The present study replicates a previous surprising finding23
that intermittent cannabis use is associated with improved retention in naltrexone treatment among opioid dependent patients, while both abstinence from cannabis and regular cannabis use during naltrexone treatment are associated with high dropout. Inspection of the retention curves () shows that most of this effect occurs during the first 30 days after completion of inpatient detoxification and induction onto naltrexone, when dropout is steepest, and when patients may continue to experience protracted withdrawal that may be promoted by antagonist or inverse agonist effects of naltrexone.44–46
Intermittent cannabis use was also associated with improved adherence to naltrexone pill-taking. The data comparing cannabis use levels before versus after treatment entry suggest patients either stay at the same level, or advance to a higher level of cannabis use after starting naltrexone, consistent with a process of self-medication. These findings are of interest, because they suggest the hypothesis that moderate cannabis use may be exerting a beneficial pharmacological effect improving the tolerability of naltrexone in the early weeks after induction, and that cannabinoid agonists might have promise for improving the effectiveness of naltrexone treatment for opioid dependence.
A beneficial effect of cannabinoid agonism early in the course of naltrexone treatment is biologically plausible. Rapid naltrexone induction during a 7 to 10 day hospitalization involves substantial withdrawal discomfort, which can be partially relieved by attenuating adrenergic activity with the alpha-2 autoreceptor agonist clonidine.47,48
During the early weeks after naltrexone induction, protracted withdrawal symptoms may persist, again likely driven in part by sympathetic nervous system activation.47,48
Data from a variety of preclinical models suggest that exogenous cannabinoids can attenuate sympathetic nervous activation, especially with intermittent rather than sustained administration.49–63
Thus, intermittent cannabis use might improve tolerability of naltrexone in the early weeks after induction by attenuating sympathetically driven withdrawal symptoms such as insomnia and agitation.
Cannabis also stimulates appetite and has antiemetic, antispasmodic and analgesic effects that have been clinically useful during cancer chemotherapy and wasting syndromes.64,65
This might be useful in helping relieve the gastrointestinal distress and other physical discomfort associated with opioid withdrawal.
Finally, cannabis might improve the tolerability of naltrex-one maintenance by furnishing an indirect dopaminergic agonist effect at the brain reward system, countering the lethargy and anhedonia that are typical of opioid withdrawal and that might be worsened or prolonged by antagonist or inverse agonist effects of naltrexone. Naltrexone has not generally been associated with anhedonia among normal controls or alcohol dependent patients.66,67
However, preclinical evidence suggests naltrexone functions as an inverse agonist in the setting of prior exposure to mu agonists,44–46
as in opioid dependence. Cannabinoid (CB1) and mu opiate receptors are both G protein coupled receptors with overlapping neuroanatomical localization,68
and both CB1 and mu agonists stimulate dopamine release from the meso-limbic dopamine neurons and function as positive reinforcers. Thus, cannabis might compensate for a deficit in dopaminergic tone related to naltrexone.
The hypothesis of a beneficial pharmacological effect of cannabis for naltrexone maintenance would need to account for the inverted U-shaped function, namely that heavier cannabis use was associated with worse treatment retention than intermittent use. It may be that heavy cannabis use identifies a subgroup with greater overall addiction severity and worse prognosis that overwhelms any beneficial pharmacological effect of cannabis. This would be consistent with the significant association between cannabis use level and baseline level of opioid use (bags per day) (see ), which has been shown to be a predictor of poor outcome for naltrexone maintenance.69
In prior analyses, the intensive behavioral therapy (BNT) was shown to have its greatest beneficial effect among patients with the higher levels of opioid dependence (more bags per day) at baseline.24,70
Similarly here, the interaction of treatment assignment with level of cannabis use suggests that BNT partially counteracts the adverse prognosis in the heavy cannabis use group (, and ).
It is possible that regular or heavy cannabis use induces tolerance, perhaps through down regulation of CB1 receptors,71
diminishing any beneficial effects. The inverted U pattern might also reflect individual differences in sensitivity to the putative beneficial effect of cannabis. Since patients would be self-medicating, in effect adjusting their own dosages, those who are most responsive to the beneficial effects might select a modest dosage level sufficient to provide substantial relief, whereas those who are less responsive may advance to more regular or heavy use without sufficient response to impact retention.
The present findings are observational, and it is also possible that the association between intermittent cannabis use and improved retention on naltrexone is accounted for by unmeasured confounds or other mechanisms, rather than a causal pharmacological effect. Baseline level of heroin use (bags per day), the most consistent predictor of naltrexone treatment in our hands,24,69,70
was controlled for in the Cox model, suggesting severity of opioid dependence at baseline is not a confound. Another approach is to consider why patients without any concurrent cannabis use would have poor outcome. For example, it has been theorized that complete abstinence early in treatment may be stressful for patients who have long relied on substance use as a coping mechanism.72
It is also possible that the cannabis abstinent group differs in their response to cannabis, experiencing it as either not reinforcing or aversive, based on constitutional or neurobiological factors that also might be associated with poor response to naltrexone.
Experimental studies are needed to determine whether cannabinoid agonists may exert a beneficial effect on opioid withdrawal or naltrexone maintenance. Haney and colleagues examined the impact of naltrexone (versus placebo) on cannabis effects,73
finding that naltrexone at 50 mg, but not 12 mg, increased the intoxicating effects of cannabis in established smokers, while in participants without a history of cannabis use, 12 mg of naltrexone enhanced the effect of cannabis.74
Such a mechanism might explain the inverted-U pattern if naltrexone caused excessive and aversive cannabis effects among the heavy users. In any case, it suggests there may be meaningful pharmacological interactions between cannabinoid and opioid systems, and that these may be conditioned by the prior history of use.
Experimental, placebo-controlled studies are needed to directly examine whether cannabinoid agonists are effective as adjuncts to opioid detoxification or naltrexone maintenance treatment and to delineate the mechanism. Oral THC (Dronabinol) is FDA approved to counteract appetite suppression and wasting syndromes and would be available in the U.S. for study. Sativex, which includes both THC and cannabidiol, is available in Canada. Other cannabinoid agonists or partial agonists might be considered as they become available for study in the future. Small, within-subjects crossover studies in the human laboratory could examine effects of cannabinoid agonists on acute opioid withdrawal, or naloxone precipitated withdrawal. Larger placebo-controlled clinical trials should examine cannabinoid effects as adjuncts to opioid detoxification or naltrexone maintenance treatment. Success in these efforts could advance the field by improving the viability of naltrexone in the treatment armamentarium for opioid dependence. Issues regarding exposing patients to a medication with its own addictive potential would also need to be carefully addressed.