Edible cannabis: An effect of longer duration and less predictable than with inhalation

Edible cannabis: An effect of longer duration and less predictable than with inhalation

On October 17, 2019, one year after the legalization of cannabis as a smoking substance, the Government of Canada legalized he sale of edible cannabis products, in the form of extracts, for inhalation (vaping) and topical use. In Québec, the new products will be offered for sale exclusively at the Société Québécoise du Cannabis (SQDC). Two new types of products could be offered: edible bakery and pastry products and cannabis extracts (hashish, skuff, vaping liquids). The Québec government has announced its intention to restrict the supply of certain cannabis products (sweets, confectionery, desserts, chocolates and topical products).

The legalization of edible cannabis products is of concern to some public health experts, mainly because of the potential risks of overdose by users and involuntary intoxication by children or pets. These products will be strictly regulated by the federal government’s “Cannabis Regulations.” The maximum THC content will be 10 mg of THC per package; it will be forbidden to add alcohol, nicotine, vitamins or minerals and there will be a limit for the amount of caffeine; the packaging must be childproof; packaging should not be attractive to young people; and no claim of health benefits will be allowed. Labelling will also be regulated and must contain THC and CBD content, a list of ingredients, a Nutrition Facts table and a warning.

In a brief (in French only) presented to the Québec Ministry of Health and Social Services, the National Institute of Public Health of Québec (INSPQ) believes that “the federal government’s approval of a wide range of new cannabis products(edible, extracted and topical) seems to be a hasty initiative.” The INSPQ believes that the marketing of these products poses several health risks: the number of users could increase and the consumption of current users could increase; there is a risk related to delayed effects that are difficult to anticipate; risk of involuntary consumption; risks associated with the consumption of cannabis extracts with a high THC content. The INSPQ supports the Québec government’s initiative to impose new regulatory restrictions on the products to be offered by the SQDC and suggests improvements to the proposed regulation:

  • Allow only the sale of edible products, including beverages, that are recognizable by the characteristic taste of cannabis. This should help to avoid unduly broadening their appeal beyond existing users and to prevent unintended consumption by distinguishing cannabis products from common food products;
  • Prohibit the sale of any cannabis drink that is sweet or has the appearance of popular beverages (for example, soft drinks or fruit juices);
  • Entrust the Vigilance Committee, an independent organization, with the mandate to ratify the assessment made by the SQDC of the conformity of the products and extracts it will offer to the definition of “attractive for minors.”

(From the INSPQ’s brief, pages 1 and 13, August 2019.)

Differences between inhaling and ingesting cannabis
Inhalation and ingestion are two very different modes of cannabis use from a pharmacological point of view. When cannabis is smoked or vaped, the high temperature generated by combustion or vaping releases volatile compounds as smoke or vapour, including the main psychoactive compound of cannabis, Δ9-tetrahydrocannabinol (THC), and cannabidiol (CBD), which has no psychoactive effect. Inhaling smoke or cannabis vapour puts cannabinoids in contact with the lung cells that absorb them and pass them quickly into the bloodstream. THC is partially delivered to the brain where it binds to cannabinoid receptors and will cause a euphoric effect. THC will also pass through the liver where it will first be metabolized to 11-OH-THC (or hydroxy-THC, psychoactive) and then inactivated to 11-nor-9-COOH-THC (or carboxy-THC, non-psychoactive). The bioavailability of cannabis by inhalation ranges from 10% to 35% and varies with the duration and depth of inhalation and the duration of puff retention.

Ingestion of cannabis products
When cannabis is ingested, 90% to 95% of the THC it contains is absorbed in the gastrointestinal tract and then delivered to the liver via the portal vein. A large proportion of THC is inactivated in the liver (carboxy-THC) before it can reach the site of action in the brain. After this “first pass” in the liver, THC and hydroxy-THC (both psychoactive) that have not been inactivated in carboxy-THC (non-psychoactive) are pumped through the heart and then routed to the brain and the periphery. The bioavailability of THC by ingestion is approximately 4%–12% and varies greatly from one individual to another.

Another major difference in the two patterns of cannabis use is the rate at which THC reaches the brain and produces its psychoactive effects. THC is detectable in the blood just seconds after taking a first puff of a cannabis cigarette, with a peak concentration 6 to 10 minutes after starting to smoke (Figure 1, red line). THC is rapidly converted to hydroxy-THC, with a peak concentration at 15 minutes (Figure 1, blue line), then carboxy-THC (green line). The two main psychoactive substances, THC and hydroxy-THC, are almost completely metabolized 2–3 hours after inhaling cannabis smoke. Traces of THC can still be detected in the blood after 7 to 27 hours depending on the dose of inhaled cannabis, while the carboxy-THC metabolite can be detected in the blood for up to 7 days after inhaling cannabis. The main cause of this slow removal of THC from the blood is the slow re-diffusion of THC from adipose tissue and other tissues into the bloodstream.

Figure 1. Mean plasma concentrations of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (11-COOH-THC) of six individuals during and after smoking a cannabis cigarette containing approximately 15.8 mg of THC. Volunteers were instructed to inhale for 2 seconds, hold the smoke for 10 seconds, and exhale and pause for 72 seconds. In total, the volunteers inhaled 8 puffs in 11.2 minutes. According to Huestis et al., 1992.

 

The absorption of THC after cannabis ingestion is much slower and erratic, with maximum THC concentrations observed after 60–120 minutes (Figure 2, red line). Almost equal amounts of THC and hydroxy-THC (Fig. 2, blue line) were found in the blood after ingesting THC at all times. Maximum levels of these two psychoactive substances were measured 2 to 3 hours after ingestion, and remained elevated up to 6 hours. The major metabolite was carboxy-THC (non-psychoactive) and is still found in large amounts 6 hours after ingesting THC-containing capsules (Fig. 2, green line).

Figure 2. Mean plasma concentrations of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (11-COOH-THC) from six individuals after ingesting gelatine capsules containing a total of 20 mg of THC. According to Wall and Perez-Reyes, 1981.

 

More hydroxy-THC is produced after ingestion of cannabis compared to inhalation (see Figures 1 and 2, blue line), but according to one study this metabolite would have a higher psychoactive potential than THC. In addition, hydroxy-THC would enter the brain faster and in greater amounts than THC. Combined with the fact that THC and hydroxy-THC are present in the bloodstream for a longer period, there is a greater risk of overdose when cannabis is ingested than when it is inhaled.

Cannabis users who are accustomed to the effect obtained by inhalation should be careful when using an edible product for the first time and use a reliable and controlled product such as those that will be available at the SQDC. New users should not take more than 5–10 mg of THC and be patient as it may take one to two hours to experience the euphoric effect. The INSPQ and other public health organizations have also suggested that the unit sizes of edible cannabis should not contain more than 5 mg of THC, which is half the limit imposed by federal law (10 mg). Since the effect will be longer lasting with an edible product, the consumer will have to plan a sufficient amount of time in their schedule and anticipate that the effects of cannabis may take more than six hours to fade. Overdose, which can cause a very unpleasant “bad trip”, should be avoided. Fortunately, it is almost impossible to die of an overdose of cannabis because it would require consuming huge amounts (kilograms). On the other hand, overdose can, in very rare cases, cause acute suicidal psychosis or exacerbate underlying cardiac problems and indirectly cause death.

Cannabidiol (CBD)
Products containing CBD (non-psychoactive) are very popular in North America, and up to 14% of Americans consume it according to a recent survey. U.S. users say they consume these products to reduce pain (40%), anxiety (20%), to improve sleep (11%), to treat arthritis (8%), migraines and headaches (5%), and reduce stress (5%). According to a U.S. study, the CBD market could reach 20 billion dollars in 2024.

Paradoxically, relatively little is known about the metabolism of this cannabinoid and its therapeutic efficacy. The only two CBD-based medications that have been licensed are Sativex for the treatment of symptoms of multiple sclerosis and Epidiolex for certain types of epilepsy in children. A dozen clinical trials are underway to treat schizophrenia, Crohn’s disease and graft-versus-host disease.

A randomized controlled trial was recently conducted to establish the safety, tolerability and pharmacokinetics of CBD. CBD was generally well tolerated (single oral doses of 1500, 3000, 4500, 6000 mg CBD) and side effects were mild. After a single oral dose, CBD is detected rapidly in the blood and reaches a maximum concentration after 4–5 hours. The major circulating metabolite was 7-carboxy-CBD (95%, inactive), followed by CBD (2%, active) and 7-hydroxy-CBD (2.3%, active), and 6-hydroxy-CBD (0.2%). The low absolute bioavailability of CBD caused by metabolism in the liver to 7-carboxy-CBD (inactive) explains why relatively high doses of CBD are required to achieve a therapeutic effect. The study found that taking CBD twice a day would maintain an effective plasma concentration for treating epilepsy.

Canadians will soon have access to edible cannabis products that will be controlled by federal and provincial laws and regulations. New users should be careful not to consume these products in excessive quantities, knowing that this mode of consumption does not produce exactly the same effects as a cannabis cigarette, particularly with regard to the much slower absorption time and prolonged duration of euphoric effects.

Eggs: To consume with moderation

Eggs: To consume with moderation

The old debate over whether egg consumption is detrimental to cardiovascular health has been revived since the recent publication of a study that finds a significant, albeit modest, association between egg or dietary cholesterol consumption and the incidence of cardiovascular disease (CVD) and all-cause mortality. Eggs are an important food source of cholesterol: a large egg (≈50 g) contains approximately 186 mg of cholesterol. The effect of eggs and dietary cholesterol on health has been the subject of much research over the last five decades, but recently it has been assumed that this effect is less important than previously thought. For example, the guidelines of medical and public health organizations have in recent years minimized the association between dietary cholesterol and CVD (see the 2013 AHA/ACC Lifestyle Guidelines and the 2015–2020 Dietary Guidelines for Americans). In 2010, the American guidelines recommended consuming less than 300 mg of cholesterol per day; however, the most recent recommendations (2014–2015) do not specify a daily limit. This change stems from the fact that cholesterol intake from eggs or other foods has not been shown to increase blood levels of LDL-cholesterol or the risk of CVD, as opposed to the dietary intake of saturated fat that significantly increases LDL cholesterol levels, a significant risk of CVD.

Some studies have reported that dietary cholesterol increases the risk of CVD, while others reported a decrease in risk or no effect with high cholesterol consumption. In 2015, a systematic review and meta-analysis of prospective studies was unable to draw conclusions about the risk of CVD associated with dietary cholesterol, mainly because of heterogeneity and lack of methodological rigour in the studies. The authors suggested that new carefully adjusted and rigorously conducted cohort studies would be useful in assessing the relative effects of dietary cholesterol on the risk of CVD.

What distinguishes the study recently published in JAMA from those published previously is its great methodological rigour, in particular a more rigorous categorization of the components of the diet, which makes it possible to isolateindependent relationships between the consumption of eggs or cholesterol from other sources and the incidence of CVD. The cohorts were also carefully harmonized, and several fine analyses were performed. The data came from six U.S. cohorts with a total of 29,615 participants who were followed for an average of 17.5 years.

The main finding of the study is that greater consumption of eggs or dietary cholesterol (including eggs and meat) is significantly associated with a higher risk of CVD and premature mortality. This association has a dose-response relationship: for every additional 300 mg of cholesterol consumed daily, the risk of CVD increases by 17% and that of all-cause mortality increases by 18%. Each serving of ½ egg consumed daily is associated with an increased risk of CVD of 6% and an increased risk of all-cause mortality of 8%. On average, an American consumes 295 mg of cholesterol every day, including 3 to 4 eggs per week. The model used to achieve these results took into account the following factors: age, gender, race/ethnicity, educational attainment, daily energy intake, smoking, alcohol consumption, level of physical activity, use of hormone therapy. These adjustments are very important when you consider that egg consumption is commonly associated with unhealthy behaviours such as smoking, physical inactivity and unhealthy eating. These associations remain significant after additional adjustments to account for CVD risk factors (e.g. body mass index, diabetes, blood pressure, lipidemia), consumption of fat, animal protein, fibre and sodium.

A review of this study suggests that the association between cholesterol and the incidence of CVD and mortality may be due in part to residual confounding factors. The authors of this review believe that health-conscious people reported eating fewer eggs and cholesterol-containing foods than they actually did. Future studies should include “falsification tests” to determine whether a “health consciousness” factor is the cause of the apparent association between dietary cholesterol and CVD risk.

Eggs, TMAO and atherosclerosis
A few years ago, a metabolomic approach identified a compound in the blood, trimethylamine-N-oxide (TMAO), which is associated with increased cardiovascular risks. TMAO is formed from molecules from the diet: choline, phosphatidylcholine (lecithin) and carnitine. Bacteria present in the intestinal flora convert these molecules into trimethylamine (TMA), then the TMA is oxidized to TMAO by liver enzymes called flavin monooxygenases. The main dietary sources of choline and carnitine are red meat, poultry, fish, dairy products and eggs (yolks). Eggs are an important source of choline (147 mg/large egg), an essential nutrient for the liver, muscles and normal foetal development, among others.

A prospective study indicated that elevated plasma concentrations of TMAO were associated with a risk of major cardiac events (myocardial infarction, stroke, death), independent of traditional risk factors for cardiovascular disease, markers of inflammation, and renal function. It has been proposed that TMAO promotes atherosclerosis by increasing the number of macrophage scavenger receptors, which carry oxidized LDL (LDLox) to be degraded within the cell, and by stimulating macrophage foam cells (i.e. filled with LDLox fat droplets), which would lead to increased inflammation and oxidation of cholesterol that is deposited on the atheroma plaques. A randomized controlled study indicates that the consumption of 2 or more eggs significantly increases the TMAO in blood and urine, with a choline conversion rate to TMAO of approximately 14%. However, this study found no difference in the blood levels of two markers of inflammation, LDLox and C-reactive protein (hsCRP).

Not all experts are convinced that TMAO contributes to the development of CVD. A major criticism is focused on fish and seafood, foods that may contain significant amounts of TMAO, but are associated with better cardiovascular health. For example, muscle tissue in cod contains 45–50 mmol TMAO/kg. For comparison, the levels of choline, a precursor of TMAO, are 24 mmol/kg in eggs and 10 mmol/kg in red meat. The only sources of choline that are equivalent to that in TMAO in marine species are beef and chicken liver. TMAO contained in fish and seafood is therefore significantly more important quantitatively than TMAO that can be generated by the intestinal flora from choline and carnitine from red meat and eggs. This was also measured: plasma levels of TMAO are much higher in people who have a fish-based diet (> 5000 μmol / L) than in people who eat mostly meat and eggs (139 μmol / L). In their response to this criticism, the authors of the article point out that not all fish contain the same amounts of TMAO and that many (e.g. sea bass, trout, catfish, walleye) do not contain any. Fish that contain a lot of TMAO are mainly deep-sea varieties (cod, haddock, halibut). The TMAO content of other fish, including salmon, depends on the environment and when they are caught.

Other experts believe this could be a case of reverse causality: the reduction in renal function associated with atherosclerosis could lead to an accumulation of TMAO, which would mean that this metabolite is a marker and not the cause of atherosclerosis. To which the authors of the hypothesis counter that the high concentration of TMAO is associated with a higher risk of cardiovascular events even when people have completely normal kidney function.

Diabetes and insulin resistance
People who are overweight (BMI> 25) and obese (BMI> 50) are at higher risk of becoming insulin resistant and having type 2 diabetes and metabolic syndrome, conditions that can, independently or in combination, lead to the development of cardiovascular disease. There is evidence that dietary cholesterol may be more harmful to diabetics. Intestinal absorption of cholesterol is impaired in diabetics, i.e. it is increased. However, in a randomized controlled trial, when diabetic patients consumed 2 eggs per day, 6 times per week, their lipid profile was not altered when their diet contained mono- and polyunsaturated fatty acids. Other studies (mostly subsidized by the egg industry) suggest that eggs are safe for diabetics.

Dr. J. David Spence of the Stroke Prevention & Atherosclerosis Research Center believes that people at risk for CVD, including diabetics, should avoid eating eggs (see also this more detailed article). This expert in prevention argues that it is the effects of lipids after a meal that matter, not fasting lipid levels. Four hours after a meal high in fat and cholesterol, harmful phenomena such as endothelial dysfunction, vascular inflammation and oxidative stress are observed. While egg whites are unquestionably a source of high-quality protein, egg yolks should not be eaten by people with cardiovascular risks or genetic predispositions to heart disease.

The association between the consumption of eggs or foods containing cholesterol and the risk of CVD is modest. But since this risk increases with the amount consumed, people who eat a lot of eggs or foods containing cholesterol have a significant risk of harming their cardiovascular health. For example, according to the study published in JAMA, people who consume two eggs per day instead of 3 or 4 per week have a 27% higher risk of CVD and a 34% higher risk of premature mortality. It is therefore prudent to minimize the consumption of eggs (less than 3 or 4 eggs per week) and meat in order to limit the high intake of cholesterol and choline and avoid promoting atherosclerosis.