal Scale, and retention in treatment at the end of the inpatient phase and at the end of the 8-week trial. The severity of opioid withdrawal during inpatient phase was lower in the dronabinol group relative to placebo group (p=0.006). Rates of successful induction onto XR-naltrexone (dronabinol 66%, placebo 55%) and completion of treatment (dronabinol 35%, placebo 35%) were not significantly different. Post hoc analysis showed that the 32% of participants who smoked marijuana regularly during the outpatient phase had significantly lower ratings of insomnia and anxiety and were more likely to complete the 8-week trial. Dronabinol reduced the severity of opiate withdrawal during acute detoxification but had no effect on rates of XR-naltrexone treatment induction and retention. Participants who elected to smoke marijuana during the trial were more likely to complete treatment regardless of treatment group assignment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Drug and alcohol dependence 07/2015; 154. DOI:10.1016/j.drugalcdep.2015.05.013 · 3.42 Impact Factor
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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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    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 · 3.42 Impact Factor
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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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    ABSTRACT: Objective: 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). Methods: Thirty-nine treatment-seeking chronic cannabis dependents (ICD-10) were studied on admission and on abstinent days 2, 4, 8 and 16, using a CWS-checklist (MWC) and the Clinical Global Impression-Severity scale (CGI-S). Simultaneously obtained serum was analysed to its concentration of THC, THC-OH and THC-COOH. Results: MWC peaked on day 4 (10.4 ± 4.6 from 39 points) and declined to 2.9 ± 2.4 points on day 16. Women had a significantly stronger CWS than men. The CWS was dominated by craving>restlessness>nervousness>sleeplessness. CGI-S peaked with 5 out of 7 points. On admission, THC and its metabolites did negatively correlate with the severity of CWS. There was no significant correlation afterwards, no matter if CWS was medicated or not. THC-OH in serum declined most rapidly below detection limit, on median at day 4. At abstinence day 16, the THC-levels of 28.2% of the patients were still above 1g/ml (range: 1.3 to 6.4 ng/ml). Conclusions: CWS increased and then decreased without any correlation between its severity and the serum-levels of THC or its main metabolites after admission. According to the CGI-S, most patients achieved the condition of 'markedly ill'. Serum THC-OH was most clearly associated with recent cannabis use. Residual THC was found in the serum of almost one-third of the patients at abstinence day 16.
    Drug and Alcohol Dependence 08/2014; 143(1). DOI:10.1016/j.drugalcdep.2014.07.027 · 3.42 Impact Factor
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