4. Inhalation versus Ingestion
This is Part 4 in a 5-part series on Dosing & Administration: Have you ever noticed a difference in the experience of "being high" between smoking a joint, for example, and eating a pot cookie? For the vast majority of Cannabis users, the answer is, "Yes". Why is that?
Look no further than pharmacokinetics for an explanation.
Pharmacokinetics is a pharmacology term that refers to how the body processes drugs. There are four essential components to pharmacokinetics:
Absorption of the drug
Metabolism of the drug
Distribution within the body
Elimination from the body
(You can learn more about the pharmacokinetics of cannabinoids here)
The focus of this article is on the metabolism of delta-9-THC (Referred to herein as THC), which is largely based on the method by which it is introduced into the bloodstream. Inhalation and ingestion are the two primary methods.
Inhalation versus ingestion When cannabinoids are inhaled, the effects are immediate. When they are ingested, the effects are delayed. This makes sense given that ingested cannabinoids must make their way thru the stomach and into the small intestine where they can be absorbed. Once absorbed, they are passed directly to the liver. This is often described as “first-pass metabolism”. In the liver, they are converted to various cannabinoid metabolites by enzymes which are present in high concentrations there. These enzymes are present in all cells, including the cells of the respiratory tract, but the metabolism that occurs in the liver is exponentially greater because of the higher concentrations there.
Pharmacokinetics Pharmacokinetic studies of cannabinoids often include “plasma concentration” graphs like the ones below. These graphs depict the concentration of THC, and its metabolites, in plasma over time. In addition to THC, there are two main metabolites which are typically measured and graphed:
1. Delta-9 THC 2. 11-OH-THC 3. 11-COOH-THC (i.e. 11-nor-9-OOH-THC)
It should be noted that there are more than 100 metabolites of CBD, but we don’t know as much about their biological activity.
Metabolism of THC Back to THC. The concentrations of THC, and its metabolites, and the ratios of one to the others, differ depending on the method by which they are introduced to the body. What also differs is the maximum concentration (Cmax) and the time required to reach the maximum concentration (Tmax).
Inhalation When THC is inhaled, the maximum concentration is greater and the time required to reach that point is shorter (See Figure 1).1,2 This is why the effects are experienced immediately. Pharmacokinetic graphs of inhaled THC show a steep slope with a high amplitude peak followed by a precipitous drop in blood levels. This reflects the high absorptive capacity of the blood vessels in the lungs and the rapid metabolism of THC in the liver.
Importantly, for at least the first hour, the concentration of THC is the highest, followed by 11-COOH-THC and then 11-OH-THC. Note that the absolute concentration of 11-OH-THC is low and the ratio of THC to 11-OH-THC is high. There is a lot more THC than 11-OH-THC.
Figure 1
Source: https://sapiensoup.com/human-metabolism-thc
Ingestion When THC is ingested, the pharmacokinetic graph looks very different (See Figure 2).1,2 The maximum concentration of THC is much less, for roughly the same administered dose (Inhaled: 15.8 mg THC; Ingested: 20 mg THC). Notice that there is no steep slope and no high peak for THC. It’s more of a slow, steady rise. This reflects the transition time thru the gastrointestinal tract, rapid metabolism in the liver and the slow dissemination of THC and its metabolites into the blood stream. Importantly, 11-COOH-THC is the compound measured in the highest concentration. 11-COOH-THC is thought to have no biological activity. It is inert.
A first glance, 11-OH-THC might not look very different from the inhalation graph above. A closer inspection will reveal that this metabolite of THC is clearly higher for longer when ingestion is the method of administration (See Figure 2).
Figure 2
Source: https://sapiensoup.com/human-metabolism-thc
The 11-OH-THC effect The important point is the concentration of 11-OH-THC, and the ratio of THC to 11-OH-THC. 11-OH-THC is up to 7 times more “potent” than THC.3 It has a much greater affinity for the cannabinoid receptor (CB1). It also crosses the blood-brain barrier more easily than THC. Not only is the concentration of 11-OH-THC higher when comparing ingestion to inhalation, but it stays higher for longer, much longer. This may explain why ingested Cannabis products are often much more potent than inhaled Cannabis products. It is also an important consideration when determining an appropriate dose of cannabinoids.
Do higher blood levels mean greater impairment? There is another dimension to this story. Namely, the subjective experience of feeling “high”, or being impaired. Interestingly, feeling “high” is poorly correlated with blood levels of THC.4 We might expect that our subjective experience would track levels of THC in the blood. The greater the concentration of THC, the greater the "high", right? This isn’t necessarily the case.
This phenomenon has been investigated by researchers. In the early 1980s, THC was administered to research subjects with a goal of understanding the degree to which the experience of feeling “high” correlated with concentrations in the blood.4 The authors stated, “It is unlikely that a range of plasma concentrations can be reliably equated with impaired performance.” This is one of the reasons why a reliable road-side test has been difficult to develop for detecting Cannabis-related driving impairment.
Figure 3 shows the concentration of THC after smoking 13mg of THC. Concentration of THC is on the left axis and the subjectively reported experience of feeling “high” is on the right axis. Notice that subjects are reporting feeling increasingly “higher” as blood levels of THC drop in the first 15 minutes.
Figure 3
Source: https://sapiensoup.com/human-metabolism-thc
Figure 4 graphs the concentration after ingesting 20 mg of THC. Notice that the concentration of THC is low and that the subjective experience of being ”high” is rising up to 180 minutes after ingestion. This graph does not include 11-OH-THC, but we know from other pharmacokinetics studies that concentrations of 11-OH-THC and THC are roughly equal when ingestion is the method of administration.
Figure 4
Source: https://sapiensoup.com/human-metabolism-thc
It should be pointed out that the correlation was different for different methods of administration. The correlation between blood levels of THC and feeling “high” was greater when individuals ingested THC (See Figure 4).
The bottom line In summary, the method of administration is a very important consideration when trying to determine the appropriate dose of cannabinoids. Inhalation produces immediate effects of short duration, which are largely mediated by THC. Ingestion produces delayed effects of longer duration, which are largely mediated by 11-OH-THC. Also, the level of impairment, or the experience of being high, is better measured by an individual’s subjective report and function than by the concentration of THC and its metabolites in blood.
In health,
Despite the favorable safety profile, dosing and administration of cannabinoids is complicated. The process should be highly individualized, and is best supervised by a trained health care professional. For more information, please consider booking a consultation (telephone or in-person) with Dr. Jamie Corroon, ND, MPH.
References
1. Huestis MA. Pharmacokinetics and metabolism of the plant cannabinoids delta9-THC, cannabidiol and cannabinol. In: Handbook of Experimental Pharmacology. Vol 168. Springer-Verlag; 2005:657-690. 2. Wall ME, Perez-Reyes M. The metabolism of delta 9-tetrahydrocannabinol and related cannabinoids in man. J Clin Pharmacol. 1981;21(8-9 Suppl):178s-189s. 3. @sapiensoupblog. Human Metabolism of THC. In: @sapiensoupblog; 2016. 4. Hollister LE, Gillespie HK, Ohlsson A, Lindgren JE, Wahlen A, Agurell S. Do plasma concentrations of delta 9-tetrahydrocannabinol reflect the degree of intoxication? J Clin Pharmacol. 1981;21(8-9 Suppl):171s-177s.
