Acute and Chronic Effects Associated With Cannabis Use — Is Partly Dependent on Route of Exposure

Legalization of cannabis in a growing number of States — coupled with the perception that “marijuana is an innocuous drug” — has led to significant increases in cannabis consumption, both for its recreational properties and for its alleged medicinal properties. Not emphasized [in the attached article and editorial], however, is the extremely serious “unintended (unexpected?) use of marijuana among individuals from ages 25 down to 12- and 10-year-olds” — at the time “when their brains are still being hard-wired for adulthood.” The result is the brain is irreversibly damaged.

It is well known that cannabis use is associated with adverse health effects, more cannabis-related emergency department (ED) visits, and cannabis-related increased hospital admissions. In the attached article, authors reviewed health records from patients presenting to the University of Colorado Health Emergency Dept from 2012 to 2016; they found a more-than-3-fold increase in cannabis-associated ED visits over this period. Authors also examined the proportions of ED visits associated with inhalable versus edible cannabis — in light of the sales of both product types in Colorado between 2014 and 2016. Their analysis showed that, although 10.7% of ED visits were attributable to edible cannabis, only 0.32% of total cannabis sales [in kilograms of tetrahydrocannabinol (THC)] represented edible products (i.e. EATING THC is more dangerous than smoking it).

Gastrointestinal (GI) symptoms were the most frequent cause of ED visits (30.7%). Cannabinoid hyper-emesis syndrome (throwing up, wretching uncontrollably) was the most common GI adverse event (and it was also the reason for most hospital admissions). In contrast, intoxication (48.3% vs 27.8%), acute psychiatric symptoms (18.0% vs. 10.9%), and cardiovascular symptoms (8.0% vs. 3.1%) were more common in patients eating THC, compared to those smoking it. The higher-than-expected number of adverse events associated with edible cannabis products — considering the frequency of sales — is consistent with prior findings, including a 2017 Poison Control Center report in which edible products accounted for 17% of cannabis-related visits to health care facilities among adults.

Route-of-administration influences effects of a drug by affecting its bioavailability, peak blood concentrations, and speed at which these two factors are achieved. For drugs with abuse potential, the rate at which they enter the brain and the speed at which they exert their

pharmacologic effects influence addictiveness. The slow rate of absorption of orally-ingested THC (peak blood levels achieved in 3 hrs) compared with inhaled THC (peak blood levels achieved within 30 min) makes it harder for users of edible cannabis to titrate the doses required to achieve the desired drug effects. Further, the slower clearance of oral (12 hrs) vs inhaled (4 hrs) THC can lead to drug accumulation — if users take additional doses when they do not experience the desired effects as quickly as expected. In addition, the wide variety of innocuous-looking edible preparations can lead to over-consumption — particularly when consumers (especially children) do not understand what they are eating. This problem can be compounded by inaccurate labeling of cannabinoid content [THC vs cannabidiol (CBD)] in edible products.

Lastly, but probably most importantly, there are large genetic interindividual differences in oral THC absorption and metabolic response — which also contributes to the unpredictability of drug effects and adverse outcomes. Some of this is due to the fat content of food ingested at the time that THC is eaten. Because THC is highly lipophilic, fatty foods increase THC absorption, but it might also affect its “first-pass” metabolism (phenomenon whereby the drug concentration is substantially decreased — before it reaches the systemic circulation) in the liver. Another factor is that sugars and amino acids are released directly into the mesenteric portal blood on its way to the liver, where they are metabolized before reaching the systemic circulation (first-pass effect), whereas fats are packaged into chylomicrons — which are then diverted into the mesenteric lymphatic system and to the brachial vein, where it first reaches the systemic circulation (thus bypassing first-pass metabolism). This phenomenon might help explain some of the serious side-effects of THC after being taken orally. 🙁


Ann Intern Med 16 Apr 2019; 170: doi:10.7326/M18-2809 & 2-page editorial

Below is a layman’s summary, recently on NBC News [click on title, if you wish to read that article]:

ER visits linked to marijuana increased at Colorado hospital after legalization, study finds

NBC News—March 25, 2019

After marijuana use was legalized in Colorado in 2012, ER visits linked to cannabis use tripled over the next five years at one of the state’s largest hospitals, according to a new analysis. Psychiatric ER visits were more common after people consumed marijuana edibles, compared to smoking or inhaling cannabis products.

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