04. Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial

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For our next Quick Take, let’s look at an article on cannabidiol. You know this as a component of marijuana, just like THC is a component. And cannabidiol, we’ll call it CBD here, is all the rage right now. It’s getting a lot of attention from users, and people are promoting it for profit. But it’s also being explored clinically with decent studies for anxiety, for insomnia, pain, certainly for epilepsy where it recently got an FDA indication for a specific kind of epilepsy called Lennox-Gastaut syndrome. It’s even been looked at for possible antipsychotic effect, which is ironic since THC and marijuana are clearly associated with causing psychosis. Where I live in Oregon in the United States, access to marijuana has been legalized, and so interest in CBD is very high. Your patients likely have access to it through internet sources, legal or otherwise, and so, in that context, new data on CBD’s effect on substance use are of interest, including some intriguing hints about its mechanism of action and addiction.

An article in the May issue of the American Journal of Psychiatry by Yasmin Hurd and her colleagues at Mount Sinai in New York explores the use of cannabidiol to block craving in abstinent heroin users. On average, these subjects had been using heroin for 13 years and were less than 1 month abstinent. This is prominent, recent heroin abstinence. The research design is somewhat complex, but the bottom line here is that CBD blocked cue-induced craving and anxiety. They showed these subjects a 3-minute video of injecting or snorting heroin, matched to the subject’s actual route of use, and then paraphernalia, like syringes or rubber tire or packets of powder resembling heroin. The comparison was a neutral cue—video scenes of nature or neutral objects. Interestingly, in the latter, the neutral context, CBD had minimal effects on craving or anxiety. But when it was given and then patients were exposed to these strong heroin-associated cues, the impact was quite strong, again lowering craving and anxiety. The point here is that CBD does not appear to be an anxiolytic as such, at least in this context. The mechanism has to do with cues. And that makes sense in terms of mechanism. There’s a dopaminergic reward pathway, but there’s also an endocannabinoid pathway involved in reward and substance use mechanism of why these things are so appealing.

That’s why the cannabinoid receptor antagonist, rimonabant, has been studied and shown efficacy in smoking cessation. Indeed, I wasn’t aware of it, but CBD, cannabidiol itself, has been studied in smoking cessation. A pilot trial in 2013 by Celia Morgan and her colleagues at the University College of London was suggestive. They found that placebo-treated smokers showed no difference in cigarettes per day using a placebo inhaler for a week. But those who were using a CBD nasal inhaler got a 40% reduction in cigarettes per day using the CBD inhaler for a week. A more recent study by Dr. Morgan’s team, led by her colleague Chandni Hindocha, examined craving and withdrawal symptoms in smokers and found a shift in what they call attentional bias. Cigarettes, which have strong attentional control in cigarette smokers who are trying not to use them, simply weren’t as appealing, even long after the last cigarette, when they were using an oral CBD as opposed to placebo.

That sets the stage then for us to look at CBD in this heroin context, where Dr. Hurd’s Mount Sinai team found decreased craving in the face of cues. They too found attentional saliency of cues—meaning, how much clout is this visual presentation of heroin-related cues? How much clout does it have? That looks like the mechanism. The CBD appeared to affect desire for the substance by affecting an individual’s level of attention toward that substance. Why is this mechanism so important? Well, for one thing, it indicates that not only is marijuana overall complicated with both highly deleterious and potentially beneficial components in THC and CBD, respectively, but even CBD is complicated. It’s not an overall anxiolytic. It’s doing something more subtle.

I should note that in all these studies, the adverse effects of CBD were minimal. In the studies by Dr. Hurd, for example, 3 of 21 subjects got mild diarrhea, and the rest of the adverse effects were presented in a supplementary data table, where all the effects were even more mild and not clearly separable from placebo. Now, the study was supported in part by GW. They’re the makers of Epidiolex, which is the one that has the FDA indication. But the investigators here were not taking money as speakers or investigators, so I think this is probably not too laundered.

The take-home point, then, is we don’t really understand cannabidiol yet, not enough, at least, to know what to do with it clinically, at least not based on good solid evidence. But the endocannabinoid pathway is relevant to much of our work as psychiatrists, and CBD clearly modulates it. Your patients may already have found it, and they can teach you through their experiences with it while we wait for more data.

Abstract

Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial

Yasmin L Hurd, Sharron Spriggs, Julia Alishayev, Gary Winkel, Kristina Gurgov, Chris Kudrich, Anna M Oprescu, Edwin Salsitz

Objective: Despite the staggering consequences of the opioid epidemic, limited nonopioid medication options have been developed to treat this medical and public health crisis. This study investigated the potential of cannabidiol (CBD), a nonintoxicating phytocannabinoid, to reduce cue-induced craving and anxiety, two critical features of addiction that often contribute to relapse and continued drug use, in drug-abstinent individuals with heroin use disorder.

Methods: This exploratory double-blind randomized placebo-controlled trial assessed the acute (1 hour, 2 hours, and 24 hours), short-term (3 consecutive days), and protracted (7 days after the last of three consecutive daily administrations) effects of CBD administration (400 or 800 mg, once daily for 3 consecutive days) on drug cue–induced craving and anxiety in drug-abstinent individuals with heroin use disorder. Secondary measures assessed participants’ positive and negative affect, cognition, and physiological status.

Results: Acute CBD administration, in contrast to placebo, significantly reduced both craving and anxiety induced by the presentation of salient drug cues compared with neutral cues. CBD also showed significant protracted effects on these measures 7 days after the final short-term (3-day) CBD exposure. In addition, CBD reduced the drug cue–induced physiological measures of heart rate and salivary cortisol levels. There were no significant effects on cognition, and there were no serious adverse effects.

Conclusions: CBD’s potential to reduce cue-induced craving and anxiety provides a strong basis for further investigation of this phytocannabinoid as a treatment option for opioid use disorder.

Reference

Hurd, Y. L., Spriggs, S., Alishayev, J., Winkel, G., Gurgov, K., Kudrich, C., Oprescu, A. M., & Salsitz, E. (2019). Cannabidiol for the reduction of cue-induced craving and anxiety in drug-abstinent individuals with heroin use disorder: A double-blind randomized placebo-controlled trial. American Journal of Psychiatry, 176(11), 911-922