CBD products - Comparing apples and oranges?
Virtually all of the pre-clinical and clinical research conducted to date investigating CBD has used the molecule itself. But that's not what consumers are using.
The vast majority of consumers are using full and broad-spectrum extracts (i.e., non-purified) of the Cannabis plant that are rich in CBD, but also contain a variety of other biologically active compounds.
Can we apply the findings from studies using purified CBD products to non-purified CBD products?
Are the pharmacokinetics, pharmacodynamics and dose-response curves the same?
Are the safety, tolerability and efficacy profiles the same?
Are we comparing apples to apples or are we comparing apples to oranges?
We need more research to answer these important questions. And we need a stable, regulated marketplace in order for manufacturers to feel comfortable investing in that research.
On the above slide, we have the chemical formula and structure of CBD (on the left), and the same information for CBD-A (on the right). CBD-A is the acid form of the molecule. CBD is the neutral, or decarboxylated, form. Ironically, the plant doesn’t actually biosynthesize CBD. It synthesizes CBD-A.
In conversations about the regulatory status of CBD, you may hear the phrase “…naturally occurring levels of CBD…” Scientifically speaking, naturally occurring levels of CBD are likely to be negligible. CBD is only present in plant material as a result of spontaneous decarboxylation, which is time and temperature dependent.
CBD is different from CBD-A. CBD is an FDA approved drug. CBD-A is not. Should these molecules be regulated differently? Should raw products be regulated differently than decarboxylated products? And do they have different effects?
There are a few animal models of nausea and vomiting that indicate that CBD-A is more potent than CBD for reducing nausea. In the study above, the effective dose of CBD-A was 1,000 times lower than the dose of CBD.
In the past, hemp and marijuana were distinguished from one another by their phenotype – physical appearance – and their intended use. Now these two types of Cannabis are distinguished by their THC content.
This is the definition of hemp from the 2018 Farm Bill (See above slide). It refers to a level of THC; Not more than 0.3% by dry weight. The Cannabis plant doesn’t actually biosynthesize THC either. It synthesizes THC-A. As with CBD, any “THC” in the plant is likely to be negligible and present as a result of spontaneous decarboxylation. According to this definition, a large number of “marijuana” plants may actually be “hemp” plants, scientifically speaking.
Notice that it says “derivatives” and “extracts”, but it doesn’t say anything about finished products. Some say, it’s implied. But the word “dry weight basis” suggests that this definition pertains to plant material, not finished products. This is an agricultural Bill.
Nonetheless most manufacturers of hemp-derived CBD products will tell you that their finished products contain less than 0.3% THC. This needs further clarification. Also, a PPM (Parts Per Million) threshold would be better than a percentage. Percentages can be manipulated via dilution.
Full and broad-spectrum extracts can contain a multitude of biologically active ingredients. Highly-purified CBD isolate products do not. As a result, they likely have different pharmacokinetics and pharmacodynamics, and different effects. Consumers are often confused by the terms “broad spectrum”, “Full spectrum” and “Whole plant”.
In some circles, “Broad-spectrum” has come to suggest that the product does not contain THC. Broad spectrum” is not a scientific or regulatory term. It is a marketing term.
If it is important that a product be “THC Free”, there should be a regulatory term, grounded in science, that defines exactly what "THC Free" means. We have regulatory terms like this for other products (e.g., “Fat free”, “Sodium Free” and “Decaffeinated”).
Why not abandon the "broad-spectrum" and "full-spectrum" confusion and just say the product is “THC Free”? Decaffeinated coffee can have up to 30mg of caffeine in it. Where should the bar be set for THC in a "THC Free" product?
Those of us who work with botanical medicines understand how the constituents in a botanical matrix may modulate the pharmacokinetics and pharmacodynamics of one another to produce a synergistic effect. In Cannabis, that synergy has a fancy name. It’s called the Entourage Effect. There is no entourage in a highly purified CBD product. There are physically no members!
Proponents of the Entourage Effect claim that a lower dose of a full-spectrum extract is equal to, if not superior to, a higher dose of an isolated CBD product, with fewer adverse effects. In fact, consumers, and healthcare providers and their patients, seem to be experiencing positive health outcomes using doses of CBD in full and broad-spectrum extracts that are well below the doses of isolated CBD used in clinical trials. When you ask research scientists about this at medical Cannabis conferences, they often smirk. The don’t think the doses that are being used are enough to do anything.
Is this an Entourage Effect or a placebo effect? We need to find out.
The Entourage Effect
There is some evidence of the Entourage Effect, though not a lot, and not of high quality. It is important remember that this phenomenon is not exclusive to Cannabis. If one considers the broader world of botanical medicine, there is reason to believe there may be a signal amid the noise.
In the field of medical Cannabis, these are two of the most commonly referenced studies when advocates seek to substantiate claims of synergy (See below). The first is a randomized, controlled pre-clinical trial conducted in mice with experimentally induced localized inflammation. The second is a meta-analysis of observational clinical studies treating refractory epilepsy with CBD products. In the second study, the meta-analysis, the patients treated with CBD-rich extracts reported a lower average dose (6.0 mg/kg/day) than those using purified CBD (25.3 mg/kg/day). And they experienced fewer adverse effects. It important to note however, that the Epidiolex patients had to adhere to a protocol per FDA standards, and the patients in the comparative studies in the meta-analysis did not.
A closer look at the first study reveals an important difference between isolates and extracts. These mice were given isolated CBD or CBD in a full-spectrum extract and then assessed for various pain and inflammation-related outcomes. It’s entitled “Overcoming the bell-shaped dose response curve of cannabidiol...”
Here (above) is the chemical composition of the extract (above), as measured by Gas Chromatography and Mass Spectrometry. This particular extract is almost 18% CBD. It also contains a small percentage of THC, roughly 1% , and some other cannabinoids, including CBC.
Is it possible that this was extracted from “hemp” (< 0.3% THC), but became “marijuana” (≥ 0.3% THC) just by virtue of the extraction process? Yes.
This is Figure 4 from the study. On the left we have the CBD isolate. On the right we have the extract. TNF-alpha concentrations are on the vertical axis. TNF-alpha is an inflammatory chemical produced by white blood cells. The various dosages of CBD are on the horizontal axis. The dose of the extract has been replaced with the dose of the CBD, so that CBD in the isolate can be compared to CBD in the extract on a per milligram basis.
On the left, with isolated CBD, we see that the lowest concentration of TNF-alpha is associated with the 25 mg/kg dose. And that higher dosages are not associated with lower concentrations. This looks like a bell-shaped curve, albeit an inverted one (Recall the name of the study: “Overcoming the bell-shaped dose response curve…”).
On the right, with the extract, we see a linear downward trend with higher dosages associated with lower concentrations of TNF-alpha. If we look carefully, we can see that 25 mg/kg of the isolate is roughly equal to between 4.5 and 9 mg/kg of the extract. It appears that the dose-response curve is different in mice, at least in terms of pain and inflammation. This is important.
The data in the above slide are from a cross-sectional study I published in 2018. Just over 2,400 individuals who reported using CBD products. Approximately 62% of them reported using CBD to treat a medical condition, or a symptom of one. When asked about symptoms or medical conditions, the Top 5 reported were pain, anxiety, depression, sleep disorders and headaches. There are other studies like this. There is a high degree of agreement between them.
Most of the clinical trials investigating the use of Cannabis, or cannabinoids, to treat pain have used either smoked Cannabis or orally delivered cannabinoids (i.e., THC, or THC and CBD together). Only a small number have used CBD on its own. I am not aware of a single RCT that has used a full or broad-spectrum CBD extract to treat pain.
The above study was published in 2003. It is a double-blind, randomized, placebo-controlled single-patient cross-over trial that was conducted over 8 weeks among patients with a neurological diagnosis, mostly MS. It includes 20 subjects. 4 subjects dropped out. The study was funded by GW pharmaceuticals. Subjects received CBD, THC, CBD and THC in a 1:1 ratio (Sativex, see below) and placebo. This study had many outcomes. The focus here is on pain.
The slide above shows table 1 from the study. Pain was self-reported and measured on a 100 point visual analog scale, where 0 was the ”worst possible” pain and 100 was the “best possible” pain. Baseline pain was approximately 30, so moderate to severe pain.
Statistically significant findings are presented in bold. In comparison with placebo, CBD and THC significantly reduced pain. CBD and THC together also reduced pain, but not significantly.
Overall, pain scores improved by about 25 points for both CBD and THC, and a little less for both of them together. This gives the impression that these different interventions are equally effective. That is not my experience in clinical practice.
It is important to note the standard deviation here is very wide. This means that some individuals experienced a lot of pain relief and others experienced a little.
You might be wondering what dose these subjects were taking.This is table 3 from the study. All subjects determined their own dose based on tolerability and efficacy. That is, they started with a low dose and titrated up based on how they felt. The table lists sprays per day, which I have converted into milligrams per day below.
Subjects used between 23-25 mg of CBD and THC. Not only are the effect sizes similar, but the dosing is similar. This gives the impression that CBD and THC are equally potent. That is not my experience in clinical practice.
Additive or synergistic?
The slide above shows the final study in this section. This is one of the phase III clinical trials for Sativex, the drug developed by GW Pharmaceuticals that contains CBD and THC in a 1:1 ratio. This study was also funded by GW as part of the FDA drug approval process for that drug. It is a randomized, double-blind, placebo-controlled study in patients with intractable cancer pain. A 30% decrease in pain was the primary end point of this study.
Notice that just over 20% of subjects experienced a 30% or greater decrease in their pain using THC, while just over 40% experienced that response level with CBD and THC in a 1:1 ratio.
Two points here. First, CBD and THC were more effective than THC alone. This contradicts the previous study. Second, there was no CBD group in this study. Or, at least, no data was published, so we don’t know how CBD fared. As a result, we don’t know if this additional analgesia was additive or synergistic.
This is a pharmacokinetic study, it shows that adding CBD to a capsule containing THC
increases the bioavailability of THC. Is this why the group in the previous study experienced more pain relief, because they absorbed more THC? Or was it because of the CBD? Both?
I am not aware of a single RCT that has used a full or broad-spectrum CBD extract to treat anxiety.
However, one was announced at a recent medical Cannabis conference in Pasadena (CannMed in Pasadena in September, 2019). This open-label, double blind trial is using a full-spectrum marijuana extract that is high in CBD. It’s a 4-week trial using sublingual administration of 10mg of CBD three times daily.
SAD not GAD*
* Social Anxiety Disorder versus Generalized Anxiety Disorder
There have been a number of clinical trials using isolated CBD conducted at the University of Sao Paolo in Brazil. These have been small trials using either healthy subjects or individuals with SAD (Social Anxiety Disorder). The experimental models typically include a stressor like a public speaking challenge and explore various outcomes, from subjectively reported anxiety to biomarkers and other anthropometric measures. These trials assessed the use of CBD a couple of hours before public speaking. These do not measure use over time for treating generalized anxiety (GAD). Notice the high dosages here - 600, 900, 400 milligrams!
The outcomes are mixed but there seems to be a signal for reduced anxiety, at least in experimentally induced social anxiety.
Notice in this particular study that 300 mg of CBD led to greater reductions in post-stress anxiety than 100 or 900 mg. When administering CBD by itself, a medium dose seems to be more effective than a high or low dose.
Also, importantly, this graph looks a lot like the inverted bell-shaped curve that was seen in the mouse model of acute pain and inflammation several slides earlier.
What is the dose response curve for a full-spectrum extract in humans suffering from social anxiety? We don't know.
And finally sleep. I am not aware of a single RCT that has used a full or broad-spectrum CBD extract to treat sleep disorders. You may be recognizing a pattern here…There are only a few RCTs investigating the use of cannabinoids; even fewer investigating CBD. Most of the studies combine them.
A 2017 review indicates that CBD may be helpful at higher doses, around 160mg/day. It describes 1 RCT where total sleep time increased and frequency of arousals decreased were experienced. It describes two other studies using lower doses where CBD had the opposite of the intended effect. It was stimulating.
You may have heard that THC and CBD have bi-phasic effects. Could this be an example of that?
This is the only RCT (above) I am aware of that has used a full or broad-spectrum CBD extract. It was funded by CV Sciences and conducted over 6 weeks. It included 65 healthy subjects.
There was a myriad of outcomes, but I’m just going to focus on the sleep outcomes here: Sleep quality and sleep quantity. The investigators reported that both of them improved by over 20%. Only the abstract of this paper is published at this time.
The physiological and clinical characteristics of full and broad-spectrum CBD products appear to be different from isolated CBD products. The clinical significance of these differences remains to be seen. We need more research comparing them in clinical trials. The passage of the 2018 Farm Bill should help to remove barriers to that research. Until then, let's not let the hype machine overtake us.