This study evaluated the effects of three medication regimens on a range of behaviors during abstinence from marijuana (withdrawal), followed by a period in which marijuana was available for self-administration (relapse) in marijuana-dependent research volunteers. The results, summarized in , demonstrate that this dose regimen of THC (20 mg tid) reversed the anorexia and weight loss associated with marijuana withdrawal, but only decreased a small subset of marijuana withdrawal symptoms. THC also increased the latency to fall asleep, and did not decrease marijuana relapse. The lofexidine dose regimen (0.6 mg qid) was sedating, worsened abstinence-related anorexia and weight loss, and also did not robustly attenuate the mood symptoms of marijuana withdrawal. Lofexidine did, however, significantly improve objective and subjective sleep measures during withdrawal, and decreased marijuana relapse compared to placebo. The combination of THC and lofexidine was also sedating, but decreased a broad range of withdrawal symptoms, including marijuana craving. This medication combination also improved objective and subjective sleep measures during marijuana abstinence, and decreased marijuana relapse compared to placebo. In fact, half the participants went all 4 days without smoking active marijuana when maintained on THC and lofexidine (compared to 25% of participants under placebo conditions). Overall, the combination of lofexidine and THC produced the most robust medication effects on sleep, marijuana craving and relapse relative to either medication alone.
Based on the literature (Haney et al., 2004
; Budney et al., 2007
), we had predicted that THC would decrease relapse by reducing the negative reinforcing effects of marijuana, i.e., a return to marijuana use to alleviate symptoms of withdrawal. However, under the present dose regimen, THC instead produced a mild but significant intoxication (good drug effect, mellow, capsule liking, increased willingness to take capsule again) without reducing marijuana craving, or the mood and sleep symptoms associated with marijuana withdrawal. Correspondingly, THC did not decrease marijuana relapse. Our earlier study, testing a lower THC dose (10 mg) administered frequently (5 times) throughout the day, produced no intoxication and attenuated a range of withdrawal symptoms, including marijuana craving (Haney et al., 2004
). Although this might suggest that lower, more frequent doses of THC would be most effective, others have shown that in an outpatient setting, among participants who were selected because they manifested symptoms of marijuana withdrawal, higher doses of THC (30 mg tid) decreased marijuana withdrawal symptoms during marijuana abstinence (Budney et al., 2007
). Thus, further research is needed to replicate the current findings, and to characterize the factors producing the most robust attenuation of marijuana withdrawal by THC, e.g., dose, frequency of dose administration, participant characteristics.
Lofexidine, when given alone, also did not decrease marijuana craving, or most mood symptoms of marijuana withdrawal but lofexidine did improve sleep during marijuana abstinence and decreased marijuana relapse. Disrupted sleep is a consistent symptom of marijuana withdrawal (Haney et al., 2003
; Budney et al., 2001
), and lofexidine significantly increased how long participants slept and how easily they perceived falling asleep during abstinence. Combining THC and lofexidine further improved sleep and decreased relapse. In opioid-dependent patients undergoing withdrawal, lofexidine improved self-report ratings of sleep initiation and maintenance compared to methadone, and improvements in sleep appeared to predict retention in treatment (Bestwick et al., 2003
). Similarly, in alcohol-dependent patients, sleep onset latency predicted relapse to alcohol use (Brower et al., 1998
). Thus, it may be that improvements in sleep are essential to decreasing relapse to marijuana use.
The mechanism for lofexidine’s utility for the treatment of opioid withdrawal is presumed to involve decreased norephinephrine release. Opioid withdrawal is associated with noradrenergic hyperactivity, and alpha-2-adrenergic receptor agonists decrease both norepinephrine release and the primarily physical symptoms of opioid withdrawal (see Herman and O’Brien, 1997
). Recently, a clinical study with opioid-dependent patients maintained on naltrexone showed that lofexidine (at twice the daily dose used presently) decreased laboratory measures of stress- and drug cue-induced craving and decreased opioid relapse compared to placebo (Sinha et al., 2007
). There is also an extensive preclinical literature showing that lofexidine decreases stress-induced drug-seeking behavior (see Shaham et al., 2003
). Given that preclinical studies show that cannabis withdrawal, like opioid withdrawal, is associated with noradrenergic hyperactivity (see Introduction), lofexidine may decrease marijuana relapse in the laboratory by the same mechanism as it decreases opioid relapse: by reducing withdrawal-related noradrenergic hyperactivity.
Similar to its effects on marijuana craving and relapse, the combination of THC and lofexidine also decreased cigarette craving and cigarette smoking during marijuana withdrawal. THC/lofexidine had this effect even though participants were not trying to cut down on cigarettes, and when there were no contingencies to discourage cigarette smoking. Neither medication alone had this effect. Although THC decreases nicotine withdrawal in mice (Balerio et al., 2004
), smoking behavior during marijuana abstinence was not decreased by THC either in this study or in our earlier study (Haney et al., 2004
). Clonidine appears to decrease smoking in clinical trials compared to placebo, but side effects decrease clonidine’s potential to treat nicotine dependence (see Covey et al., 2000
). These data suggest that lofexidine might be further explored for smoking cessation.
Lofexidine, either alone or with THC, decreased blood pressure, but rarely produced clinically significant hypotension, consistent with findings in opioid-dependent patients (Bearn et al., 1998
). Lofexidine, alone or in combination with THC, also substantially increased ratings of sedation, but again, the effect did not appear to be aversive. Participants reported that lofexidine produced a mild effect, which they did not particularly like or dislike. In fact, certain positive ratings of THC capsules were reduced when lofexidine was combined with THC. Lofexidine alone also decreased food intake in abstinent marijuana smokers, and shifted the balance of macronutrient intake from fat to carbohydrates.
There were few significant medication effects on psychomotor task performance. All three medication conditions improved performance on the rapid information task compared to placebo. Lofexidine alone significantly increased the number of errors made on a repeated acquisition and divided attention task. These impairments did not occur if lofexidine was given in combination with THC.
There are several issues to consider with the present design. First, given the study length and range of conditions, only one dose of each medication was assessed, limiting our conclusions to the doses selected. Second, the sample was small and not broadly diverse, as there were no women or non-Hispanic Caucasians enrolled, further limiting the generalizability of the conclusions. Third, the study objective was to compare medication effects, so there was no baseline condition to compare to marijuana abstinence to demonstrate withdrawal. Not all marijuana smokers endorse symptoms of withdrawal, and in fact only half of those currently enrolled demonstrated the time-dependent increase in ratings of irritability and restlessness that define marijuana withdrawal. Some studies have dealt with this variability by only analyzing medication effects in participants who demonstrate withdrawal symptoms (e.g., Budney et al., 2001
). An alternative strategy, adopted herein, is to include all participants. A recent study reported that a large percentage (60%) of daily cigarette smokers (≥ 10 cigarettes/day) also do not report experiencing symptoms of nicotine withdrawal (Donny and Dierker, 2007
). Yet studies developing medications to treat nicotine dependence do not typically distinguish among those who do and those who do not experience withdrawal. Thus, our conclusions about the effects of THC and lofexidine during marijuana abstinence are based on daily marijuana smokers whether they report withdrawal or not. Importantly, the overall pattern of medication effects described above was the same when only those endorsing withdrawal were analyzed, e.g., THC increased irritability in those undergoing withdrawal as it did for the group as a whole.
To conclude, we have developed a laboratory procedure to assess the effects of medications on factors that likely contribute to marijuana relapse. Medications with distinct mechanisms of action were tested: a cannabinoid agonist and a medication to decrease norepinephrine release. The combination of THC and lofexidine was most effective in reducing symptoms of marijuana withdrawal and shifting choice away from marijuana and toward saving money when the opportunity to relapse was presented. Lofexidine alone decreased relapse, but without an apparent improvement in mood during marijuana abstinence. Lofexidine did, however, improve sleep during marijuana abstinence, suggesting that improving sleep, and perhaps decreasing a stress response during marijuana abstinence decreases relapse. Although the model overall cannot be validated in lieu of clinical data with these medications in treatment seekers, the present results suggest that a future dose-ranging study of THC and lofexidine combinations is warranted.