5. Cannabis and the dose-response relationship
This is Part 5 in a 5-part series on Dosing & Administration: An individual’s response to a given dose of THC, CBD or other cannabinoid(s) is dependent upon many factors.
(You can learn more about the factors that influence dosing and administration of cannabinoids here)
One key determinant of the dose-response relationship is the pharmacology of the drug itself. In this case, a cannabinoid. The pharmacokinetics and pharmacodynamics depend on the drug in question, and the biology of the individual receiving it.
(You can learn more about pharmacokinetics of cannabinoids here)
The dose-response relationship for a given drug is typically characterized in toxicology studies, where the pharmacokinetics and pharmacodynamics of the drug being evaluated are elucidated.
(You can learn more about toxicology studies involving cannabinoids here)
Before embarking on a discussion of the dose-response relationship for selected cannabinoids, however, let’s first clarify the difference between dose and potency.
Dose versus potency Potency is often used interchangeably with dose. This can be confusing because they are different, but related. Potency is the amount of a constituent, like THC, expressed as a percentage of the overall material, typically by weight. Potency is a concentration. A potency (i.e. Percentage) of 15% THC, or greater, is generally considered potent. Admittedly, this is an arbitrary cutoff. Some types of Cannabis flower have a percentage of THC that exceeds 25%. These types would be considered very potent. Cannabis extracts (i.e. Concentrates) may contain a percentage of THC that exceeds 85%. These products should be administered in small doses.
When talking about Cannabis, dose is the amount of a constituent, like THC, expressed in units of weight (i.e. Mass), typically in milligrams. A 3 mg dose of THC is considered a low dose.
Keep in mind that the weight of an individual constituent is only a fraction of the weight of the Cannabis flower in question. If you had a "piece" of Cannabis flower on the scale, and it weighed 25 mg, and had a potency of 12% THC, then the dose of THC in that piece of flower would be 3 mg (25 mg x 12% = 3 mg).
Looking at it from a different angle: If you smoked a 25 mg piece of Cannabis flower which had a potency of 15% THC, and then you smoked a 25 mg piece which had a potency of 25% THC, you would be receiving two totally different doses (See Figure 1).
Figure 1
In this example, the percent absorbed (i.e. Bioavailability) is held constant at 35%. It should be noted that the bioavailability of cannabinoids is highly dependent on the method by which they are administered, as well as the individual's biological makeup. In this example, the method is inhalation.
(You can learn more about the how the method of administration influences the dose here. You can learn more about the role of biological variability here.)
Dose-response Back to the dose-response relationship. In an ideal world, a linear dose-response relationship would exist between a given drug and the desired, therapeutic response in an individual. That means that each incremental increase in the dose of the drug would result in a corresponding increase in the therapeutic response. While most dose-response curves are not completely linear, they are often sigmoidal (i.e. S-shaped) and monophasic (See Figure 2). This simply means that the relationship is roughly linear until it reaches a single plateau. At that point, incremental increases in the dose of the drug no longer result in a change in the response.
Figure 2
In this ideal world, we can determine the maximum effective dose – the dose at which it makes no sense to exceed because there is no clinical benefit.
Cannabinoids and the dose-response relationship In 2007, a randomized, controlled trial was conducted among patients with chronic pain who were taking opioids.1 The investigators wondered if dronabinol, a semi-synthetic analog to THC, might produce added analgesia, pain relief above and beyond the opioids. They noted that 10mg of dronabinol led to decreased pain intensity and increased satisfaction, as compared to placebo. Meanwhile, 20mg of dronabinol led to no more pain relief than 10mg.
It should also be pointed out that dronabinol is a semi-synthetic version of THC. The dose-response relationship for naturally-occurring THC may be different. Also, dronabinol is an isolated compound. When one ingests dronabinol, they are ingesting very little else. The same cannot be said for the THC found in medical Cannabis products (e.g. Flower, extracts, edibles, etc.). These products typically contain a variety of compounds including CBD , secondary cannabinoids, terpenes, flavonoids and others. The dose-response relationship may be different for isolates than for whole-plant extracts.
In other words, taking 10 mg of THC in a whole plant extract may illicit a different response than taking 10 mg of semi-synthetic, isolated THC.
THC and other cannabinoids In another randomized, controlled trial subjects were administered 25 mg of dried Cannabis flower (i.e. Bud) to inhale three times a day.2 There were four different potencies of THC-dominant Cannabis flower – 0% THC, 2.5%, 6% and 9.4%. With a linear dose-response relationship, more pain relief would be expected with each incremental increase in dose (In this example, an increase in potency results in an increase in dose because the amount of starting material is held constant (25 mg).
Interestingly, the 6.0% potency resulted in basically the same pain relief as the 2.5% potency. That is, the 6% potency resulted in no more pain relief than the 2.5% potency. Other studies have also found that a higher potency does not necessarily illicit a greater therapeutic response (See below).
To be clear, the highest potency in this study was actually the most effective, but a linear curve was not demonstrated.
“A single inhalation of 25 mg of 9.4% THC herbal cannabis three times daily for five days reduced the intensity of pain, improved sleep and was well tolerated.”
Inverted U-shaped curve A study conducted at UCSD in participants suffering from chronic, neuropathic pain demonstrated an U-shaped dose-response curve for inhaled Cannabis.3 With a U-shaped, or bell-shaped curve the most effective dose is in the middle of the dosing range, not at the higher or lower end. This curve is often referred to as an “inverted U-shaped” curve depending on how the data is graphed.
A U-shaped curve was also demonstrated for CBD in a randomized controlled trial conducted at the University of Sao Paolo in Brazil. Participants with social anxiety were given a placebo, clonazepam (i.e. A prescription anti-anxiety medication) or one of three doses of isolated CBD – 100 mg, 300 mg or 900 mg.
It was only the 300 mg dose of CBD that resulted in a statistically significant reduction in post-stress anxiety (See Figure 3), as compared to both placebo and clonazepam. More is not necessarily better.
Figure 3
Isolates versus whole-plant extracts It is important to recognize that the pharmacokinetics, pharmacodynamics and the dose-response relationship may be different for isolated cannabinoids as opposed to cannabinoids that exist in their natural state. That is, surrounded by other compounds – other cannabinoids, terpinoids, flavonoids, etc. These other compounds modulate the effects of one another and ultimately produce a different dose-response curve than an isolate.
For example, a pre-clinical experiment was conducted in mice to determine the differences in anti-nociceptive (i.e. Pain relieving) effects between isolated CBD and CBD in a whole plant extract.4 An noxious chemical was first injected into the paws of the mice in order to induce an inflammatory pain state. They were then given CBD, both intraperitoneally and orally. A filament was then used to poke their paws to elicit pain. The retraction of the paw was used as a proxy for the pain-relieving effects of CBD. The greater the pressure required on the filament to stimulate paw retraction, the more pain relief was thought to be demonstrated by CBD (See Figure 4).
Figure 4
Figure 3 shows a comparison of the dose response curves for orally administered CBD. On the left, there is a decrease in the response as the dose of isolated CBD is increased (Left). In other words, a higher dose of CBD does not lead to greater pain relief. In fact, it leads to less. On the right, a linear dose-response curve is approximated for the whole plant extract (i.e. Clone 202 extract). In other words, a higher dose of CBD in a whole plant extract DOES appear to lead to greater pain relief.
Studies of this type are needed in human beings so that we can draw more sound conclusions.
The bottom line In summary, the dose-response relationship between cannabinoids and various health-related outcomes has yet to be fully elucidated. Pre-clinical experiments suggest that the response to semi-synthetic and/or isolated cannabinoids may be different than naturally-occurring ones. Further, both linear and U-shaped dose-response relationships have been demonstrated for cannabinoids. More studies of this type are needed before the dose-response relationship can be reliably utilized as a basis for a personalized dosing program.
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 telephone or in-person consultation with Dr. Jamie Corroon, ND, MPH.
References
1. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. The journal of pain : official journal of the American Pain Society. 2008;9(3):254-264. 2. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):E694-701. 3. Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. 2007;107(5):785-796. 4. Gallily R, Yekhtin Z, Hanus L. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by using Cannabis extract enriched in Cannabidiol. Pharmacology & Pharmacy,. 2015;6:75-85.
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