Why do some people fail to quit cannabis and how can we help them?

Recent study investigates the mechanisms behind cannabis use disorder and possible treatments

Cannabis use has been growing steadily worldwide, and while many people have a positive experience with the drug, a considerable number of long-term users finds it very difficult to quit. As such, practitioners are seeing an increase in cases of cannabis use disorder for which, unfortunately, they have no good therapeutic yet.

Part of the problem lies in our scarce knowledge of the physiology of cannabis intake, and in particular, what drives its withdrawal symptoms to be more intense among some people but not others. For instance, women  usually develop addiction faster than men and are less likely to respond to therapy.

Dr. Nicolas Schlienz and colleagues from John Hopkins School of Medicine and the Geisel School of Medicine (U.S.) tried to understand these issues by reviewing  published data from the last five years of research in field. Their article was published last April in the journal Current Addiction Reports.

Recent reports have described cannabis withdrawal symptoms in fine detail. These usually start 24 to 48 hours following an abrupt cessation by long-term users, and include irritability, anxiety, sleep problems, reduced appetite, weight loss, depressed mood and some physical problems like abdominal pain and headaches. The severity of symptoms peaks around the second and fifth days after cessation, and can take more than three weeks to subside. Most people who fail to quit blame it on the severity of their withdrawal symptoms.

Researchers generally agree that THC is to blame for the withdrawal symptoms of cannabis. The main psychoactive compound of cannabis acts on cannabinoid receptors 1 and 2 (CB1 and CB2), and after a prolonged exposure, THC seems to drive a reduction in the number of these (mostly of CB1). This attempt by the body to adjust to the new levels of cannabinoids backfires when long-term users suddenly quit and cannabinoid concentrations plummet.

This explanation is well supported by preclinical and clinical evidence. A 2012 brain imaging study showed that daily cannabis users have a lower density of CB1 receptors compared to non-users, and that this reduction correlates with years of use. Importantly, the levels of receptors returned to normal after 30 days of supervised abstinence, which is when withdrawal symptoms usually subside. This result was replicated in 2016 and extended to show that the levels of CB1 receptors on the second day of abstinence correlate with the severity of the symptoms reported by the participants. Researchers have also been able to test this mechanism in rats with resource to pharmacological interventions.

Unfortunately, less progress has been made towards understanding the sexual differences in cannabis withdrawal symptoms. This is likely due to observed differences in the endocannabinoid system between males and females, but at this point it is unclear what the important players are. This is rendered worse by women being underrepresented or completely excluded from participating in human studies, usually for no good reason other than facilitating data analysis.

On another front, researchers have started looking at ways to hopefully counteract cannabis withdrawal symptoms. One such possibility is to block the activity of enzymes that degrade anandamide (an endogenous cannabinoid that acts similarly to THC) to temporarily increase its levels once users quit using the drug. So far animal studies have yielded mixed results, and no clinical trials in humans have been published. However, preliminary results presented at a conference in 2015 suggest that patients receiving an anandamide enzyme blocker experienced fewer cannabis withdrawal symptoms than those given placebo and reported a higher reduction in cannabis use.

These are but the first steps in understanding cannabis addiction. More research is needed to understand the many complexities of the endocannabinoid system that facilitate dependence. Hopefully, with the recent interest and funding towards these problems, it will not be long before practitioners can provide good treatment to their patients.

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